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Exploring the role of genetic variations in NAFLD: implications for disease pathogenesis and precision medicine approaches
European Journal of Medical Research volume 29, Article number: 190 (2024)
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver diseases, affecting more than one-quarter of people worldwide. Hepatic steatosis can progress to more severe forms of NAFLD, including NASH and cirrhosis. It also may develop secondary diseases such as diabetes and cardiovascular disease. Genetic and environmental factors regulate NAFLD incidence and progression, making it a complex disease. The contribution of various environmental risk factors, such as type 2 diabetes, obesity, hyperlipidemia, diet, and sedentary lifestyle, to the exacerbation of liver injury is highly understood. Nevertheless, the underlying mechanisms of genetic variations in the NAFLD occurrence or its deterioration still need to be clarified. Hence, understanding the genetic susceptibility to NAFLD is essential for controlling the course of the disease. The current review discusses genetics’ role in the pathological pathways of NAFLD, including lipid and glucose metabolism, insulin resistance, cellular stresses, and immune responses. Additionally, it explains the role of the genetic components in the induction and progression of NAFLD in lean individuals. Finally, it highlights the utility of genetic knowledge in precision medicine for the early diagnosis and treatment of NAFLD patients.
Background
Non-alcoholic fatty liver disease (NAFLD) is a spectrum ranging from benign simple hepatic steatosis to more advanced forms involving inflammation and fibrosis formation, namely non-alcoholic steatohepatitis (NASH) and cirrhosis, which are also critical predisposing factors in hepatocellular carcinoma (HCC) pathogenesis [1]. This condition is one the most common causes of chronic liver disease [2], afflicting more than one-quarter of the worldwide population [3]. NAFLD burden is progressively increasing and is projected to become the leading cause of liver transplantation. However, no effective therapeutic option for its advanced forms has been found to relieve its cost burden to date [4].
NAFLD incidence and progression depend on various factors, including environmental, genetic, metabolic, and immunologic. Environmental risk factors such as high-fat diets and physical inactivity can develop obesity and type two diabetes mellitus (T2DM) that enhance the accumulation of lipid droplets in hepatocytes. Subsequently, cellular stresses such as oxidative stress could mediate inflammation and fibrosis [5]. However, with similar environmental and metabolic risk factors, a broad inter-individual and inter-ethnic diversity of the phenotypes exists, indicating distinct susceptibility of patients to disease onset and progression [6]. Familial clustering and epidemiological findings suggest a critical role for genetic polymorphisms in determining personalized susceptibility to NAFLD [7]. Various studies demonstrate a higher incidence of liver steatosis and fibrosis in the first-degree relatives of NAFLD probands compared to those of healthy controls [8, 9]. Besides, data related to epidemiological studies on the US population indicate that NAFLD prevalence in African Americans is significantly lower compared to whites and Latinos, who suffer the most [10].
The genetic implication of NAFLD is mainly mediated via single nucleotide polymorphisms (SNPs) in genes contributing to hepatic uptake of fatty acids, lipid droplet biology, very low-density lipoproteins (VLDLs) transportation, de novo lipogenesis (DNL), gluconeogenesis, glycogenolysis, insulin resistance (IR), endoplasmic reticulum stress (ER stress), oxidative stress, autophagy and inflammation [11]. The presence of multiple SNPs associated with NAFLD provides a more comprehensive understanding of the underlying genetic factors contributing to the disease. Furthermore, discussing the effect of different types of mutations on NAFLD can provide valuable insights into the genetic underpinnings of the disease and the identification of preventive and therapeutic strategies [12].
Initial genetic studies were conducted on selective candidate genes. They focused on finding an association between some gain or losing function mutations on the specific genes and NAFLD onset or progress. However, these studies only evaluated limited genes at once. They were unsuccessful in finding new variants or deciphering the probable interplay between different SNPs that affect the course of the disease [13, 14]. Subsequently, genome-wide association studies (GWAS) followed by whole-genome and whole-exome sequencing strategies have significantly improved our understanding of NAFLD hereditability via simultaneous study on millions of SNPs in the genome and a specific phenotype. GWAS, as a population scale study, has uncovered a significant number of variants closely associated with the development of NAFLD in different stages. In these studies, various genes could be simultaneously evaluated to decode the independent association that exists between a genetic variation and the NAFLD [4].
A comprehensive understanding of the polygenic structure of NAFLD is also the prerequisite for risk assessment and developing treatment strategies. Since the genetic signature of each patient is unique, detecting defective genes will show us the affected pathogenic molecular pathways and aid us in early detection, designing effective therapies, and even helping the patients to change their lifestyle in a specific manner [15].
In summary, here we aimed to appraise the contribution of genetics in the pathogenesis of NAFLD. For a better understanding and according to the gene function, we have categorized the genetic polymorphisms regarding their function into lipid and glucose metabolism, cellular stress, and immune system subgroups. Likewise, we discussed the contribution of genetic polymorphism in lean NAFLD. Furthermore, to overcome the inadequacies associated with NAFLD diagnosis and treatment, we discuss the importance of finding these genetic polymorphisms and their potential application in translational medicine to screen genetically predisposed individuals and alleviate the burden of NAFLD by developing precision medicine.
Metabolic-related genes influencing NAFLD
Lipid metabolism
Accumulation of lipid droplets (LDs) in hepatocytes is the initiation point in NAFLD onset, and it is essential to explore the respective metabolic processes. LDs mainly consist of triglycerides (TGs), derived from increased hepatic free fatty acid (FFA) flux due to lipolysis of adipose tissue and de novo lipogenesis in hepatocytes [16]. In the context of increased hepatic FFAs, various gene families control the endoplasmic reticulum function of LD formation [17]. The LDs’ surface contains proteins, which are involved in lipid generation, stabilization, and degradation (Fig. 1) [18, 19]. The most important genes that play a role in lipid metabolism are summarized in Table 1.
The PNPLA3 gene, the primary gene involved in LD metabolism, is widely expressed in human hepatocytes and hepatic stellate cells (HSCs) and encodes membrane proteins found on the surface of lipid droplets. PNPLA3 protein displays lipase activity toward retinyl esters and triglycerides in hepatocytes and hepatic stellate cells, respectively. The stimulation of lipophagy, which eliminates excess lipids collected in hepatocytes, is caused by PNPLA3’s interaction with LC3-II on the surface of lipid droplets [20, 21]. Genetic alterations in PNPLA3 affect LD protein content and interfere with LD degradation [17, 22]. A substitution mutation at position 148 of this gene results in a loss-of-function protein (I148M) that is strongly associated with increased liver fat content and decreased lipid catabolism [23]. This mutation also exacerbates liver inflammation and increases the risk of NASH disease [24]. Indeed, this genetic variant is associated with steatohepatitis, elevated plasma liver enzymes, liver fibrosis, and cirrhosis [25]. In a recent study, the G allele of rs738409 in the PNPLA3 gene was shown to be a risk factor for NAFLD in children. The results, which determine the relationship between gene and polymorphism, showed that the risk of NASH with the GG genotype is higher than GC and CC genotypes [26]. According to Akkiz et al. study, the rs738409 C>G SNP is strongly associated with increased liver fat content and causes progression to NASH [27]. The adverse impact of SNPs in the PNPLA3 gene is well established in various populations. In a study on American, African, European, and Spanish subjects, rs738409 was powerfully associated with augmented liver fat and inflammation in all populations. In this study, the highest frequency of the G allele was found in the Spanish population [20]. Also, in another similar study, evidence of a strong association between the rs738409 variant and susceptibility to NASH was found in both Asian and Caucasian populations. However, this susceptibility was higher in the Caucasian population with the rs738409 variant [28]. Besides rs738409 C>G, there are some other PNPLA3 SNPs that may contribute to NAFLD incidence and/or progression. However, there are limited data in this regard. rs2294918 G>A, rs139051 T>C, and rs6006460 G>T are among the most important SNPs in PNPLA3 gene [29, 30]. Surprisingly some of these SNPs have protective role against rs738409 C>G and could potentially be utilized through gene editing techniques to target the expression of defective variants [31].
Hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) is another LD-associated protein with liver-specific function. This protein contributes to retinoid metabolism via retinol dehydrogenase (RDH) activity. HSD17B13 also contributes to the pathogenesis of NAFLD by targeting LDs in hepatocytes [32, 33]. Loss-of-function splice variant rs72613567 T>TA of the HSD17B13 gene diminishes the risk of NAFLD progression and chronic liver disease through regulation of lipid metabolism and decreasing liver LD biogenesis [34]. The A allele of rs72613567 is shown to have a protective effect against NAFLD, alcoholic liver disease, and hepatocellular carcinoma [35]. Notably, the presence of the HSD17B13 rs72613567 A allele mitigates the increase in alanine transaminase (ALT) and aspartate aminotransferase (AST) levels among carriers of PNPLA3 rs738409 G allele [36].
MBOAT7 is the other key gene in lipid metabolism, which encodes an enzyme with lysophosphatidylinositol acyltransferase activity that catalyzes phosphatidylinositol production. MBOAT7 causes lipid kinetics changes in liver cells by increasing phosphatidylcholines (PC) and phosphatidylserine contained arachidonic acid in the liver and reduces the risk of steatosis [37]. Recent studies have shown that MBOAT7-knocked-out mice suffer from TG and liver fat content increment [38]. The rs641738 C>T variant of MBOAT7 impairs lipid homeostasis by enhancing phosphatidylinositol turnover and promoting triglyceride synthesis, which consequently leads to liver steatosis and inflammation [38]. The increase in liver lipid content leads to an elevation in DNL and the progression of NASH through the overexpression of SREBP-1c, which functions as a transcription factor in the lipogenesis pathway [39]. In Lieu et al. study, the loss of function of the adjacent gene MBOAT7 boosts the progression of fatty liver disease. However, the effects of the rs641738 variant on the development of NAFLD seem to be distinguished in different ethnicities [40]. A cross-sectional cohort revealed that the rs641738 variant in the MBOAT7 gene is associated with an increased risk of NAFLD progression in European individuals [41]. Likewise, the rs626283 risk variant is demonstrated to influence the progression of NASH by modulating intrahepatic fat and affecting glucose metabolism in the Caucasian population [42].
Lipid transport
An increase in fatty acid circulation enhances TG accumulation in the liver, which is the consequence of high fat uptake, an increase in adipose tissue lipolysis, and T2DM [43]. The imbalance between the uptake and export of TG in the liver is one of the main features of NAFLD. Lipids can either be released as VLDL particles or oxidized in mitochondria in order to be eliminated from the liver [44]. TM6SF2, a regulator of liver fat metabolism, prevents lipid aggregation by controlling TG secretion and hepatic LD content. According to a recent study, TM6SF2 silencing leads to reduced lipoprotein production and export, as well as developing small LDs in hepatocytes. Lacking the TM6SF2 gene dramatically increases ER stress and mitochondrial dysfunction in result of alterations in these organelles morphology [6]. Phosphatidylcholine is a major component of biological membranes which maintains the function of ER, membrane homeostasis and contact sites between ER and mitochondria [45]. The TM6SF2 gene deficiency reduces PC levels and results in shapeless ERs [6]. Although the precise function of TM6SF2 in the context of NAFLD is mostly unknown, a study by Li et al. demonstrated that overexpression of TM6SF2 reduced hepatic lipid accumulation in HFD-fed mouse models, whereas knockdown of TM6SF2 was shown to promote inflammation and hepatic lipid accumulation [12]. TM6SF2 rs58542926 increases the risk of lipid accumulation in hepatocytes and decreases circulating fatty acids in serum by reducing VLDL secretion [6]. Although the association of TM6SF2 rs58542926 and the spectrum of NAFLD disease is controversial, several studies have demonstrated that the loss-of-function variant rs58542926 could be considered a risk factor in NAFLD and fibrosis progression [46]. The TM6SF2 C>T variant downregulates the TM6SF2 protein expression and has been associated with decreased LDL levels and cardiovascular risk, as well as increased T2DM risk [12]. In a meta-analysis, Li et al. found that NAFLD risk increased with the presence of rs58542926 and demonstrated a positive correlation between rs58542926 and ALT in both children and adults. Moreover, this variant is negatively associated with total cholesterol, LDL, and TG [47]. A recent study in the Chinese Han population by Li et al. observed high levels of TG, AST, and ALT and showed an association between the TM6SF2 variant and NAFLD [48].
FA transportation into peripheral organs as TG-rich lipoproteins (VLDLs) is linked to ER stress and NAFLD progression. The assembly of VLDL accompanies by the function of apoB and MTTP genes, and low expression of hepatic MTTP is reported to associate with the pathogenesis of NAFLD [49]. Although several MTTP SNPs have been identified, a common polymorphism rs1800591-493 G>T contributes to NAFLD by decreasing the expression of MTTP and impairing the potential ability of this gene to export lipids [50]. Although Tan et al. found no association between NAFLD and the rs1800591 polymorphism of the MTTP gene in a meta-analysis, it is suggested that this polymorphism could be used as a biomarker for early diagnosis of NAFLD [51].
The gene APOC3 plays an essential role in the transport and clearance of residual chylomicrons. Aside from being involved in the formation of VLDL, APOC3 also functions as one of the major inhibitors of TG-rich particles [52]. The rs2854116 variant is associated with susceptibility to the development of NAFLD and IR by increasing the plasma concentration of Apoc3 and sequentially inhibiting the clearance of lipoprotein lipase and triglycerides. Consequently, the liver absorbs higher concentrations of chylomicron remnants leading to greater levels of TG accumulation [53]. A meta-analysis by Tong et al. reported that the APOC3 polymorphism rs2854116 might be involved in the development of NAFLD and could be a potential therapeutic target for NAFLD [54]. It has been shown that another mutation in APOC3 rs2070667 is responsible for exacerbating the pathological factors associated with NAFLD, mainly because of its inhibitory effect on PUFA-containing TG levels in serum [55].
FATP5, also called SLC27A5 is mainly expressed in the liver and participates in controlling FFA uptake. As well as carrying out its function as a fatty acid transporter, FATP5 can also activates long-chain fatty acids (LCFAs) through covalent coenzyme A attachment [56]. It has been reported that deletion or silencing of FATP5 reduces triglyceride levels in the liver and ameliorates diet-induced steatosis in rats [57]. The FATP5 variant rs56225452 gain-of-function was found to be associated with an increased risk of hepatic steatosis, elevated ALT levels, and enlarged insulin resistance [58].
Eventually, among the variants affecting liver damage through the metabolism of lipids, the most significant impact is related to the PNPLA3 I148M variant, followed by MBOAT7 rs641738 and E167K TM6SF2 [59].
Glucose metabolism
The liver is responsible for maintaining glucose homeostasis and insulin has a crucial function in this regard. Insulin controls glucose metabolism and results in glucose uptake through the phosphorylation of insulin receptor substrate, which regulates multiple downstream processes [74]. As Fig. 2 demonstrates, following the entrance of glucose in the liver, glucose 6-phosphate (G6P) is produced by glucokinase in several pathways, such as glycolysis and glycogenesis [75]. During glycolysis, the excess glucose in the liver is used to provide energy and can also turn into acetyl-CoA to synthesize free fatty acids. Moreover, extra glucose is stored as glycogen during glycogenesis, in which insulin activates GSK3/GS by the PI3K/AKT pathway [76].
Due to hyperinsulinemia in NAFLD, de novo lipogenesis and insulin resistance can be induced via upregulation of SREBP-1c and inhibition of insulin receptors through reduced expression and sensitivity of IRS1/2. Also, IR increases gluconeogenesis and diminishes hepatic glycogen synthesis, resulting in high glucose levels [77]. Consequently, ChREBP, a carbohydrate-signaling transcription factor, is activated and contributes to the progression of NAFLD by de novo lipogenesis. Type 2 diabetes mellitus (T2DM) can activate a similar mechanism in the liver. IR and high glucose, which are triggers of T2DM, accelerate DNL via SREBP and ChREBP cascades, respectively. Several studies have reported that T2DM patients are more likely to suffer from NAFLD [78]. There is growing evidence that multiple SNPs are associated with glucose metabolism dysregulation and IR, which are potential causes of liver dysfunction (Table 2).
The glucose accumulation in hepatocytes is controlled by the glucokinase enzyme encoded by GCK, which phosphorylates glucose to G6P during glycolysis. Subsequently, G6P is converted to pyruvate to generate acetyl-CoA, a substrate that participates in DNL to produce FFA and TG. Moreover, G6P can turn into glucose-1-phosphate and participate in the glycogen synthesis pathway. It is reported that GCK gene expression is upregulated in the fatty liver and has a significant correlation with liver triglyceride content and DNL-related genes, including FASN, ACC-1, and ACC-2 [79, 80]. Glucokinase regulator protein (GCKR), known as glucokinase inhibitor, is responsible for adjusting glucose storage and disposal, as well as controlling de novo lipogenesis through regulating glucose flow into hepatocytes [81]. GCKR rs1260326 (P446L) is a missense variant that increases glucose uptake and DNL by reducing the ability of glucokinase inhibitory effect [82]. The GCKR rs1260326-T is associated with metabolism-related mechanisms, such as glycolysis, fatty acid circulation, and saturation. Yuan et al. observed an increase in TG levels of rs1260326-T carriers and demonstrated an association between GCKR rs1260326-T and fatty liver by studying the elderly Chinese Han population [72]. Furthermore, Nahass et al. confirmed that GCKR rs1260326 allele T was associated with susceptibility to NAFLD [83]. Another GCKR gene variant, rs780094, is reported to increase triglyceride levels in the Chinese population [46]. Both GCKR variants of rs780094 and rs1260326 contribute to NAFLD, considering the activation of DNL [46]. Furthermore, a recent study of a rare nonsense mutation rs149847328 has demonstrated a decrease in GCKR protein expression in patients carrying the rs149847328 variant in comparison with NAFLD patients with the wild‐type allele [84].
To adjust glucose homeostasis in a normal physiological state, insulin binds to its receptor on hepatocytes and triggers the tyrosine kinase activity of the insulin receptor. Consequently, the IRS-1/2 is phosphorylated and activates the PI3K/AKT pathway, leading to gluconeogenesis suppression and glycogen synthesis through Forkhead box protein O1 (FOXO1) and GSK3, respectively. Furthermore, the activation of IRS can lead to an increase in SREBP1-C gene expression and a rise in fatty acid synthesis by promoting lipogenesis [85]. Thereby, malfunction of the IRS impairs insulin signaling and increases the risk of insulin resistance. The loss-of-function rs1801278 Gly927Arg polymorphism diminishes the IRS-1 activity and inhibits the insulin receptor autophosphorylation, causing a reduction in insulin signaling [86]. A recent Pakistani population study demonstrated a correlation between the Gly972Arg variant of IRS-1 and insulin resistance in T2DM [87]. IRS-2 polymorphisms are also linked to IR, T2DM, and hyperinsulinemia, in line with Dabiri et al. study that suggested a considerable association between the IRS-2 rs2289046 variant and NAFLD [88].
Another important gene in glucose metabolism is ENPP1, which encodes a transmembrane glycoprotein that inhibits insulin receptor activity and decreases insulin signaling. ENPP1 regulates insulin actions via physical interactions with the α-subunit and inhibiting the β-subunit of the insulin receptor. The overexpression of ENPP1 in the liver causes IR and declines glucose uptake [89]. Gain-of-function K121Q mutation promotes the interaction between ENPP1 and insulin receptors and consequently inhibits insulin signaling. Dongiovanni et al. demonstrated a correlation between the IRS-1 972Arg and ENPP1 121Gln with increased hepatic insulin resistance by measuring the AKT activity of patients suffering from fatty liver. In their study, patients who carried both ENPP1 and IRS-1 SNPs were more susceptible to developing fibrosis than those positive for ENPP1 or IRS-1. However, the role of the ENPP1 variant was more prominent in this regard [90].
Internal cellular stresses and genetic susceptibility
Hyperglycemia and lipid accumulation in hepatocytes trigger cellular stresses mainly via disrupting ER function and mitochondrial damage [98, 99]. ER stress accompanies an overload of misfolded/unfolded proteins and gives rise to oxidative stress via enhancing reactive oxygen species (ROS) production. The ROS may activate different signaling pathways and cause genomic mutations and lesions in favor of NAFLD progression toward HCC [100, 101]. In addition to ER stress, elevated FFA β-oxidation in mitochondria also increases ROS production, which causes oxidative stress and mitochondrial damage [102, 103]. The defense mechanism of cells to reduce ROS is to induce mitophagy and remove the damaged mitochondria. However, the disruption in mitophagy during NAFLD enhances the inflammatory state, which plays a vital role in NAFLD progression toward steatohepatitis [104, 105].
The oxidative stress and ER stress contribute to LD accumulation in hepatocytes by activating crucial lipogenesis transcription factors, including SREBP-1c. To counteract the accumulation of lipid droplets, hepatocytes use lipophagy to degrade intracellular LDs [106, 107]. Accordingly, defective hepatic lipophagy is one of the key players in the progression of simple fatty liver to NASH [108]. It is demonstrated that genetic inhibition of lipophagy elevates TG and LD content, declines hepatic FA oxidation, and consequently induces NAFLD/NASH [109, 110]. Increased FFA β-oxidation in mitochondria leads to the production of high amounts of ROS [111]. In the normal physiological state, the increased ROS production in the mitochondria is negated by antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX). The decline in the function of these enzymes and the subsequent elevation in ROS causes the disease to progress toward NASH [112].
As shown in Fig. 3, regulation of hepatic LD catabolism is conducted via lipophagy, in which the interaction of LDs with LC3 and adipose triglyceride lipase (ATGL) promotes SIRT1 activity [113]. In the initiation phase, immunity related GTPase M (IRGM) through phosphorylation of AMPK, ULK1, and Beclin-1, as well as cross-linking with ATG16L1 and SH3GLB1 causes lipophagy enhancement [114]. IRGM also controls mitophagy via regulating mitochondrial biogenesis and interacting with mitofilin and PINK1 [115]. Moreover, IRGM suppresses NF-κB and MAPK/p38 inflammatory pathways by inhibiting the activation of the NLRP3 and PYCARD complex [116]. A previous study demonstrated that IRGM expression is significantly lower in the liver of NAFLD patients [117]. In contrast, the overexpression of IRGM decreased lipid droplet content during NASH [118]. It was shown that the genetic defect in lipophagy mediated by IRGM rs13361189 and rs10065172 TT genotype interferes with mitochondrial function, disrupts liver fat metabolism, provokes inflammation, and induces hepatic steatosis (Table 3) [119]. In obese children and adolescents from a Han Chinese population, rs10065172 C>T has been identified as a polymorphism associated with NAFLD [120]. Also, in obese Italian children, the risk allele of rs10065172 is associated with increased plasma aminotransferase levels and mild steatosis [121].
In the liver, SOD participates in lipid peroxidation, reduction of mitochondrial ROS, and protection against oxidative stress [122]. Total knockout or knockdown of the Sod2 gene causes ROS-derived disorders and lipid deposition. The expression of SOD2 is decreased in the liver of NASH patients [123]. CAT and GPX preserve the liver from lipid accumulation and inflammation by removing the hydrogen peroxide produced due to SOD2 activity [124]. Elevation of ROS increases lipid peroxidation, mitochondrial dysfunction, and apoptosis rate [125]. Thus, establishing a balance between oxidative stress and antioxidative factors protects cells from hepatic stellate cell stimulation and NASH induction [126, 127]. SOD2 rs4880 47T>C [128] and CAT-262C>T rs1001179 SNPs in the antioxidative genes disrupt their enzymatic activity (Table 3). SOD2 rs4880 47T>C variant is associated with advanced fibrosis in an allele dosage-dependent manner [112]. Concludingly, ROS content increases and enhances the susceptibility for developing NASH and advanced fibrosis in the carriers of these SNPs (Table 3).
Genetic factors related to immune system imbalance
Inflammation and immune responses caused by cellular stress and cellular damage are the main causes of the progression of steatosis toward NASH [132]. Inflammation is characterized by immune activation through various signaling pathways, lipid accumulation, and oxidative stress [133]. However, NASH is not only associated with metabolic risk factors, but also with genetic alterations. Accordingly, polymorphisms in genes encoding inflammatory cytokines could lead to some liver disease. The most significant associations are brought by genetic variants involved in the regulation of inflammation, such as IL-32, TNF-α, IL-6, and IL-1β, which are frequently altered in NAFLD/NASH (Table 4).
IL-32, as a pro-inflammatory cytokine, is highly expressed in the liver during liver disease [134]. Its transcription is upregulated in obese individuals with severe NAFLD (particularly in carriers of the PNPLA3 I148M risk variant) and can be induced by lipotoxicity in hepatocytes [135]. A recent study reported that IL-32 rs9788910 is associated with elevated liver enzyme levels and NAFLD progression [136]. IL-32 elevates the localization of STAT3 in the IL-6 promoter through STAT3 phosphorylation. Notably, the hepatic STAT3 signaling is increased in patients carrying the PNPLA3 risk variant [137,138,139]. IL-32 may also affect the course of NASH progression by enhancing the expression of IL-1, TNF-α and IL-8 through the NF-κB and the p38/MAPK pathways [140]. In fact, when NF-κB is activated by TNF-α stimulation, the expression of NLRP3 and pro-IL-1β increases (Fig. 4). NLRP3 is a critical component of innate immunity, highly expressed in the Kupffer cells [141]. Increased expression of NLRP3 has a substantial role in obesity-induced inflammation and worsens NASH [142]. NLRP3 inflammasome complex formation causes caspase 1-dependent release of the pro-inflammatory cytokines, including IL-1β and IL-18 [143]. IL-18 triggers the secretion of other pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-8. The cytokines produced in the liver by Kupffer cells and hepatocytes negatively affect lipid metabolism and hepatic inflammation [144]. Therefore, it is not surprising that higher serum TNF-α levels were found in NASH patients compared to healthy controls. In the Russian population, the association of TNF gene polymorphism -308G>A rs1800629 with the development of NASH has been determined. Carriers of the A allele of the TNF gene marker -308G>A significantly increase the risk of developing NASH [145].
IL-6 is another crucial factor in inflammation, acting mainly through the IL-6/STAT3 pathway [146]. The IL-6-174G>C rs1800795 is associated with NASH progression and can also determine the genetic predisposition to develop this disease [147]. It also increases the production of various inflammatory cytokines through the synergistic interaction between STAT3, followed by the hyper-activation of NF-κB [148]. In a study on Caucasian NAFLD patients, the presence of the IL-6 rs1800795 C allele accompanied an escalated risk for severe steatosis, whereas it was associated with less IL-6 expression in the liver and lower progressive inflammation and fibrosis [149]. Conversely, patients with the G allele of rs1800795 have boosted risks for the progression of liver diseases, especially NASH and ALD, toward severe forms of the disease [150]. According to recent studies, IL-6 has modulated activation of the JAK–STAT3 signaling pathway through cooperation with the inflammatory cytokine IL-1β (Fig. 4). Indeed, IL-1β in NAFLD contribute to steatosis’ progression toward NASH and fibrosis. In addition, IL-1β also plays an important role in stimulating the activation of hepatic stellate cells and the accumulation of triglycerides and cholesterol in hepatocytes and the formation of fat droplets. In this regard, a Japanese cohort revealed that the gain-of-function of the IL-1β-511C>T rs16944 variant plays a major role in the development of NAFLD through its involvement in disease stages ranging from simple steatosis’ progression toward NASH and fibrosis [149, 151].
On the other hand, the known effects of the CB2 receptor in modulating the inflammatory response by inhibiting NF-κB transmission into the nucleus, reducing the production of TNFα and IL-6, IL-1B and increasing IL-10 play an important role in preventing the progression of steatosis to steatohepatitis [152, 153]. CNR2 is associated with high expression in the liver and a missense mutation of this receptor rs35761398 is demonstrated to obliterate the anti-inflammatory receptor function, induce an inflammatory state, and increase the susceptibility for NASH [154].
Genetic predisposition in lean NAFLD individuals
Despite the critical role of obesity in NAFLD induction and progression, about 5% to 26% of patients who express this condition have a normal body mass index (BMI). These patients are categorized as “lean NAFLD” [159]. Surprisingly, a recent systematic review indicated that lean NAFLD accompanies worse outcomes and higher mortality rates compared to NAFLD in obese patients. A more prominent presence of underlying genetic disorders, as well as inefficiencies with lean NAFLD diagnosis and management, may explain these findings [160].
Lean NAFLD has a distinct distribution all over the world. Its prevalence in Asians is higher compared to the people of western countries, even though stricter cutoffs define them (BMI < 23 kg/m2 for Asians vs. BMI < 25 kg/m2 for non-Asians) [161, 162]. The epidemiological findings further imply the pivotal role of the genetic component in the pathophysiology of lean NAFLD [163].
Lean NAFLD is categorized into two principal subtypes. The first subtype constitutes the majority. It comprises metabolically obese normal-weight patients, who usually have increased visceral adiposity and waist circumference and develop insulin resistance [162]. Many of these patients have hepatic steatosis and exhibit a lipodystrophic phenotype due to an impaired ability to store lipids subcutaneously [164]. Lean NAFLD individuals of the first subtype and obese patients with NAFLD have shared pathophysiology, and they identically respond to lifestyle interventions [160].
However, the second subtype is substantially caused by defective genetic disorders. Population-based studies on lean individuals have identified several SNPs contributing to NAFLD induction and progression. NAFLD induction in the studies is usually defined as the presence of intrahepatic triglyceride levels above 5%. Among them, SNPs in PNPLA3, TM6SF2, APOB, MTTP, PEMT, and CETP are the most established, while the contribution of other genetic variants has not been confirmed [69, 70, 165, 166].
PNPLA3 rs738409 is the most commonly studied genetic variation in the context of lean NAFLD induction and progression. Recent studies have revealed that the PNPLA3 rs738409 G allele is more prevalent among lean NAFLD individuals than in obese patients and it escalated the risk of NAFLD incidence over twice in these patients [167,168,169]. On the other hand, the PNPLA3 G allele pathogenic contribution is not restricted to NAFLD induction. In a retrospective cohort study conducted on biopsy-proven Italian NAFLD patients, Fracanzani et al. demonstrated that the presence of the rs738409 G allele was the only variable that could enhance the risk of NASH and liver fibrosis development [170].
As previously discussed, TM6SF2 rs58542926 C>T is indicated to contribute to NAFLD induction and its progression to advanced fibrosis [171]. Intriguingly, there is evidence to demonstrate a higher prevalence of this risk variant in lean NAFLD patients [167, 170, 172]. Cohort and cross-sectional studies on biopsy-proven NAFLD patients demonstrated that the risk variants of the TM6SF2 also increase the susceptibility to inflammation, NASH, and fibrosis to a greater proportion in lean individuals compared to obese subjects [170, 173].
More than 60 different loss-of-function mutations could occur in the APOB gene and cause hypobetalipoproteinemia. This autosomal codominant disorder hampers the production of functional APOB proteins, which per se impedes VLDL secretion and leads to hepatic accumulation of TGs. Since hypobetalipoproteinemia accompanies fat malabsorption and failure to thrive, NAFLD screening should be considered in the affected lean subjects [174]. Notably, mutations in the MTTP gene, which encodes the apoB chaperone protein, can also inhibit the production of beta-lipoproteins and induce a more severe form of the disorder called abetalipoproteinemia [175]. To evaluate the effect of APOB and MTTP genetic polymorphisms on lean NAFLD, Di Filippo et al. conducted a cohort study and merged their results with data derived from previously published works to add statistical strength to their research. They observed that in spite of the mutations in the APOB gene, mutations in the MTTP gene are associated with significantly lower BMI in patients (mean BMI of 25.3 and 19.7, respectively), indicating the close correlation between MTTP polymorphism and lean NAFLD [166].
The PEMT gene encodes enzymes contributing to the hepatic synthesis of phosphatidylcholines. rs7946 C>T in PEMT is demonstrated to simultaneously protect against obesity and insulin resistance while exacerbating NAFLD severity in animal studies [176, 177]. A study on the PEMT mRNA expression in NAFLD patients further supported these findings and reported a significant correlation between lower PEMT mRNA levels (due to missense mutation) and lower BMI and NASH incidence [177]. A clinical study using the whole-exome sequencing method on lean NAFLD-inducing genetic variants further confirmed previous findings and demonstrated a threefold higher NAFLD incidence in lean subjects with the defective variant [70].
CETP has a critical role in transferring triglycerides between lipoproteins. The association of two SNPs in the CETP gene (rs12447924 and rs12597002) and NAFLD development in lean subjects have been documented in a cohort study of Australian adolescents. In this study, the prevalence of NAFLD was 3–5% in lean wild-type females. However, the risk for lean NAFLD was significantly higher among female homozygotes (25–33%) and heterozygotes carriers of SNPs (10–15%). Surprisingly, a similar association was not recorded in male or obese subjects, necessitating further in-depth studies to uncover underlying etiologies [69].
Collectively, lean individuals should not be considered privileged from NAFLD-related severe complications. Especially those harboring high-risk genetic variants might be subjected to unexpected health complications, necessitating effective diagnostic and therapeutic measures for these vulnerable subpopulations.
Application of the genetic knowledge in precision medicine of NAFLD
Although to date there is no clinically available precision treatment for NAFLD tackling a special genetic variant, the genetic background consideration for the treatment of each patient substantially determines their response to available treatments [178]. Genetic data could be applied to intervene in the disease course in several ways. Primarily, it can help reduce the disease burden by proposing behavioral modifications to each patient. As so, a cohort study revealed that a 12-month lifestyle modification accompanied a more pronounced decrease in hepatic fat content, total blood cholesterol, and LDL in the carriers of the PNPLA3 I148M (especially in homozygous carriers) compared to wild-type individuals [179].
Secondarily, genetics could aid us in the early diagnosis and stratification of patients at high risk for developing severe forms of NAFLD. Although low-risk populations only require interventions after appearing the clinical manifestations of the disease, those at higher risk of NAFLD progression necessitate more invasive diagnostic procedures (i.e., liver biopsy) and early therapeutic interventions [15]. Notably, utilizing genetic information for precision cancer screening is a promising approach, which previously has shown efficacy in predicting the incidence of various cancers. SNPs in genes such as PNPLA3, GCKR, TM6SF2, and MBOAT7 are independently associated with hepatocarcinogenesis [180]. However, due to the complexity of contributing factors in NAFLD progression, each SNP is unexpected to be a strong risk predictor, and guidelines do not advocate routine genotyping to find them [7, 181]. Thus, to establish accurate HCC risk estimation models, besides the genetic profile of each individual, the condition of other HCC risk factors, such as diabetes and obesity, should be considered [180]. On the other hand, some genetic variants have inhibitory/inducive roles in the pathogenesis of other diseases, which may affect the screening strategies. For instance, TM6SF2 risk variant carriers are less likely to develop cardiovascular disease and require a lower threshold for cardiac disease screening. In line with the increasing demand for NAFLD precision medicine, various companies have recently emerged which introduce risk score assessment services easily available for each individual [7].
Ultimately, pharmacotherapy could be personalized according to genetic data. PNPLA3, TM6SF2, HSD17B13, GCKR, and DGAT2 genetic variations have gained much interest in the genetic-based precision medicine of NAFLD (Table 5). Due to the strongly implemented role of the PNPLA3 I148M variant in NAFLD induction and progression, the primary focus of recent research is on this genetic polymorphism [178]. PNPLA3 high-risk populations are demonstrated to not benefit from conventional therapeutic options targeting hepatic lipogenesis [14]. A multi-center cohort study on NAFLD patients showed that the protective effect of statin therapy, as a means to inhibit cholesterol synthesis, on steatohepatitis was significantly lower in the carriers of the PNPLA3 risk variant. In contrast, in this study, carriers of the TM6SF2 risk variant and wild-type individuals benefited from statin therapy [182]. Likewise, Omega-3 reduces the expression of SREBP1c (a regulator of hepatic lipogenesis) and consequently suppresses de novo lipogenesis. A randomized controlled clinical trial (registration number NCT00760513) evaluating the effect of omega-3 on NAFLD treatment revealed that in spite of TM6SF2 risk variant carriers, those harboring PNPLA3 148M were less responsive regarding the reduction in hepatic fat content. It might be because of already existing reduced de novo lipogenesis in PNPLA3 I148M carriers [183]. Overcoming undesirable PNPLA3 phenotype could be achieved via three major approaches, including targeting PNPLA3 with (i) RNA interference, (ii) small molecules, or (iii) interfering NAFLD-related metabolic pathways [184].
RNA interference using antisense oligonucleotides (ASOs) is a novel strategy, targeting the mRNA to reach long-lasting downregulation of the PNPLA3 proteins translation in the carriers of risk variants [184]. Concordantly, Linden et al. conducted a preclinical study on PNPLA3 148M harboring mice fed a NASH-inducing diet. They utilized ASOs to downregulate the production of PNPLA3 mutant proteins and demonstrated a significant reduction in liver fat content, inflammation, and fibrogenesis [185]. Based on such promising outcomes, an ASO compound, namely ION839, is registered for phase 1 clinical trials in obese NASH subjects homozygous for the PNPLA3 risk variant (NCT04142424, NCT04483947).
Another potential approach is based on using small molecules to negate the detrimental effects related to the PNPLA3 I148M variant. Schwartz et al. have recently demonstrated the ability of an anti-cancer small molecule called momelotinib to suppress PNPLA3 expression in human hepatocytes and stellate cells via inhibiting the BMP/ACVR1/SMAD signaling pathway [186].
Interfering metabolic pathways contributing to undesirable effects related to the PNPLA3 I148M variant (such as HSD17B13 inhibition) is another promising approach to counteract the NAFLD burden [139]. PNPLA3 G allele carriers in NAFLD patients exhibit more severe forms of the disease, and the prevalence of advanced liver fibrosis, cirrhosis, and HCC is higher among them. Notably, simultaneous carriage of the HSD17B13 rs72613567:TA variant is indicated to negate the detrimental effects related to the presence of the PNPLA3 148M alleles [187]. Using exome sequence data from over 46 thousand individuals, Abul-Husn et al. demonstrated the capability of the HSD17B13 splicing variant (rs72613567:TA) in dampening the mRNA expression of PNPLA3 and its related liver injury in an allele dosage-dependent manner. Accordingly, they proposed HSD17B13 inhibition as a potential strategy to modify the risk of NAFLD progression in PNPLA3 148M allele carriers [35]. Concordantly, another study indicated that the HSD17B13 rs72613567:TA presence significantly attenuates the risk of alcohol-induced cirrhosis and HCC in the PNPLA3 148M allele carriers [188]. Due to the proven role of the rs72613567 insertion/deletion variant of HSD17B13, it could serve as a potential target for genetic-based precision medicine to treat NASH and liver fibrosis [15]. The application of post-transcriptional gene silencing using RNAi to suppress HSD17B13 expression has recently been introduced by Arrowhead (NCT04202354) and Alnylam Pharmaceuticals (NCT04565717) as a potential solution to treat NAFLD/NASH. Data released from phase I of the Arrowhead clinical trial indicated promising results regarding suppression of HSD17B13 at mRNA and protein levels as well as serum ALT and AST of patients. Likewise, INI-678 (an HSD17B13 inhibitor), introduced by Inipharm, has demonstrated efficacy in decreasing liver fibrosis in a human liver-on-a-chip-model, opening a gate for broader application of small-molecule therapy in genetic-based precision medicine of NAFLD [189]. Interestingly, other members of the HSD17B13 family, such as HSD17B11, with high similarity and widely recognized binding sites for small molecules, could serve as substitutes to improve the number of available choices [15].
However, targeting the TM6SF2 gene directly may not be a proper idea in NAFLD-based precision medicine. Although the upregulation of the TM6SF2 gene leads to a decrease in NAFLD incidence, it accompanies an unwanted increase in the content of blood lipids. It enhances the risk of cardiovascular diseases such as myocardial infarction [190]. Conversely, de novo lipogenesis targeting is one of the most effective NAFLD therapies for TM6SF2 and GCKR risk variant carriers [178]. In this context, acetyl-CoA carboxylase (ACC) inhibitors and fatty acid synthase (FAS) inhibitors, which target critical enzymes in the de novo lipogenesis process, have gained much interest [191]. TM6SF2 risk variant accompanies enhanced de novo lipogenesis and decreased VLDL secretion capability. An ACC inhibitor called MK-4074 has recently shown promising results regarding de novo lipogenesis decrease and prevention from liver steatosis and NASH in the carriers of the TM6SF2 defective variant [12]. Likewise, the GCKR P446L variant is associated with elevated glucokinase activity, glycolysis, hepatic glucose uptake, and de novo lipogenesis. Accordingly, it could be hypothesized that ACC and FAS inhibitors can be effective choices for treating GCKR P446L carriers. However, further studies should be conducted to corroborate the idea [181].
NAFLD genetic risk variants could also predict the liver-correlated adverse effects of other drugs. PNPLA3 and TM6SF2 risk variant carriers are indicated to enhance the risk of liver damage in response to some anti-diabetic agents, while some other anti-diabetic medications privileged these events. To hit on an example, PNPLA3 risk carriers are indicated to develop more liver fat accumulation as well as AST and ALT enzyme elevation following the treatment with basal insulin peglispro compared to insulin glargine [192, 193].
Conclusion
Several polymorphisms are known to be associated with the pathogenesis of NAFLD and its progression to advanced stages. Accordingly, various molecular mechanisms might be affected, including lipid metabolism and transport, glucose metabolism, oxidative stress, ER stress, and inflammation. Gene polymorphisms could explain patient variability in response to treatment and the rate of disease progression. To date, polymorphisms in PNPLA3, TM6SF2, HSD17B13, MBOAT7, and GCKR have attracted more attention in the use of disease-associated variants for precision medicine. However, there is an urgent need for further research to explain the precise molecular mechanisms of these SNPs and pave the way for the development of new drugs. In addition, the possibility that genetic variations may vary by population group and ethnicity must also be considered. Therefore, future studies are needed to investigate other variants that may be associated with NAFLD pathogenesis, intending to screen patients and personalize the treatments.
Availability of data and materials
Not applicable.
Abbreviations
- NAFLD:
-
Non-alcoholic fatty liver disease
- NASH:
-
Non-alcoholic steatohepatitis
- HCC:
-
Hepatocellular carcinoma
- T2DM:
-
Type two diabetes mellitus
- SNP:
-
Single nucleotide polymorphisms
- DNL:
-
De novo lipogenesis
- IR:
-
Insulin resistance
- ER stress:
-
Endoplasmic reticulum stress
- GWAS:
-
Genome-wide association studies
- LD:
-
Lipid droplet
- FFA:
-
Free fatty acid
- HSC:
-
Hepatic stellate cells
- PC:
-
Phosphatidylcholine
- LCFA:
-
Long-chain fatty acid
- ROS:
-
Reactive oxygen species
- BMI:
-
Body mass index
- ASO:
-
Antisense oligonucleotide
References
Orci LA, Sanduzzi-Zamparelli M, Caballol B, Sapena V, Colucci N, Torres F, et al. Incidence of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression. Clin Gastroenterol Hepatol. 2022;20(2):283-92.e10.
Wang J, Conti DV, Bogumil D, Sheng X, Noureddin M, Wilkens LR, et al. Association of genetic risk score with NAFLD in an ethnically diverse cohort. Hepatol Commun. 2021;5(10):1689–703.
Chen LJ, Lin XX, Guo J, Xu Y, Zhang SX, Chen D, et al. Lrp6 genotype affects individual susceptibility to nonalcoholic fatty liver disease and silibinin therapeutic response via Wnt/β-catenin-Cyp2e1 signaling. Int J Biol Sci. 2021;17(14):3936–53.
Eslam M, George J. Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology. Nat Rev Gastroenterol Hepatol. 2020;17(1):40–52.
Ramai D, Tai W, Rivera M, Facciorusso A, Tartaglia N, Pacilli M, et al. Natural progression of non-alcoholic steatohepatitis to hepatocellular carcinoma. Biomedicines. 2021;9(2):184.
Longo M, Meroni M, Paolini E, Erconi V, Carli F, Fortunato F, et al. TM6SF2/PNPLA3/MBOAT7 loss-of-function genetic variants impact on NAFLD development and progression both in patients and in in vitro models. Cell Mol Gastroenterol Hepatol. 2022;13(3):759–88.
Choudhary NS, Duseja A. Genetic and epigenetic disease modifiers: non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Transl Gastroenterol Hepatol. 2021;6:2.
Caussy C, Bhargava M, Villesen IF, Gudmann NS, Leeming DJ, Karsdal MA, et al. Collagen formation assessed by N-terminal propeptide of type 3 procollagen is a heritable trait and is associated with liver fibrosis assessed by magnetic resonance elastography. Hepatology. 2019;70(1):127–41.
Sookoian S, Pirola CJ, Valenti L, Davidson NO. Genetic pathways in nonalcoholic fatty liver disease: insights from systems biology. Hepatology. 2020;72(1):330–46.
Shaheen M, Schrode KM, Pan D, Kermah D, Puri V, Zarrinpar A, et al. Sex-specific differences in the association between race/ethnicity and NAFLD among US population. Front Med (Lausanne). 2021;8: 795421.
Meroni M, Longo M, Tria G, Dongiovanni P. Genetics is of the essence to face NAFLD. Biomedicines. 2021;9(10):1359.
Li Z-Y, Wu G, Qiu C, Zhou Z-J, Wang Y-P, Song G-H, et al. Mechanism and therapeutic strategy of hepatic TM6SF2-deficient non-alcoholic fatty liver diseases via in vivo and in vitro experiments. World J Gastroenterol. 2022;28(25):2937.
Du X, DeForest N, Majithia AR. Human genetics to identify therapeutic targets for NAFLD: challenges and opportunities. Front Endocrinol (Lausanne). 2021;12: 777075.
Trépo E, Valenti L. Update on NAFLD genetics: from new variants to the clinic. J Hepatol. 2020;72(6):1196–209.
Sookoian S, Pirola CJ. Precision medicine in nonalcoholic fatty liver disease: new therapeutic insights from genetics and systems biology. Clin Mol Hepatol. 2020;26(4):461–75.
Scorletti E, Carr RM. A new perspective on NAFLD: focusing on lipid droplets. J Hepatol. 2021;76(4):934–45.
Mashek DG. Hepatic lipid droplets: a balancing act between energy storage and metabolic dysfunction in NAFLD. Mol Metab. 2021;50: 101115.
Farías MA, Diethelm-Varela B, Navarro AJ, Kalergis AM, González PA. Interplay between lipid metabolism, lipid droplets, and DNA virus infections. Cells. 2022;11(14):2224.
Li X, Wang TX, Huang X, Li Y, Sun T, Zang S, et al. Targeting ferroptosis alleviates methionine–choline deficient (MCD)-diet induced NASH by suppressing liver lipotoxicity. Liver Int. 2020;40(6):1378–94.
Cavalcante LN, Porto J, Mazo D, Longatto-Filho A, Stefano JT, Lyra AC, et al. African genetic ancestry is associated with lower frequency of PNPLA3 G allele in non-alcoholic fatty liver in an admixed population. Ann Hepatol. 2022;27(6): 100728.
Wagner C, Hois V, Pajed L, Pusch L-M, Wolinski H, Trauner M, et al. Lysosomal acid lipase is the major acid retinyl ester hydrolase in cultured human hepatic stellate cells but not essential for retinyl ester degradation. Biochim Biophys Acta (BBA) Mol Cell Biol Lipids. 2020;1865(8): 158730.
Ortiz R, Geleta M, Gustafsson C, Lager I, Hofvander P, Löfstedt C, et al. Oil crops for the future. Curr Opin Plant Biol. 2020;56:181–9.
Mazo DF, Malta FM, Stefano JT, Salles APM, Gomes-Gouvea MS, Nastri ACS, et al. Validation of PNPLA3 polymorphisms as risk factor for NAFLD and liver fibrosis in an admixed population. Ann Hepatol. 2019;18(3):466–71.
Rady B, Nishio T, Dhar D, Liu X, Erion M, Kisseleva T, et al. PNPLA3 downregulation exacerbates the fibrotic response in human hepatic stellate cells. PLoS ONE. 2021;16(12): e0260721.
Tardelli M, Bruschi FV, Fuchs CD, Claudel T, Auer N, Kunczer V, et al. Absence of adiponutrin (PNPLA3) and monoacylglycerol lipase synergistically increases weight gain and aggravates steatohepatitis in mice. Int J Mol Sci. 2021;22(4):2126.
Tang S, Zhang J, Mei TT, Guo HQ, Wei XH, Zhang WY, et al. Association of PNPLA3 rs738409 G/C gene polymorphism with nonalcoholic fatty liver disease in children: a meta-analysis. BMC Med Genet. 2020;21(1):1–9.
Akkiz H, Taskin E, Karaogullarindan U, Delik A, Kuran S, Kutlu O. The influence of RS738409 I148M polymorphism of patatin-like phospholipase domain containing 3 gene on the susceptibility of non-alcoholic fatty liver disease. Medicine. 2021;100(19): e25893.
Zheng Y, Wang L, Wang J, Liang T, Zhao T. Impact of patatin-like phospholipase domain-containing-3 rs738409 polymorphism in chronic liver disease: a meta-analysis of 27,365 subjects. Gastroenterol Hepatol Res. 2020;2(4):119–24.
Donati B, Motta BM, Pingitore P, Meroni M, Pietrelli A, Alisi A, et al. The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage. Hepatology. 2016;63(3):787–98.
Peng X-E, Wu Y-L, Lin S-W, Lu Q-Q, Hu Z-J, Lin X. Genetic variants in PNPLA3 and risk of non-alcoholic fatty liver disease in a Han Chinese population. PLoS ONE. 2012;7(11): e50256.
Kubiliun MJ, Cohen JC, Hobbs HH, Kozlitina J. Contribution of a genetic risk score to ethnic differences in fatty liver disease. Liver Int. 2022;42(10):2227–36.
Su W, Wu S, Yang Y, Guo Y, Zhang H, Su J, et al. Phosphorylation of 17β-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice. Nat Commun. 2022;13(1):1–18.
Hudert CA, Alisi A, Anstee QM, Crudele A, Draijer LG, Furse S, et al. Variants in MARC1 and HSD17B13 reduce severity of NAFLD in children, perturb phospholipid metabolism, and suppress fibrotic pathways. medRxiv. 2020. https://doi.org/10.1101/2020.06.05.20120956.
Chen H, Zhang Y, Guo T, Yang F, Mao Y, Li L, et al. Genetic variant rs72613567 of HSD17B13 gene reduces alcohol-related liver disease risk in Chinese Han population. Liver Int. 2020;40(9):2194–202.
Abul-Husn NS, Cheng X, Li AH, Xin Y, Schurmann C, Stevis P, et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018;378(12):1096–106.
Vilar-Gomez E, Pirola CJ, Sookoian S, Wilson LA, Liang T, Chalasani N. The protection conferred by HSD17B13 rs72613567 polymorphism on risk of steatohepatitis and fibrosis may be limited to selected subgroups of patients with NAFLD. Clin Transl Gastroenterol. 2021;12(9): e00400.
Meroni M, Dongiovanni P, Longo M, Carli F, Baselli G, Rametta R, et al. Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes. EBioMedicine. 2020;52: 102658.
Tanaka Y, Shimanaka Y, Caddeo A, Kubo T, Mao Y, Kubota T, et al. LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover. Gut. 2021;70(1):180–93.
Varadharajan V, Massey WJ, Brown JM. Membrane-bound O-acyltransferase 7 (MBOAT7) driven phosphatidylinositol remodeling in advanced liver disease. J Lipid Res. 2022;63: 100234.
Teo K, Abeysekera KW, Adams L, Aigner E, Anstee QM, Banales JM, et al. rs641738C> T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: a meta-analysis. J Hepatol. 2021;74(1):20–30.
Jonas W, Schürmann A. Genetic and epigenetic factors determining NAFLD risk. Mol Metab. 2021;50: 101111.
Umano GR, Caprio S, Di Sessa A, Chalasani N, Dykas DJ, Pierpont B, et al. The rs626283 variant in theMBOAT7Gene is associated with insulin resistance and fatty liver in Caucasian obese youth. Off J Am Coll Gastroenterol. 2018;113(3):376–83.
Liu Z, Zhang Y, Graham S, Wang X, Cai D, Huang M, et al. Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping. J Hepatol. 2020;73(2):263–76.
Magee N, Ahamed F, Eppler N, Jones E, Ghosh P, He L, et al. Hepatic transcriptome profiling reveals early signatures associated with disease transition from non-alcoholic steatosis to steatohepatitis. Liver Res. 2022;6(4):238–50.
Ishiwata-Kimata Y, Le QG, Kimata Y. Induction and aggravation of the endoplasmic-reticulum stress by membrane-lipid metabolic intermediate phosphatidyl-N-monomethylethanolamine. Front Cell Dev Biol. 2022;9: 743018.
Liao S, An K, Liu Z, He H, An Z, Su Q, et al. Genetic variants associated with metabolic dysfunction-associated fatty liver disease in western China. J Clin Lab Anal. 2022;36(9): e24626.
Li X-Y, Liu Z, Li L, Wang H-J, Wang H. TM6SF2 rs58542926 is related to hepatic steatosis, fibrosis and serum lipids both in adults and children: a meta-analysis. Front Endocrinol. 2022;13:1026901.
Li Y, Liu S, Gao Y, Ma H, Zhan S, Yang Y, et al. Association of TM6SF2 rs58542926 gene polymorphism with the risk of nonalcoholic fatty liver disease and colorectal adenoma in Chinese Han population. BMC Biochem. 2019;20(1):3.
Williams PT. Quantile-dependent expressivity of postprandial lipemia. PLoS ONE. 2020;15(2): e0229495.
Prata TVG, Manchiero C, Dantas BP, da Silva Nunes AK, Tengan FM, Magri MC. Effect of MTTP-493G/T, I128T, Q95H and Q244E polymorphisms on hepatic steatosis in patients with chronic hepatitis. Clinics. 2022;77: 100094.
Tan J, Zhang J, Zhao Z, Zhang J, Dong M, Ma X, et al. The association between SNPs Rs1800591 and Rs3816873 of the MTTP gene and nonalcoholic fatty liver disease: a meta-analysis. Saudi J Gastroenterol. 2020;26(4):171.
Chen B-F, Chien Y, Tsai P-H, Perng P-C, Yang Y-P, Hsueh K-C, et al. A PRISMA-compliant meta-analysis of apolipoprotein C3 polymorphisms and nonalcoholic fatty liver disease. J Chin Med Assoc. 2021;84(10):923–9.
Wang J, Ye C, Fei S. Association between APOC3 polymorphisms and non-alcoholic fatty liver disease risk: a meta-analysis. Afr Health Sci. 2020;20(4):1800–8.
Tong M, Wang F. APOC3 rs2854116, PNPLA3 rs738409, and TM6SF2 rs58542926 polymorphisms might influence predisposition of NAFLD: a meta-analysis. IUBMB Life. 2020;72(8):1757–64.
Xu Q-Y, Li H, Cao H-X, Pan Q, Fan J-G. APOC3 rs2070667 associates with serum triglyceride profile and hepatic inflammation in nonalcoholic fatty liver disease. BioMed Res Int. 2020;2020:8869674.
Geng Q-S, Yang M-J, Li L-F, Shen Z-B, Wang L-H, Zheng Y-Y, et al. Over-expression and prognostic significance of FATP5, as a new biomarker, in colorectal carcinoma. Front Mol Biosci. 2022;8:1329.
Ran L-S, Wu Y-Z, Gan Y-W, Wang H-L, Wu L-J, Zheng C-M, et al. Andrographolide ameliorates hepatic steatosis by suppressing FATP2-mediated fatty acid uptake in mice with nonalcoholic fatty liver disease. J Nat Med. 2022;77:1–14.
Auinger A, Valenti L, Pfeuffer M, Helwig U, Herrmann J, Fracanzani A, et al. A promoter polymorphism in the liver-specific fatty acid transport protein 5 is associated with features of the metabolic syndrome and steatosis. Horm Metab Res. 2010;42(12):854–9.
Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology. 2016;150(5):1219-30.e6.
Gabriel-Medina P, Ferrer-Costa R, Rodriguez-Frias F, Ciudin A, Augustin S, Rivera-Esteban J, et al. Influence of type 2 diabetes in the association of PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms in NASH advanced liver fibrosis. Biomedicines. 2022;10(5):1015.
Chung GE, Lee Y, Yim JY, Choe EK, Kwak M-S, Yang JI, et al. Genetic polymorphisms of PNPLA3 and SAMM50 are associated with nonalcoholic fatty liver disease in a Korean population. Gut Liver. 2018;12(3):316.
Li Q, Qu H-Q, Rentfro AR, Grove ML, Mirza S, Lu Y, et al. PNPLA3 polymorphisms and liver aminotransferase levels in a Mexican American population. Clin Invest Med. 2012;35(4):E237.
Chatterjee A, Basu A, Das K, Chowdhury A, Basu P. Exome-wide scan identifies significant association of rs4788084 in IL27 promoter with increase in hepatic fat content among Indians. Gene. 2021;775: 145431.
Zusi C, Morandi A, Maguolo A, Corradi M, Costantini S, Mosca A, et al. Association between MBOAT7 rs641738 polymorphism and non-alcoholic fatty liver in overweight or obese children. Nutr Metab Cardiovasc Dis. 2021;31(5):1548–55.
Vespasiani-Gentilucci U, Dell’Unto C, De Vincentis A, Baiocchini A, Delle Monache M, Cecere R, et al. Combining genetic variants to improve risk prediction for NAFLD and its progression to cirrhosis: a proof of concept study. Can J Gastroenterol Hepatol. 2018;2018:7564835.
Sakamoto Y, Oniki K, Kumagae N, Morita K, Otake K, Ogata Y, et al. Beta-3-adrenergic receptor rs4994 polymorphism is a potential biomarker for the development of nonalcoholic fatty liver disease in overweight/obese individuals. Dis Markers. 2019;2019:4065327.
Lazo M, Xie J, Alvarez CS, Parisi D, Yang S, Rivera-Andrade A, et al. Frequency of the PNPLA3 rs738409 polymorphism and other genetic loci for liver disease in a Guatemalan adult population. Liver Int. 2022;42(6):1470–4.
Zhang RN, Shen F, Pan Q, Cao HX, Chen GY, Fan JG. PPARGC1A rs8192678 G>A polymorphism affects the severity of hepatic histological features and nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease. World J Gastroenterol. 2021;27(25):3863–76.
Adams LA, Marsh JA, Ayonrinde OT, Olynyk JK, Ang WQ, Beilin LJ, et al. Cholesteryl ester transfer protein gene polymorphisms increase the risk of fatty liver in females independent of adiposity. J Gastroenterol Hepatol. 2012;27(9):1520–7.
Bale G, Vishnubhotla RV, Mitnala S, Sharma M, Padaki RN, Pawar SC, et al. Whole-exome sequencing identifies a variant in phosphatidylethanolamine N-methyltransferase gene to be associated with lean-nonalcoholic fatty liver disease. J Clin Exp Hepatol. 2019;9(5):561–8.
Carranza-González L, León-Cachón RB, González-Zavala MA, Ríos-Ibarra C, Morlett-Chávez J, Sánchez-Domínguez C, et al. ACE, APOA5, and MTP gene polymorphisms analysis in relation to triglyceride and insulin levels in pediatric patients. Arch Med Res. 2018;49(2):94–100.
Yuan F, Gu Z, Bi Y, Yuan R, Niu W, Ren D, et al. The association between rs1260326 with the risk of NAFLD and the mediation effect of triglyceride on NAFLD in the elderly Chinese Han population. Aging (Albany NY). 2022;14(6):2736.
Enooku K, Tsutsumi T, Kondo M, Fujiwara N, Sasako T, Shibahara J, et al. Hepatic FATP5 expression is associated with histological progression and loss of hepatic fat in NAFLD patients. J Gastroenterol. 2020;55:227–43.
Fujii H, Kawada N, Japan Study Group of Nafld (JSG-NAFLD). The role of insulin resistance and diabetes in nonalcoholic fatty liver disease. Int J Mol Sci. 2020;21(11):3863.
Chadt A, Al-Hasani H. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflügers Archiv-Eur J Physiol. 2020;472(9):1273–98.
Armandi A, Rosso C, Caviglia GP, Bugianesi E. Insulin resistance across the spectrum of nonalcoholic fatty liver disease. Metabolites. 2021;11(3):155.
Smith GI, Shankaran M, Yoshino M, Schweitzer GG, Chondronikola M, Beals JW, et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Investig. 2020;130(3):1453–60.
Velázquez AM, Bentanachs R, Sala-Vila A, Lázaro I, Rodríguez-Morató J, Sánchez RM, et al. ChREBP-driven DNL and PNPLA3 expression induced by liquid fructose are essential in the production of fatty liver and hypertriglyceridemia in a high-fat diet-fed rat model. Mol Nutr Food Res. 2022;66(7):2101115.
Wang S. Effects of amino acids supplementation on lipid and glucose metabolism in HepG2 cells. Nutrients. 2020;14(15):3050.
Xing Y, Ren X, Li X, Sui L, Shi X, Sun Y, et al. Baicalein enhances the effect of acarbose on the improvement of nonalcoholic fatty liver disease associated with prediabetes via the inhibition of de novo lipogenesis. J Agric Food Chem. 2021;69(34):9822–36.
Lee GH, Phyo WW, Loo WM, Kwok R, Ahmed T, Shabbir A, et al. Validation of genetic variants associated with metabolic dysfunction-associated fatty liver disease in an ethnic Chinese population. World J Hepatol. 2020;12(12):1228.
Riccio S, Melone R, Vitulano C, Guida P, Maddaluno I, Guarino S, et al. Advances in pediatric non-alcoholic fatty liver disease: from genetics to lipidomics. World J Clin Pediatr. 2022;11(3):221.
El Nahass YI, Darwish MK, Mogawer S. PNPLA3 and GCKR gene polymorphisms influence genetic susceptibility to NAFLD in obese Egyptians. Front Sci Res Technol. 2020;1(1):46–51.
Pirola CJ, Flichman D, Dopazo H, Fernandez Gianotti T, San Martino J, Rohr C, et al. A rare nonsense mutation in the glucokinase regulator gene is associated with a rapidly progressive clinical form of nonalcoholic steatohepatitis. Hepatol Commun. 2018;2(9):1030–6.
Uehara K, Sostre-Colón J, Gavin M, Santoleri D, Leonard K-A, Jacobs RL, et al. Activation of liver mTORC1 protects against NASH via dual regulation of VLDL-TAG secretion and de novo lipogenesis. Cell Mol Gastroenterol Hepatol. 2022;13(6):1625–47.
Bhatt SP, Guleria R. Association of IRS1 (Gly972Arg) and IRS2 (Gly1057Asp) genes polymorphisms with OSA and NAFLD in Asian Indians. PLoS ONE. 2021;16(8): e0245408.
Albegali AA, Shahzad M, Mahmood S, Ullah MI. Genetic association of insulin receptor substrate-1 (IRS-1, rs1801278) gene with insulin resistant of type 2 diabetes mellitus in a Pakistani population. Mol Biol Rep. 2019;46(6):6065–70.
Dabiri R, Mahmoudi T, Sabzikarian M, Asadi A, Farahani H, Nobakht H, et al. A 3′-untranslated region variant (rs2289046) of insulin receptor substrate 2 gene is associated with susceptibility to nonalcoholic fatty liver disease. Acta Gastro-Enterol Belg. 2020;83(2):271–6.
Arianti R, Ariani NL, Muhammad AA, Sadewa AH, Farmawati A, Hastuti P, et al. Influence of single nucleotide polymorphism of ENPP1 and ADIPOQ on insulin resistance and obesity: a case–control study in a Javanese population. Life. 2021;11(6):552.
Dongiovanni P, Valenti L, Rametta R, Daly A, Nobili V, Mozzi E, et al. Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease. Gut. 2010;59(2):267–73.
Xiao Q, Lauschke VM. The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders. NPJ Genom Med. 2021;6(1):41.
Oh S-W, Lee J-E, Shin E, Kwon H, Choe EK, Choi S-Y, et al. Genome-wide association study of metabolic syndrome in Korean populations. PLoS ONE. 2020;15(1): e0227357.
Peter A, Stefan N, Cegan A, Walenta M, Wagner S, Königsrainer A, et al. Hepatic glucokinase expression is associated with lipogenesis and fatty liver in humans. J Clin Endocrinol Metab. 2011;96(7):E1126–30.
Sliz E, Sebert S, Würtz P, Kangas AJ, Soininen P, Lehtimäki T, et al. NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects. Hum Mol Genet. 2018;27(12):2214–23.
Siddiqui KA, Chavan S, Mandot AK, Rathi P, Somani V, Banka N. Glucokinase receptor genetic polymorphism in Indian population and its association with non alcoholic fatty liver disease. J Clin Exp Hepatol. 2022;12:S8.
Stender S, Smagris E, Lauridsen BK, Kofoed KF, Nordestgaard BG, Tybjærg-Hansen A, et al. Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride. Hepatology. 2018;67(6):2182–95.
Anstee QM, Darlay R, Cockell S, Meroni M, Govaere O, Tiniakos D, et al. Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆. J Hepatol. 2020;73(3):505–15.
Yuan M, Gong M, Zhang Z, Meng L, Tse G, Zhao Y, et al. Hyperglycemia induces endoplasmic reticulum stress in atrial cardiomyocytes, and mitofusin-2 downregulation prevents mitochondrial dysfunction and subsequent cell death. Oxid Med Cell Longev. 2020;2020:6569728.
Jennings MJ, Hathazi D, Nguyen CDL, Munro B, Münchberg U, Ahrends R, et al. Intracellular lipid accumulation and mitochondrial dysfunction accompanies endoplasmic reticulum stress caused by loss of the co-chaperone DNAJC3. Front Cell Dev Biol. 2021;9: 710247.
Aryal YP, Lee ES, Kim TY, Sung S, Kim JY, An SY, et al. Stage-specific expression patterns of ER stress-related molecules in mice molars: Implications for tooth development. Gene Expr Patterns. 2020;37: 119130.
Gabbia D, Cannella L, De Martin S. The role of oxidative stress in NAFLD–NASH–HCC transition—focus on NADPH oxidases. Biomedicines. 2021;9(6):687.
Abulikemu A, Zhao X, Xu H, Li Y, Ma R, Yao Q, et al. Silica nanoparticles aggravated the metabolic associated fatty liver disease through disturbed amino acid and lipid metabolisms-mediated oxidative stress. Redox Biol. 2022;59: 102569.
Ramanathan R, Ali AH, Ibdah JA. Mitochondrial dysfunction plays central role in nonalcoholic fatty liver disease. Int J Mol Sci. 2022;23(13):7280.
Li R, Xin T, Li D, Wang C, Zhu H, Zhou H. Therapeutic effect of Sirtuin 3 on ameliorating nonalcoholic fatty liver disease: the role of the ERK-CREB pathway and Bnip3-mediated mitophagy. Redox Biol. 2018;18:229–43.
De Gaetano A, Gibellini L, Zanini G, Nasi M, Cossarizza A, Pinti M. Mitophagy and oxidative stress: the role of aging. Antioxidants (Basel). 2021;10(5):794.
Zhang S, Peng X, Yang S, Li X, Huang M, Wei S, et al. The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders. Cell Death Dis. 2022;13(2):1–11.
Ma M, Xie W, Li X. Identification of autophagy-related genes in the progression from non-alcoholic fatty liver to non-alcoholic steatohepatitis. Int J General Med. 2021;14:3163.
Liu K, Qiu D, Liang X, Huang Y, Wang Y, Jia X, et al. Lipotoxicity-induced STING1 activation stimulates MTORC1 and restricts hepatic lipophagy. Autophagy. 2022;18(4):860–76.
Griffin JD, Bejarano E, Wang XD, Greenberg AS. Integrated action of autophagy and adipose tissue triglyceride lipase ameliorates diet-induced hepatic steatosis in liver-specific PLIN2 knockout mice. Cells. 2021;10(5):1016.
Albhaisi S, Sanyal AJ. Gene-environmental interactions as metabolic drivers of nonalcoholic steatohepatitis. Front Endocrinol. 2021;12: 665987.
Wu LX, Xu YC, Hogstrand C, Zhao T, Wu K, Xu YH, et al. Lipophagy mediated glucose-induced changes of lipid deposition and metabolism via ROS dependent AKT-Beclin1 activation. J Nutr Biochem. 2022;100: 108882.
Huang YS, Chang TE, Perng CL, Huang YH. Genetic variations of three important antioxidative enzymes SOD2, CAT, and GPX1 in nonalcoholic steatohepatitis. J Chin Med Assoc. 2021;84(1):14–8.
Byrnes K, Blessinger S, Bailey NT, Scaife R, Liu G, Khambu B. Therapeutic regulation of autophagy in hepatic metabolism. Acta Pharm Sin B. 2022;12(1):33–49.
Xu Y, Shen J, Ran Z. Emerging views of mitophagy in immunity and autoimmune diseases. Autophagy. 2020;16(1):3–17.
Guo X, Zhang W, Wang C, Zhang B, Li R, Zhang L, et al. IRGM promotes the PINK1-mediated mitophagy through the degradation of Mitofilin in SH-SY5Y cells. FASEB J. 2020;34(11):14768–79.
Mehto S, Chauhan S, Jena KK, Chauhan NR, Nath P, Sahu R, et al. IRGM restrains NLRP3 inflammasome activation by mediating its SQSTM1/p62-dependent selective autophagy. Autophagy. 2019;15(9):1645–7.
Schwerbel K, Kamitz A, Krahmer N, Hallahan N, Jähnert M, Gottmann P, et al. Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation. J Hepatol. 2020;73(4):771–82.
Zhang Z, Xun Y, Rong S, Yan L, SoRelle JA, Li X, et al. Loss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity. Nat Commun. 2022;13(1):4136.
Simon TG, Van Der Sloot KWJ, Chin SB, Joshi AD, Lochhead P, Ananthakrishnan AN, et al. IRGM gene variants modify the relationship between visceral adipose tissue and NAFLD in patients with Crohn’s disease. Inflamm Bowel Dis. 2018;24(10):2247–57.
Lin Y-C, Chang P-F, Lin H-F, Liu K, Chang M-H, Ni Y-H. Variants in the autophagy-related gene IRGM confer susceptibility to non-alcoholic fatty liver disease by modulating lipophagy. J Hepatol. 2016;65(6):1209–16.
Bellini G, Del Giudice EM, Nobili V, Rossi F. The IRGM rs10065172 variant increases the risk for steatosis but not for liver damage progression in Italian obese children. J Hepatol. 2017;67(3):653–5.
Kasai S, Shimizu S, Tatara Y, Mimura J, Itoh K. Regulation of Nrf2 by mitochondrial reactive oxygen species in physiology and pathology. Biomolecules. 2020;10(2):320.
Tokinoya K, Sekine N, Aoki K, Ono S, Kuji T, Sugasawa T, et al. Effects of renalase deficiency on liver fibrosis markers in a nonalcoholic steatohepatitis mouse model. Mol Med Rep. 2021;23(3):1.
Sabir U, Irfan HM, Alamgeer, Ullah A, Althobaiti YS, Alshehri FS, et al. Downregulation of hepatic fat accumulation, inflammation and fibrosis by nerolidol in purpose built western-diet-induced multiple-hit pathogenesis of NASH animal model. Biomed Pharmacother. 2022;150: 112956.
Lee W, An G, Park H, Lim W, Song G. Diflubenzuron leads to apoptotic cell death through ROS generation and mitochondrial dysfunction in bovine mammary epithelial cells. Pestic Biochem Physiol. 2021;177: 104893.
Ke Z, Zhao Y, Tan S, Chen H, Li Y, Zhou Z, et al. Citrus reticulata Blanco peel extract ameliorates hepatic steatosis, oxidative stress and inflammation in HF and MCD diet-induced NASH C57BL/6 J mice. J Nutr Biochem. 2020;83: 108426.
Zhou Y, Long D, Zhao Y, Li S, Liang Y, Wan L, et al. Oxidative stress-mediated mitochondrial fission promotes hepatic stellate cell activation via stimulating oxidative phosphorylation. Cell Death Dis. 2022;13(8):1–15.
Satapathy SK, Tran QT, Kovalic AJ, Bontha SV, Jiang Y, Kedia S, et al. Clinical and genetic risk factors of recurrent nonalcoholic fatty liver disease after liver transplantation. Clin Transl Gastroenterol. 2021;12(2): e00302.
Simon TG, Deng X, Liu CT, Chung RT, Long MT. The immunity-related GTPase M rs13361189 variant does not increase the risk for prevalent or incident steatosis; results from the Framingham heart study. Liver Int. 2019;39(6):1022–6.
Toda-Oti KS, Stefano JT, Cavaleiro AM, Carrilho FJ, Correa-Gianella ML, Oliveira C. Association of UCP3 polymorphisms with nonalcoholic steatohepatitis and metabolic syndrome in nonalcoholic fatty liver disease Brazilian patients. Metab Syndr Relat Disord. 2022;20(2):114–23.
Schneider CV, Schneider KM, Conlon DM, Park J, Vujkovic M, Zandvakili I, et al. A genome-first approach to mortality and metabolic phenotypes in MTARC1 p.Ala165Thr (rs2642438) heterozygotes and homozygotes. Med (N Y). 2021;2(7):851-863.e3.
Li J, Wang T, Liu P, Yang F, Wang X, Zheng W, et al. Hesperetin ameliorates hepatic oxidative stress and inflammation via the PI3K/AKT-Nrf2-ARE pathway in oleic acid-induced HepG2 cells and a rat model of high-fat diet-induced NAFLD. Food Funct. 2021;12(9):3898–918.
Tao W, Sun W, Liu L, Wang G, Xiao Z, Pei X, et al. Chitosan oligosaccharide attenuates nonalcoholic fatty liver disease induced by high fat diet through reducing lipid accumulation, inflammation and oxidative stress in C57BL/6 mice. Mar Drugs. 2019;17(11):645.
Mohamed MS, Ghaly S, Azmy KH, Mohamed GA. Assessment of interleukin 32 as a novel biomarker for non-alcoholic fatty liver disease. Egypt Liver J. 2022;12(1):1–8.
Bruschi FV, Tardelli M, Herac M, Claudel T, Trauner M. Metabolic regulation of hepatic PNPLA3 expression and severity of liver fibrosis in patients with NASH. Liver Int. 2020;40(5):1098–110.
Gokuladhas S, Schierding W, Fadason T, Choi M, O’Sullivan JM. Deciphering the genetic links between NAFLD and co-occurring conditions using a liver gene regulatory network. bioRxiv. 2021. https://doi.org/10.1101/2021.12.08.471841.
Park J, Zhao Y, Zhang F, Zhang S, Kwong AC, Zhang Y, et al. IL-6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease. J Hepatol. 2023;78(1):45–56.
Pang L, Huynh J, Alorro MG, Li X, Ernst M, Chand AL. STAT3 signalling via the IL-6ST/gp130 cytokine receptor promotes epithelial integrity and intestinal barrier function during DSS-induced colitis. Biomedicines. 2021;9(2):187.
Bianco C, Casirati E, Malvestiti F, Valenti L. Genetic predisposition similarities between NASH and ASH: identification of new therapeutic targets. JHEP Rep. 2021;3(3): 100284.
Xin T, Chen M, Duan L, Xu Y, Gao P. Interleukin-32: its role in asthma and potential as a therapeutic agent. Respir Res. 2018;19(1):124.
Inzaugarat ME, Johnson CD, Holtmann TM, McGeough MD, Trautwein C, Papouchado BG, et al. NLR family pyrin domain-containing 3 inflammasome activation in hepatic stellate cells induces liver fibrosis in mice. Hepatology. 2019;69(2):845–59.
Yu L, Hong W, Lu S, Li Y, Guan Y, Weng X, et al. The NLRP3 inflammasome in non-alcoholic fatty liver disease and steatohepatitis: therapeutic targets and treatment. Front Pharmacol. 2022;13: 780496.
Buscetta M, Di Vincenzo S, Miele M, Badami E, Pace E, Cipollina C. Cigarette smoke inhibits the NLRP3 inflammasome and leads to caspase-1 activation via the TLR4-TRIF-caspase-8 axis in human macrophages. FASEB J. 2020;34(1):1819–32.
Qu J, Wang W, Zhang Q, Li S. Inhibition of lipopolysaccharide-induced inflammation of chicken liver tissue by selenomethionine via TLR4-NF-κB-NLRP3 signaling pathway. Biol Trace Elem Res. 2020;195(1):205–14.
Kurbatova I, Topchieva L, Dudanova O. Gene TNF polymorphism-308G> A (rs1800629) and its relationship with the efficiency of ursodeoxycholic acid therapy in patients with nonalcoholic steatohepatitis. Bull Exp Biol Med. 2017;164(2):181–5.
Hirano T. IL-6 in inflammation, autoimmunity and cancer. Int Immunol. 2021;33(3):127–48.
Bhatt SP, Guleria R, Vikram NK, Vivekanandhan S, Singh Y, Gupta AK. Association of inflammatory genes in obstructive sleep apnea and non alcoholic fatty liver disease in Asian Indians residing in north India. PLoS ONE. 2018;13(7): e0199599.
Zhang C, Ma K, Yang Y, Wang F, Li W. Glaucocalyxin A suppresses inflammatory responses and induces apoptosis in TNF-a-induced human rheumatoid arthritis via modulation of the STAT3 pathway. Chem Biol Interact. 2021;341: 109451.
Nelson JE, Handa P, Aouizerat B, Wilson L, Vemulakonda LA, Yeh MM, et al. Increased parenchymal damage and steatohepatitis in Caucasian non-alcoholic fatty liver disease patients with common IL1B and IL6 polymorphisms. Aliment Pharmacol Ther. 2016;44(11–12):1253–64.
Wang X, Yan Z, Ye Q. Interleukin-6 gene polymorphisms and susceptibility to liver diseases: a meta-analysis. Medicine. 2019;98(50): e18408.
Xin X, Jin Y, Wang X, Cai B, An Z, Hu YY, et al. A combination of geniposide and chlorogenic acid combination ameliorates nonalcoholic steatohepatitis in mice by inhibiting Kupffer cell activation. Biomed Res Int. 2021;2021:6615881.
Abidi AH, Alghamdi SS, Dabbous MK, Tipton DA, Mustafa SM, Moore BM. Cannabinoid type-2 receptor agonist, inverse agonist, and anandamide regulation of inflammatory responses in IL-1β stimulated primary human periodontal ligament fibroblasts. J Periodontal Res. 2020;55(5):762–83.
Xu A, Yang Y, Shao Y, Wu M, Sun Y. Activation of cannabinoid receptor type 2-induced osteogenic differentiation involves autophagy induction and p62-mediated Nrf2 deactivation. Cell Commun Signal. 2020;18(1):9.
Rossi F, Bellini G, Alisi A, Alterio A, Maione S, Perrone L, et al. Cannabinoid receptor type 2 functional variant influences liver damage in children with non-alcoholic fatty liver disease. PLoS ONE. 2012;7(8): e42259.
Damavandi N, Zeinali S. Association of xenobiotic-metabolizing enzymes (GSTM1 and GSTT 1), and pro-inflammatory cytokines (TNF-α and IL-6) genetic polymorphisms with non-alcoholic fatty liver disease. Mol Biol Rep. 2021;48(2):1225–31.
Akbulut UE, Emeksiz HC, Citli S, Cebi AH, Korkmaz HAA, Baki G. IL-17A, MCP-1, CCR-2, and ABCA1 polymorphisms in children with non-alcoholic fatty liver disease. J Pediatr (Rio J). 2019;95(3):350–7.
El-Derany MO. Polymorphisms in interleukin 13 signaling and interacting genes predict advanced fibrosis and hepatocellular carcinoma development in non-alcoholic steatohepatitis. Biology (Basel). 2020;9(4):75.
Petta S, Grimaudo S, Cammà C, Cabibi D, Di Marco V, Licata G, et al. IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with non-alcoholic fatty liver disease. J Hepatol. 2012;56(6):1356–62.
Eslam M, Chen F, George J. NAFLD in lean Asians. Clin Liver Dis (Hoboken). 2020;16(6):240–3.
Wong W-K, Chan W-K. Nonalcoholic fatty liver disease: a global perspective. Clin Ther. 2021;43(3):473–99.
Chen F, Esmaili S, Rogers GB, Bugianesi E, Petta S, Marchesini G, et al. Lean NAFLD: a distinct entity shaped by differential metabolic adaptation. Hepatology. 2020;71(4):1213–27.
Yoshida K, Yokota K, Kutsuwada Y, Nakayama K, Watanabe K, Matsumoto A, et al. Genome-wide association study of lean nonalcoholic fatty liver disease suggests human leukocyte antigen as a novel candidate locus. Hepatol Commun. 2020;4(8):1124–35.
Maier S, Wieland A, Cree-Green M, Nadeau K, Sullivan S, Lanaspa MA, et al. Lean NAFLD: an underrecognized and challenging disorder in medicine. Rev Endocr Metab Disord. 2021;22(2):351–66.
Zarghamravanbakhsh P, Frenkel M, Poretsky L. Metabolic causes and consequences of nonalcoholic fatty liver disease (NAFLD). Metabol Open. 2021;12: 100149.
Feldman A, Eder SK, Felder TK, Kedenko L, Paulweber B, Stadlmayr A, et al. Clinical and metabolic characterization of lean Caucasian subjects with non-alcoholic fatty liver. Am J Gastroenterol. 2017;112(1):102–10.
Di Filippo M, Moulin P, Roy P, Samson-Bouma ME, Collardeau-Frachon S, Chebel-Dumont S, et al. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J Hepatol. 2014;61(4):891–902.
Ahadi M, Molooghi K, Masoudifar N, Namdar AB, Vossoughinia H, Farzanehfar M. A review of non-alcoholic fatty liver disease in non-obese and lean individuals. J Gastroenterol Hepatol. 2021;36(6):1497–507.
Lin H, Wong GL, Whatling C, Chan AW, Leung HH, Tse CH, et al. Association of genetic variations with NAFLD in lean individuals. Liver Int. 2022;42(1):149–60.
DiStefano JK, Gerhard GS. NAFLD in normal weight individuals. Diabetol Metab Syndr. 2022;14(1):45.
Fracanzani AL, Petta S, Lombardi R, Pisano G, Russello M, Consonni D, et al. Liver and cardiovascular damage in patients with lean nonalcoholic fatty liver disease, and association with visceral obesity. Clin Gastroenterol Hepatol. 2017;15(10):1604-11.e1.
Younes R, Bugianesi E. NASH in lean individuals. Semin Liver Dis. 2019;39(1):86–95.
Chen VL, Chen Y, Du X, Handelman SK, Speliotes EK. Genetic variants that associate with cirrhosis have pleiotropic effects on human traits. Liver Int. 2020;40(2):405–15.
Wang Q, You H, Ou X, Zhao X, Sun Y, Wang M, et al. Non-obese histologically confirmed NASH patients with abnormal liver biochemistry have more advanced fibrosis. Hepatol Int. 2019;13(6):766–76.
Buryska S, Ahn JC, Allen AM, Simha V, Simonetto DA. Familial hypobetalipoproteinemia: an underrecognized cause of lean NASH. Hepatology. 2021;74(5):2897–8.
Takahashi M, Okazaki H, Ohashi K, Ogura M, Ishibashi S, Okazaki S, et al. Current diagnosis and management of abetalipoproteinemia. J Atheroscler Thromb. 2021;28(10):1009–19.
Wan S, van der Veen JN, Bakala N’Goma JC, Nelson RC, Vance DE, Jacobs RL. Hepatic PEMT activity mediates liver health, weight gain, and insulin resistance. Faseb j. 2019;33(10):10986–95.
Nakatsuka A, Matsuyama M, Yamaguchi S, Katayama A, Eguchi J, Murakami K, et al. Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis. Sci Rep. 2016;6:21721.
Romeo S, Sanyal A, Valenti L. Leveraging human genetics to identify potential new treatments for fatty liver disease. Cell Metab. 2020;31(1):35–45.
Shen J, Wong GL, Chan HL, Chan RS, Chan HY, Chu WC, et al. PNPLA3 gene polymorphism and response to lifestyle modification in patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol. 2015;30(1):139–46.
Ioannou GN. Epidemiology and risk-stratification of NAFLD-associated HCC. J Hepatol. 2021;75(6):1476–84.
Carlsson B, Lindén D, Brolén G, Liljeblad M, Bjursell M, Romeo S, et al. Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2020;51(12):1305–20.
Dongiovanni P, Petta S, Mannisto V, Mancina RM, Pipitone R, Karja V, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol. 2015;63(3):705–12.
Scorletti E, West AL, Bhatia L, Hoile SP, McCormick KG, Burdge GC, et al. Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: Results from the WELCOME trial. J Hepatol. 2015;63(6):1476–83.
Cherubini A, Casirati E, Tomasi M, Valenti L. PNPLA3 as a therapeutic target for fatty liver disease: the evidence to date. Expert Opin Ther Targets. 2021;25(12):1033–43.
Lindén D, Ahnmark A, Pingitore P, Ciociola E, Ahlstedt I, Andréasson A-C, et al. Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice. Mol Metab. 2019;22:49–61.
Schwartz BE, Rajagopal V, Smith C, Cohick E, Whissell G, Gamboa M, et al. Discovery and targeting of the signaling controls of PNPLA3 to effectively reduce transcription, expression, and function in pre-clinical NAFLD/NASH settings. Cells. 2020;9(10):2247.
De Benedittis C, Bellan M, Crevola M, Boin E, Barbaglia MN, Mallela VR, et al. Interplay of PNPLA3 and HSD17B13 variants in modulating the risk of hepatocellular carcinoma among hepatitis C patients. Gastroenterol Res Pract. 2020;2020:4216451.
Seko Y, Yamaguchi K, Tochiki N, Yano K, Takahashi A, Okishio S, et al. Attenuated effect of PNPLA3 on hepatic fibrosis by HSD17B13 in Japanese patients with non-alcoholic fatty liver disease. Liver Int. 2020;40(7):1686–92.
Zhang HB, Su W, Xu H, Zhang XY, Guan YF. HSD17B13: a potential therapeutic target for NAFLD. Front Mol Biosci. 2021;8: 824776.
Pirola CJ, Sookoian S. The dual and opposite role of the TM6SF2-rs58542926 variant in protecting against cardiovascular disease and conferring risk for nonalcoholic fatty liver: a meta-analysis. Hepatology. 2015;62(6):1742–56.
Xu X, Poulsen KL, Wu L, Liu S, Miyata T, Song Q, et al. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther. 2022;7(1):287.
Guzman CB, Duvvuru S, Akkari A, Bhatnagar P, Battioui C, Foster W, et al. Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist. Hepatol Commun. 2018;2(5):561–70.
Pillai S, Duvvuru S, Bhatnagar P, Foster W, Farmen M, Shankar S, et al. The PNPLA3 I148M variant is associated with transaminase elevations in type 2 diabetes patients treated with basal insulin peglispro. Pharmacogenom J. 2018;18(3):487–93.
Mak L-Y, Gane E, Schwabe C, Yoon KT, Heo J, Scott R, et al. A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis. J Hepatol. 2022;78(4):684–92.
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Mahmoudi, S.K., Tarzemani, S., Aghajanzadeh, T. et al. Exploring the role of genetic variations in NAFLD: implications for disease pathogenesis and precision medicine approaches. Eur J Med Res 29, 190 (2024). https://doi.org/10.1186/s40001-024-01708-8
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DOI: https://doi.org/10.1186/s40001-024-01708-8