Nonalcoholic Fatty Liver Disease Susceptibility Research Articles

Prevalence of nonalcoholic fatty liver disease in patients with hepatitis B: A meta-analysis.

The prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with chronic hepatitis B (CHB) has increased in recent clinical practice; however, the relationship between CHB and hepatic steatosis (HS) remains controversial. To shed light on the potential association between NAFLD and hepatitis B virus (HBV) infection. We conducted a systematic literature search using multiple databases, including PubMed, the Cochrane Library, Web of Science, and EMBASE, to identify relevant studies. Predefined inclusion criteria were used to determine the eligibility of the studies for further analysis. Comprehensive meta-analysis software was used for statistical analysis, which covered 20 studies. The results indicated a lower NAFLD susceptibility in HBV-infected individuals (pooled OR = 0.87; 95%CI = 0.69-1.08; I 2 = 91.1%), with diabetes (P = 0.015), body mass index (BMI; P = 0.010), and possibly age (P = 0.061) as heterogeneity sources. Of note, in four studies (6197 HBV patients), HBV-infected individuals had a reduced NAFLD risk (OR = 0.68, 95%CI = 0.51-0.89, P = 0.006). A positive link between hyperlipidemia and metabolic syndrome emerged in hepatitis B patients, along with specific biochemical indicators, including BMI, creatinine, uric acid, fasting blood glucose, and homeostasis model assessment of insulin resistance. HBV infection may provide protection against HS; however, the occurrence of HS in patients with HBV infection is associated with metabolic syndrome and specific biochemical parameters.

Observational and genetic association of non-alcoholic fatty liver disease and calcific aortic valve disease.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a predominant driver of chronic liver disease globally and is associated with increased cardiovascular disease morbidity and mortality. However, the association between NAFLD and calcific aortic valve disease remains unclear. We aimed to prospectively investigate the association between NAFLD and incident aortic valve calcification (AVC), as well as its genetic relationship with incident calcific aortic valve stenosis (CAVS). A post hoc analysis was conducted on 4226 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) database. We employed the adjusted Cox models to assess the observational association between NAFLD and incident AVC. Additionally, we conducted two-sample Mendelian randomization (MR) analyses to investigate the genetic association between genetically predicted NAFLD and calcific aortic valve stenosis (CAVS), a severe form of CAVD. We repeated the MR analyses by excluding NAFLD susceptibility genes linked to impaired very low-density lipoprotein (VLDL) secretion. After adjustment for potential risk factors, participants with NAFLD had a hazard ratio of 1.58 (95% CI: 1.03-2.43) for incident AVC compared to those without NAFLD. After excluding genes associated with impaired VLDL secretion, the MR analyses consistently showed the significant associations between genetically predicted NAFLD and CAVS for 3 traits: chronic elevation of alanine aminotransferase (odds ratio = 1.13 [95% CI: 1.01-1.25]), imaging-based NAFLD (odds ratio = 2.81 [95% CI: 1.66-4.76]), and biopsy-confirmed NAFLD (odds ratio = 1.12 [95% CI: 1.01-1.24]). However, the association became non-significant when considering all NAFLD susceptibility genes. NAFLD was independently associated with an elevated risk of incident AVC. Genetically predicted NAFLD was also associated with CAVS after excluding genetic variants related to impaired VLDL secretion.

Six-gene prognostic signature for non-alcoholic fatty liver disease susceptibility using machine learning.

nonalcoholic fatty liver disease (NAFLD) is a common liver disease affecting the global population and its impact on human health will continue to increase. Genetic susceptibility is an important factor influencing its onset and progression, and there is a lack of reliable methods to predict the susceptibility of normal populations to NAFLD using appropriate genes. RNA sequencing data relating to nonalcoholic fatty liver disease was analyzed using the "limma" package within the R software. Differentially expressed genes were obtained through preliminary intersection screening. Core genes were analyzed and obtained by establishing and comparing 4 machine learning models, then a prediction model for NAFLD was constructed. The effectiveness of the model was then evaluated, and its applicability and reliability verified. Finally, we conducted further gene correlation analysis, analysis of biological function and analysis of immune infiltration. By comparing 4 machine learning algorithms, we identified SVM as the optimal model, with the first 6 genes (CD247, S100A9, CSF3R, DIP2C, OXCT 2 and PRAMEF16) as predictive genes. The nomogram was found to have good reliability and effectiveness. Six genes' receiver operating characteristic curves (ROC) suggest an essential role in NAFLD pathogenesis, and they exhibit a high predictive value. Further analysis of immunology demonstrated that these 6 genes were closely connected to various immune cells and pathways. This study has successfully constructed an advanced and reliable prediction model based on 6 diagnostic gene markers to predict the susceptibility of normal populations to NAFLD, while also providing insights for potential targeted therapies.

NAMPT gene rs2058539 variant is a risk factor for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease is a chronic liver disease and a growing global epidemic. The aim of this study was to investigate the association between a visfatin gene (NAMPT) variant and nonalcoholic fatty liver disease, owing to the connection between this disease and insulin resistance, obesity, inflammation, and oxidative stress, and the role of visfatin in these metabolic disorders. In the present case-control study, we enrolled 312 genetically unrelated individuals, including 154 patients with biopsy-proven nonalcoholic fatty liver disease and 158 controls. The rs2058539 polymorphism of NAMPT gene was genotyped using the PCR-RFLP method. Genotype and allele distributions of NAMPT gene rs2058539 polymorphism conformed to the Hardy-Weinberg equilibrium both in the case and control groups (p>0.05). The distribution of NAMPT rs2058539 genotypes and alleles differed significantly between the cases with nonalcoholic fatty liver disease and controls. The "CC" genotype of the NAMPT rs2058539 compared with "AA" genotype was associated with a 2.5-fold increased risk of nonalcoholic fatty liver disease after adjustment for confounding factors [p=0.034; odds ratio (OR)=2.52, 95% confidence interval (CI)=1.36-4.37]. Moreover, the NAMPT rs2058539 "C" allele was significantly overrepresented in the nonalcoholic fatty liver disease patients than controls (p=0.022; OR=1.77, 95%CI=1.14-2.31). Our findings indicated for the first time that the NAMPT rs2058539 "CC" genotype is a marker of increased nonalcoholic fatty liver disease susceptibility; however, it needs to be supported by further investigations in other populations.

Insulin-like growth factor binding protein 3 promoter variant (rs2854744) is associated with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and a growing global epidemic. In NAFLD, liver fat surpasses 5% of hepatocytes without the secondary causes of lipid accumulation or excessive alcohol consumption. Given the link between NAFLD and insulin resistance, the possible association between the rs2854744 (-202 G>T) promoter polymorphism of insulin-like growth factor binding protein 3 (IGFBP3) gene and NAFLD was investigated in this study. In this genetic case-control association study, the IGFBP3 rs2854744 genotypes of 315 unrelated individuals, including 156 patients with biopsy-proven NAFLD and 159 controls, were determined using polymerase chain reaction/restriction fragment length polymorphism analyses. The "GT+TT" genotype of the IGFBP3 rs2854744 polymorphism, compared with the "GG" genotype, was associated with a 2.7-fold increased risk of NAFLD after adjustment for confounding factors (P = 0.009; odds ratio [OR] = 2.71; 95% confidence interval [CI] = 1.19-3.18). Additionally, the IGFBP3 rs2854744 "T" allele, in comparison with the "G" allele, was significantly overrepresented in NAFLD patients than the controls (P = 0.008; OR = 1.85; 95%CI = 1.23-2.94). Our findings first indicated that the IGFBP3 rs2854744 "GT+TT" genotype is a marker of increased NAFLD susceptibility; however, it needs to be supported by further investigations in other populations.

Cathepsin D mediates prenatal caffeine exposure-caused NAFLD susceptibility in male rat offspring by regulating autophagy

Epidemiological evidence has revealed that non-alcoholic fatty liver disease (NAFLD) harbors an intrauterine origin. Autophagy is known to be involved in the protective mechanism in the development of adult NAFLD, but whether it engages in the occurrence of fetal-originated NAFLD remains unclear. In this study, a rat model of fetal-originated NAFLD was established by giving a high-fat diet or chronic stress after birth on prenatal caffeine exposure (PCE) male offspring. The alterations of liver morphologic analysis, lipid metabolism, and autophagy before and after birth were determined to confirm autophagy mechanism, NAFLD susceptibility, and intrauterine origin in PCE male adult offspring. Our results revealed that PCE-induced intrauterine high concentration of corticosterone exposure blocked autophagic flux by inhibiting cathepsin D expression in hepatocytes, leading to β-oxidation inhibition and lipid accumulation in the liver. Moreover, high concentration of corticosterone upregulated miR-665 by activating the glucocorticoid receptor to suppress cathepsin D, thus causing lysosomal degradation dysfunction and autophagy flux blockade. Notably, hepatic overexpression of cathepsin D could reverse PCE-induced postnatal NAFLD susceptibility in male rat offspring. This study elucidates the epigenetic programming mechanism of intrauterine autophagy-related fetal-originated NAFLD susceptibility, and identifies cathepsin D as its early intervention target, providing an experimental basis for exploring early prevention and treatment strategies for fetal-originated NAFLD.

Genetic predisposition to nonalcoholic fatty liver disease: insights from ANGPTL8 gene variants in Iranian adults

Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease with a global prevalence, and modulation of ANGPTL8 expression has emerged as a promising predictor of NAFLD susceptibility. This research was conducted to scrutinize ANGPTL8 protein expression in NAFLD patients and elucidate the interplay between ANGPTL8 gene polymorphisms and their lipid profiles, thus shedding new light on the pathophysiology of this complex disease. The study comprised 423 unrelated participants, including 222 healthy controls and 201 individuals with NAFLD, screened using FibroScan/ultrasonography and laboratory tests. The main goal focused on the genotype and allele frequency distribution in the ANGPTL8 gene, specifically analyzing two genetic variations: rs737337 (T/C) and rs2278426 (C/T). The participants diagnosed with NAFLD were slightly younger (P ≥ 0.05) and had a higher body mass index (BMI) than the individuals in the control group. Notably, there was a significant difference in the occurrence of the rs737337 polymorphism between the NAFLD and control groups, with a lower frequency observed in the NAFLD group. Our results indicated that individuals with the TC + CC genotype and C allele of rs737337 (T/C) had a decreased risk of higher levels of ALT and AST. Conversely, those with the CT, CT + TT genotype, and T allele of rs2278426 (C/T) exhibited an increased risk of higher levels of ALT and AST. The results imply that the rs2278426 (C/T) variant of the ANGPTL8 gene is more strongly linked to an increased risk of NAFLD compared to the rs737337 polymorphism. However, additional research is needed to understand the specific molecular mechanisms responsible for the upregulation of ANGPTL8 in individuals with NAFLD.

Residential green and blue spaces with nonalcoholic fatty liver disease incidence: Mediating effect of air pollutants

BackgroundThis study aimed to investigate the relationship of residential green and blue spaces with incident nonalcoholic fatty liver disease (NAFLD), and explore the potential mediation effects of air pollutants and modification effect of genetic susceptibility. Methods411,200 UK Biobank participants without prior liver diseases were included. Land use data were used to estimate residential green and blue spaces (land coverage percentage) at 300 m and 1000 m buffer. The study outcome was incident NAFLD, ascertained through linkage to hospital admissions and death registry records. Results5198 NAFLD cases were documented after a median follow-up of 12.5 years. Green and blue spaces were inversely associated with the hazard of NAFLD: per standard deviation (SD) increment of green space coverage at 300 m (SD: 14.5 %; HR, 0.88, 95 %CI, 0.86–0.91) and 1000 m (SD: 14.1 %; HR, 0.88, 95 %CI, 0.86–0.91) buffer, and blue space coverage at 300 m (SD: 1.0 %; HR,0.95, 95 %CI, 0.93–0.98) and 1000 m (SD: 1.2 %; HR,0.96, 95 %CI, 0.93–0.99) buffer were related with a 4–12 % reduction of NAFLD incidence. The beneficial effects of approximately 25–52 % of green space exposure and about 5–35 % of blue space exposure on NAFLD incidence were mediated by the reduction of PM2.5, NO2 and NOx (All Pindirect effect <0.05). Moreover, genetic susceptibility of NAFLD did not modify the relationship of green and blue spaces with NAFLD incidence. ConclusionResidential green and blue spaces were inversely related to NAFLD incidence. These results suggest that green and blue spaces are modifiable factors that may help prevent NAFLD, and therefore, can be considered as a novel environmental strategy to promote liver health at the community level, rather than only at the individual level.

Insulin receptor substrate 2 gene Gly1057Asp polymorphism is a risk factor for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), which is an emerging global chronic liver disease, has a close association with insulin resistance. We aimed to determine whether the Gly1057Asp (rs1805097) polymorphism of the insulin receptor substrate 2 (IRS2) gene is associated with NAFLD. Using the polymerase chain reaction-restriction fragment length polymorphism method, 135 patients with biopsy-proven NAFLD and 135 controls underwent IRS2 genotype analysis. Genotype and allele distributions of the IRS2 gene Gly1057Asp variant conformed to the Hardy-Weinberg equilibrium in both the case and control groups (P > .05). The Asp/Asp genotype of IRS2 gene Gly1057Asp polymorphism compared with Gly/Gly genotype was associated with a 2.1-fold increased risk for NAFLD after adjustment for confounding factors (P = .029; odds ratio = 2.10, 95% CI = 1.23-3.97). Our findings revealed for the first time that the Gly1057Asp Asp/Asp genotype of the IRS2 gene is a marker of increased NAFLD susceptibility; however, studies in other populations are required to confirm the results.

243-OR: A Novel Platform for Genetic Screening of NAFLD-Associated Genes Identifies UBE2G2 and Other Genes That Alter Hepatic Lipid Accumulation

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver failure that is prevalent in 70% of people with diabetes. Human genetic studies (i.e. GWAS) have identified dozens of potentially causal genes/loci increasing NAFLD susceptibility but translation into actionable drug targets has been impeded by a lack of cellular and molecular mechanistic studies. To address this knowledge gap, we developed a platform for high-throughput genetic perturbation and assessment of fatty acid-triggered lipid accumulation (i.e. hepatic steatosis) in human hepatocytes by combining mechanized cell culture in multi-well plates with high-content microscopy and automated image analysis. We then deployed this platform to screen 106 genes nominated by NAFLD biomarker GWAS, knocking out each gene via CRISPR and scoring the phenotypic changes of the resulting engineered cells in response to oleate treatment. Analysis of over 24,000 images across all gene knockouts revealed 32 genes whose deletion caused significant alterations in cellular lipid droplet (LD) numbers and/or droplet size distribution. Here, we highlight ubiquitin-conjugating enzyme E2 G2 (UBE2G2), whose knockout robustly increases the size of cellular LDs that form in response to oleate stimulation in both the primary screen and subsequent validation. UBE2G2 localizes to the LD surface and is essential for the sterol-induced degradation of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Thus we propose that deletion of UBE2G2 may increase cholesterol derivative content in LDs, thereby increasing LD size. In summary, we demonstrate the successful development and use of a platform for genetic screening of hepatocyte steatosis in vitro and identify multiple NAFLD-associated genes of previously unknown function that likely operate during this early stage of NAFLD pathogenesis. We acknowledge input: Seunghan Lee, Lifeng Wang, David Frederick, Alessandro Pocai Disclosure S. Hu: None. S. Khandavilli: None. R.Y. Diao: None. J. Raum: Employee; Janssen Research &amp; Development, LLC. N. Azhar: Employee; Janssen Research &amp; Development, LLC. I. Bakaj: Employee; Janssen Research &amp; Development, LLC. G. Cowley: Employee; Janssen Research &amp; Development, LLC. B. Rady: Employee; Janssen Research &amp; Development, LLC. D.F. Reilly: Employee; Janssen Research &amp; Development, LLC. A.R. Majithia: None. Funding National Institutes of Health (RDK01DK123422)

The Influence of Sex Hormones in Liver Function and Disease.

The liver performs a multitude of bodily functions, whilst retaining the ability to regenerate damaged tissue. In this review, we discuss sex steroid biology, regulation of mammalian liver physiology and the development of new model systems to improve our understanding of liver biology in health and disease. A major risk factor for the development of liver disease is hepatic fibrosis. Key drivers of this process are metabolic dysfunction and pathologic activation of the immune system. Although non-alcoholic fatty liver disease (NAFLD) is largely regarded as benign, it does progress to non-alcoholic steatohepatitis in a subset of patients, increasing their risk of developing cirrhosis and hepatocellular carcinoma. NAFLD susceptibility varies across the population, with obesity and insulin resistance playing a strong role in the disease development. Additionally, sex and age have been identified as important risk factors. In addition to the regulation of liver biochemistry, sex hormones also regulate the immune system, with sexual dimorphism described for both innate and adaptive immune responses. Therefore, sex differences in liver metabolism, immunity and their interplay are important factors to consider when designing, studying and developing therapeutic strategies to treat human liver disease. The purpose of this review is to provide the reader with a general overview of sex steroid biology and their regulation of mammalian liver physiology.

Investigation of FGF21 mRNA levels and relative mitochondrial DNA copy number levels and their relation in nonalcoholic fatty liver disease: a case-control study.

Background: Although the exact mechanisms of nonalcoholic fatty liver disease (NAFLD) are not fully understood, numerous pieces of evidence show that the variations in mitochondrial DNA (mtDNA) level and hepatic Fibroblast growth factor 21 (FGF21) expression may be related to NAFLD susceptibility. Objectives: The main objective of this study was to determine relative levels of mtDNA copy number and hepatic FGF21 expression in a cohort of Iranian NAFLD patients and evaluate the possible relationship. Methods: This study included 27 NAFLD patients (10 with nonalcoholic fatty liver (NAFL) and 17 with non-alcoholic steatohepatitis (NASH)) and ten healthy subjects. Total RNA and genomic DNA were extracted from liver tissue samples, and then mtDNA copy number and FGF21 expression levels were assessed by quantitative real-time PCR. Results: The relative level of hepatic mtDNA copy number was 3.9-fold higher in patients than in controls (p < 0.0001). NAFLD patients showed a 2.9-fold increase in hepatic FGF21 expression compared to controls (p < 0.013). Results showed that hepatic FGF21 expression was positively correlated with BMI, serum ALT, and AST levels (p < 0.05). The level of mitochondrial copy number and hepatic FGF21 expression was not significantly associated with stages of change in hepatic steatosis. Finally, there was a significant correlation between FGF21 expression and mitochondrial copy number in NAFLD patients (p = 0.027). Conclusion: Our findings suggest a considerable rise of hepatic FGF21 mRNA levels and mtDNA-CN and show a positive correlation between them in the liver tissue of NAFLD patients.

Fasting glucose mediates the influence of genetic variants of SOD2 gene on lean non-alcoholic fatty liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD) imposes an enormous burden on public health, and a large proportion of NAFLD patients are lean with normal body weight, which is rarely mentioned. We conducted this study to determine the mediation effects of fasting glucose on the relationships between genetic variants of SOD2 and the susceptibility of lean NAFLD in the elderly Chinese Han population. Methods: Data in this manuscript were collected in a cross-sectional study among 5,387 residents (aged ≥60years) in the Zhangjiang community center, Shanghai, China, in 2017. Ten (single nucleotide polymorphisms) SNPs previously reported to be related to NAFLD and obesity, including rs9939609, rs1421085, rs9930506, rs626283, rs641738, rs4880, rs58542926, rs738409, rs2281135, and rs2294918 were genotyped. The associations between genetic variations in SOD2 and fasting glucose in five genetic models were analyzed with the SNPassoc R package and rechecked with regression analysis. Mediation models were conducted to explore whether fasting glucose can mediate the association between SNPs and the susceptibility of lean NAFLD. Results: In this study, lean NAFLD individuals had a higher waist circumference and waist-to-hip ratio, ALT, and fasting glucose than lean non-NAFLD individuals (p < 0.050). In comparison, the AA genotypic frequency of rs4880 in SOD2 gene was much lower in lean NAFLD patients (p = 0.005). And rs4800 had a significant indirect effect on lean NAFLD incidence mediated by fasting glucose (p < 0.001). Conclusion: For the first time, the mediation effect of fasting glucose on the association of rs4880 in SOD2 with the susceptibility of lean NAFLD was clarified in the elderly Chinese Han population. It emphasized the connection between glucose homeostasis and oxidative stress in the mechanisms of lean NAFLD.

Association of glutathione S-transferases (GSTT1, GSTM1 and GSTP1) genes polymorphisms with nonalcoholic fatty liver disease susceptibility: A PRISMA-compliant systematic review and meta-analysis.

Background:Glutathione S-transferases (GSTs) genes single-nucleotide polymorphisms (SNPs) have been connected with the susceptibility of nonalcoholic fatty liver disease (NAFLD), but with inconsistent results across the current evidences. The present work was schemed to explore the association between GSTs genes polymorphisms and the NAFLD vulnerability via meta-analysis.Methods:PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure and Wanfang were retrieved for eligible literatures previous to March 10, 2021. The odds ratio (OR) of the dichotomic variables and the standardized mean difference of quantitative variables with corresponding 95% confidence intervals (95%CIs) were computed to evaluate the strength of the associations. The quality of included studies were assessed via using Newcastle-Ottawa Scale (NOS).Results:In total, 7 case-control studies encompassing 804 NAFLD patients and 1362 disease-free controls in this meta-analysis. Ultimately, this analysis included 6, 5 and 5 studies for GSTM1, GSTT1 and GSTP1 polymorphisms, respectively. The pooled data revealed that the GSTs genes SNPs had conspicuous associations with NAFLD susceptibility: for GSTM1, null versus present, OR = 1.46, 95%CI 1.20 to 1.79, P = .0002; for GSTT1, null versus present, OR = 1.34, 95%CI 1.06 to 1.68, P = .01; for GSTP1, Ile/Val or Val/Val versus Ile/Ile, OR = 1.60, 95%CI 1.23 to 2.09, P = .0005.Conclusion:This work revealed that the GSTM1 null, GSTT1 null and GSTP1-Val genotypes might be related to increased NAFLD susceptibility.

The genetic interactions between non-alcoholic fatty liver disease and cardiovascular diseases.

The ongoing debate on whether non-alcoholic fatty liver disease (NAFLD) is an active contributor or an innocent bystander in the development of cardiovascular disease (CVD) has sparked interests in understanding the common mediators between the two biologically distinct entities. This comprehensive review identifies and curates genetic studies of NAFLD overlapping with CVD, and describes the colinear as well as opposing correlations between genetic associations for the two diseases. Here, CVD described in relation to NAFLD are coronary artery disease, cardiomyopathy and atrial fibrillation. Unique findings of this review included certain NAFLD susceptibility genes that possessed cardioprotective properties. Moreover, the complex interactions of genetic and environmental risk factors shed light on the disparity in genetic influence on NAFLD and its incident CVD. This serves to unravel NAFLD-mediated pathways in order to reduce CVD events, and helps identify targeted treatment strategies, develop polygenic risk scores to improve risk prediction and personalise disease prevention.

Association of sorting and assembly machinery component 50 homolog gene polymorphisms with nonalcoholic fatty liver disease susceptibility.

Background:Sorting and assembly machinery component 50 homolog (SAMM50) gene single-nucleotide polymorphisms (SNPs) have been connected with the susceptibility of nonalcoholic fatty liver disease (NAFLD), but with inconsistent results across the current evidence. The present work was schemed to explore the association between SAMM50 gene SNPs and NAFLD vulnerability via meta-analysis.Methods:PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang were retrieved for eligible literature previous to June 10, 2021. The odds ratios (ORs) of the dichotomic variables and the standardized mean difference of quantitative variables with corresponding 95% confidence intervals (95% CIs) were computed to evaluate the strength of the associations. The quality of included studies was assessed using Newcastle-Ottawa Scale (NOS).Results:In total, 8 case-control studies encompassing 6297 NAFLD patients and 7306 disease-free controls in this meta-analysis. Ultimately, this analysis included 8, 6, and 5 studies for rs2143571, rs3761472, and rs738491 polymorphisms respectively. The pooled data revealed that the 3 polymorphisms had conspicuous associations with NAFLD susceptibility: rs2143571, A vs. G, OR=1.51, 95% CI, 1.37–1.66, P < .01; rs3761472, A vs. G, OR=1.50, 95% CI, 1.35–1.67, P < .01; rs738491, A vs. G, OR=1.51, 95% CI, 1.40–1.63, P < .01.Conclusion:This meta-analysis suggests that rs2143571, rs3761472, and rs738491 polymorphisms of the SAMM50 gene are appreciably associated with augmented risk of NAFLD vulnerability. It will provide the latest evidence to support the susceptibility of SAMM50 gene polymorphisms and NAFLD, and provide strategies for the prevention and treatment of NAFLD.

Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage

The primary hepatic consequence of obesity is non-alcoholic fatty liver disease (NAFLD), affecting about 25% of the global adult population. Non-alcoholic steatohepatitis (NASH) is a severe form of NAFLD characterized by liver lipid accumulation, inflammation, and hepatocyte ballooning, with a different degree of hepatic fibrosis. In the light of rapidly increasing prevalence of NAFLD and NASH, there is an urgent need for improved understanding of the molecular pathogenesis of these diseases. The aim of this study was to decipher the possible role of STE20-type kinase MAP4K4 in the regulation of hepatocellular lipotoxicity and susceptibility to NAFLD. We found that MAP4K4 mRNA expression in human liver biopsies was positively correlated with key hallmarks of NAFLD (i.e., liver steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis). We also found that the silencing of MAP4K4 suppressed lipid deposition in human hepatocytes by stimulating β-oxidation and triacylglycerol secretion, while attenuating fatty acid influx and lipid synthesis. Furthermore, downregulation of MAP4K4 markedly reduced the glycolysis rate and lowered incidences of oxidative/endoplasmic reticulum stress. In parallel, we observed suppressed JNK and ERK and increased AKT phosphorylation in MAP4K4-deficient hepatocytes. Together, these results provide the first experimental evidence supporting the potential involvement of STE20-type kinase MAP4K4 as a component of the hepatocellular lipotoxic milieu promoting NAFLD susceptibility.

Evaluation of allelic frequency and genetic risk score of non-alcoholic fatty liver disease in a population of Southern Italy

Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver diseases, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). The risk of developing NAFLD is highly variable among individuals and determined by environmental and genetic factors. GWAS studies identified several genetic risk factors, and genetic risk scores (GRS) were developed for risk stratification. NAFLD susceptibility is significantly associated with four genetic variants: PNPLA3 rs738409 C>G, TM6SF2 rs58542926 C>T, rs641738 C>T close to MBOAT7 locus, GCKR rs1260326 C>T.

Maternal high fat diets based on olive oil protect offspring against nafld features through epigenetic alterations

Rationale: Dietary fatty liver composition plays a role in nonalcoholic fatty liver disease (NAFLD) pathogenesis, being the main hepatic manifestation of metabolic syndrome. Maternal obesogenic diet exposure contributes to NAFLD susceptibility. We examined if a maternal high fat diet (HFD) based on extra virgin olive oil (EVOO), rich in monounsaturated fatty acids, reduces the risk of offspring NAFLD through epigenetic microRNA changes.

A PRISMA-compliant meta-analysis of apolipoprotein C3 polymorphisms and nonalcoholic fatty liver disease.

The relationship between apolipoprotein C3 (APOC3) gene polymorphisms and nonalcoholic fatty liver disease (NAFLD) risk has been investigated in many studies, with inconclusive findings. This meta-analysis evaluated the effect of APOC3 promoter region polymorphisms (-455T/C and -482C/T) on NAFLD susceptibility. A comprehensive search of eligible studies up to October 2020 was performed on Medline, Embase, Web of Science, and Google Scholar databases. No restriction was imposed on language, publication date, or publication status. Odds ratios (ORs) with their 95% confidence intervals (CIs) were calculated to assess the combined effect sizes. The levels of heterogeneity, sensitivity, subgroup, and publication bias were analyzed subsequently. This meta-analysis included eight studies, consisting of 1,511 patients with NAFLD and 1,900 controls fulfilling the inclusion criteria and exclusion criteria. The pooled analysis showed significant associations between APOC3 -455T/C polymorphism and NAFLD risk in allelic (OR = 1.33; 95% CI = 1.05-1.67), dominant (OR = 1.34; 95% CI = 1.04-1.72), and recessive (OR = 1.60; 95% CI = 1.06-2.40) models. Ethnicity-based stratification showed that -455T/C polymorphism was significantly associated with NAFLD risk in the non-Asian but not in the Asian population. No association was evident between -482C/T polymorphism and NAFLD risk. Our findings suggest that APOC3 promoter region polymorphism -455T/C may be associated with NAFLD risk in the non-Asian but not in the Asian population. Additional studies with other functional polymorphisms are needed to discover APOC3 gene effects on NAFLD.