Dataset Information

Genetic and epigenetic determinants of non-alcoholic fatty liver disease (NAFLD) in lean individuals: a systematic review.

ABSTRACT:

Background

Non-alcoholic fatty liver disease (NAFLD) is common in obese individuals, but its occurrence in lean individuals and the underlying mechanisms are not well understood. This study aimed to systematically review the literature on the genetic and epigenetic factors influencing NAFLD in lean individuals.

Methods

A comprehensive search was conducted on April 2^nd, 2023, in seven databases using specific criteria. Only peer-reviewed studies in English, focusing on genetic or epigenetic effects on NAFLD in lean individuals, were included for qualitative synthesis. The Newcastle Ottawa Scale (NOS) was used for quality assessment. This study is registered with PROSPERO (CRD42023413809).

Results

Following PRISMA guidelines, 18 studies were included in this review. The studies were conducted globally, with varying sample sizes and study designs. The NOS quality assessment revealed a moderate overall quality with variations in risk of bias and limitations in comparability and ascertainments of exposure among contributing studies. Genetic determinants related to lipid metabolism, inflammation, and oxidative stress pathways were identified, including PNPLA3 and TM6SF2 gene variants associated with increased NAFLD risk in lean individuals. Epigenetic modifications, particularly depletion of histone variants, were also implicated. However, some studies found no significant associations between genetic or clinical characteristics and lean NAFLD. Less frequent genetic risk factors, such as CETP and APOC3 gene variants, were reported.

Conclusions

This systematic review underscores the importance of investigating genetic and epigenetic factors in lean NAFLD. The findings highlight the role of PNPLA3 and TM6SF2 gene variants and suggest potential epigenetic contributions. Further research is needed to fully understand the genetic and epigenetic mechanisms underlying NAFLD in lean individuals.

SUBMITTER: Njei B

PROVIDER: S-EPMC10838615 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Publications

Genetic and epigenetic determinants of non-alcoholic fatty liver disease (NAFLD) in lean individuals: a systematic review.

Njei Basile B Al-Ajlouni Yazan A YA Ugwendum Derek D Abdu Manasik M Forjindam Anim A Mohamed Mouhand F MF

Translational gastroenterology and hepatology 20231206

<h4>Background</h4>Non-alcoholic fatty liver disease (NAFLD) is common in obese individuals, but its occurrence in lean individuals and the underlying mechanisms are not well understood. This study aimed to systematically review the literature on the genetic and epigenetic factors influencing NAFLD in lean individuals.<h4>Methods</h4>A comprehensive search was conducted on April 2<sup>nd</sup>, 2023, in seven databases using specific criteria. Only peer-reviewed studies in English, focusing on g ...[more]

PMID: 38317742

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Project description:Background & aimsAround 20% of patients with non-alcoholic fatty liver disease (NAFLD) are lean. Increasing evidence suggests that lean NAFLD is a unique subtype of the disease. We aimed to explore the metabolic profile, genetic basis, causal risk factors, and clinical sequelae underlying lean NAFLD.MethodsNAFLD was diagnosed by whole liver proton density fat fraction ≥5%. Whole liver proton density fat fraction and hepatic iron were quantified using magnetic resonance imaging in the UK Biobank. Individuals in this study were stratified according to the World Health Organization criteria of obesity, into lean, overweight, and obese. Mediation analysis, Mendelian randomisation analysis, and Bayesian networks were used to identify a risk factor or a clinical sequela of lean/obese NAFLD.ResultsLean NAFLD manifested a distinct metabolic profile, featured by elevated hepatic iron and fasting glucose. Four loci, namely, HFE rs1800562, SLC17A3-SLC17A2-TRIM38 rs9348697, PNPLA3 rs738409, and TM6SF2 rs58542926, were associated with lean NAFLD (p <5 × 10-8). HFE rs1800562 was specifically associated with lean NAFLD and demonstrated a significant mediation effect through elevating hepatic iron. Type 2 diabetes was the most pronounced clinical sequela of lean NAFLD, followed by liver cirrhosis.ConclusionsOur study suggested that HFE plays a potential steatogenic role rather than regulating iron homoeostasis in patients with lean NAFLD. The increased liver iron deposition is associated with lean NAFLD, whereas obese NAFLD is not related to hepatic iron. The clinical management of patients with lean NAFLD shall be concerned with the prevention and treatment of type 2 diabetes and liver cirrhosis.Impact and implicationsLean NAFLD has a distinct natural history from obese NAFLD. This study underscored liver iron content and the genetic variant of the iron homoeostasis gene HFE as major risks of lean NAFLD, in addition to the unique metabolic profile. The development of type 2 diabetes or liver cirrhosis shall be closely monitored and prevented in patients with lean NAFLD.

Project description:BackgroundThere is limited knowledge about the risk of non-alcoholic fatty liver disease (NAFLD) associated with cardiometabolic disorders in lean persons. This study examines the contribution of cardiometabolic disorders to NAFLD risk among lean individuals and compares to non-lean individuals.MethodsWe analyzed longitudinal data from 6,513 participants of a yearly voluntary routine health testing conducted at the Hospital Israelita Albert Einstein, Brazil. NAFLD was defined as hepatic ultrasound diagnosed fatty liver in individuals scoring below 8 on the alcohol use disorders identification test. Our main exposure variables were elevated blood glucose, elevated blood pressure (BP), presence of atherogenic dyslipidemia (AD, defined as the combination of elevated triglycerides and low HDL cholesterol) and physical inactivity (<150 minutes/week of moderate activity). We further assessed the risk of NAFLD with elevations in waist circumference and high sensitivity C-reactive protein (HsCRP).ResultsOver 15,580 person-years (PY) of follow-up, the incidence rate of NAFLD was 7.7 per 100 PY. In multivariate analysis adjusting for likely confounders, AD was associated with a 72% greater risk of NAFLD (IRR: 1.72 [95% CI:1.32-2.23]). Elevated blood glucose (IRR: 1.71 [95%CI: 1.29-2.28]) and physical inactivity (IRR: 1.46 [95%CI: 1.28-1.66]) were also independently associated with increased risk of NAFLD. In lean individuals, AD, elevated blood glucose and elevated BP were significantly associated with NAFLD although for elevated blood glucose, statistical significance was lost after adjusting for possible confounders. Physical inactivity and elevations in HsCRP were not associated with the risk of NAFLD in lean individuals only. Among lean (and non-lean) individuals, there was an independent association between progressively increasing waist circumference and NAFLD.ConclusionCardiometabolic risk factors are independently associated with NAFLD. However, there are significant differences in the metabolic risk predictors of NAFLD between lean and non-lean individuals. Personalized cardiovascular disease risk stratification and appropriate preventive measures should be considered in both lean and non-lean individuals to prevent the development of NAFLD.

Project description:Liver fibrosis is the excessive expression and accumulation of extracellular matrix proteins in the liver. Fibrotic scarring occurs as the consequence of chronic injury and inflammation. While the successful treatment of hepatitis B and C reduced the burden of liver disease related to viral hepatitis, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) are nowadays the leading causes of hepatic fibrosis worldwide. Although basic research activities have significantly advanced our understanding of the molecular disease pathogenesis, the present therapeutic options for fibrosis are still limited. In advanced disease stages, liver transplantation often remains the only curative treatment. This highlights the necessity of preventive strategies to avoid complications of fibrosis, particularly cirrhosis, portal hypertension and liver cancer. Lifestyle modifications (weight loss, exercise, healthy diet) are the basis for prevention and treatment of NAFLD-associated fibrosis. In the present review, we discuss recent advances in antifibrotic prevention and therapy. In particular, we review the current concepts for antifibrotic drug candidates in the treatment of NAFLD and NASH. While some compounds aim at reverting pathogenic liver metabolism, an alternative approach is to disconnect the injury (e.g., NAFLD) from inflammation and/or fibrosis. Investigational drugs typically target metabolic pathways, insulin resistance, hepatocyte death, inflammatory cell recruitment or activation, the gut-liver axis, matrix expression or matrix turnover. While several promising drug candidates failed in phase 2 or 3 clinical trials (including elafibranor, emricasan and selonsertib), promising results with the farnesoid X receptor agonist obeticholic acid, the pan-PPAR agonist lanifibranor and the chemokine receptor CCR2/CCR5 inhibitor cenicriviroc support the expectation of an effective pharmacological therapy for liver fibrosis in the near future. Tackling NAFLD-associated fibrosis from different directions by combinatorial drug treatment and effective lifestyle changes hold the greatest prospects.

Dataset Information

Genetic and epigenetic determinants of non-alcoholic fatty liver disease (NAFLD) in lean individuals: a systematic review.

Background

Methods

Results

Conclusions

Publications

Genetic and epigenetic determinants of non-alcoholic fatty liver disease (NAFLD) in lean individuals: a systematic review.

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