Unraveling the pathogenesis of non‐alcoholic fatty liver diseases through genome‐wide association studies

Abstract

Non‐alcoholic fatty liver disease (NAFLD) is a significant health burden around the world, affecting approximately 25% of the population. Recent advances in human genetic databases have allowed for the identification of various single nucleotide polymorphisms associated with NAFLD‐related traits. Investigating the functions of these genetic factors provides insight into the pathogenesis of NAFLD and potentially identifies novel therapeutic targets for NAFLD. In this review, we summarized current research on genes with NAFLD‐associated mutations, highlighting phospholipid remodeling and spatially clustered loci as common pathological and genetic features of these mutations. These features suggest a complex yet intriguing mechanism of dissociated steatosis and insulin resistance, which is observed in a subset of patients and may lead to more precise therapy against NAFLD in the future.

Exploring the impact of lipid droplets on the evolution and progress of hepatocarcinoma

“…Consequently, the altered lipid composition stemming from TM6SF2 deficiency is likely to disrupt VLDL secretion and lipid absorption in both the liver and intestine. Thus, the pathological effects associated with a lack of TM6SF2 may stem from an imbalance in phospholipid composition ( Tian and Wang, 2023 ).…”

NAFLD in the 21st Century: Current Knowledge Regarding Its Pathogenesis, Diagnosis and Therapeutics

“…As previously mentioned, NAFLD seems to be the consequence of fat accumulation, inflammation, increased production of ROS, hepatic cell damage, and apoptosis. The "multi-hit" hypothesis refers to the interplay of genetic and environmental factors, such as diet, the gut microbiota, and hormonal components, with hepatic fat aggregation lying at the heart of the problem [27][28][29][30][31][32][33][34][35][36]. Literally, patatin-like phospholipase domain-containing protein 3(PNPLA3),atransmembrane 6 superfamily member 2 (TM6SF2), glucokinase regulatory protein (GCKR), and membrane-boundO-acyltransferase 7(MBOAT7)are major genes associated with NAFLD.…”

“…Literally, patatin-like phospholipase domain-containing protein 3(PNPLA3),atransmembrane 6 superfamily member 2 (TM6SF2), glucokinase regulatory protein (GCKR), and membrane-boundO-acyltransferase 7(MBOAT7)are major genes associated with NAFLD. More specifically, genome-wide association studies (GWAS) have demonstrated that single nucleotide polymorphisms (SNPs) in the above-mentioned genes have been related to NAFLD development [28]. SNPs in PNPLA3 have been more extensively studied than SNPs in other genes.…”