Non-alcoholic fatty liver disease: Genetic susceptibility

The prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) is increasing, particularly in individuals who consume minimal to no alcohol. Currently, NAFLD affects at least 32% of the global population. Although not all but approximately 5-10% cases of NAFLD progress to non-alcoholic steatohepatitis (NASH), a condition arising from lipotoxicity. Patients with NASH may further develop liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). However, it is important to note that progression from NAFLD to NASH and HCC is not inevitable for all patients. The pathogenesis of HCC in the context of NAFLD and NASH remains poorly understood, however, fat accumulation, often due to obesity or metabolic syndrome, leads to lipotoxicity. In individuals with type 2 diabetes (T2D), elevated insulin levels promote lipolysis in adipose tissue and activate lipid-synthesizing enzymes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1), which contribute to lipid accumulation in the liver. Additionally, high glucose levels in T2D can alter gene regulation by activating carbohydrate response-element binding protein (ChREBP) and insulin can increase the activity of sterol regulatory element binding protein (SREBP-1c). These lipogenic transcription factors are known to directly or indirectly activate patatin-like phospholipase domain-containing protein 3 (PNPLA3). Recent research has found elevated levels of angiotensinogen (AGT) and des-angiotensin in both experimental animals and patients with NAFLD. Emerging evidence highlights the significance of genetic factors in the risk of developing NAFLD. Here we explore the association between specific genes and hepatosteatosis, detailing the roles of T2D and obesity in the progression from NAFLD to NASH, and involvement of hepatic stellate cells in liver fibrosis. Additionally, we examine the impact of genes such as PNPLA3, MBOAT7, TM6SF2, GKRP, CCN3, and AGT as well as role of single nucleotide polymorphisms in gene regulation and their contribution to the risk of NAFLD.