Novel insights into the genetic landscape of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD), the most common liver disorder worldwide, is epidemiologically associated with overweight, insulin resistance features and type 2 diabetes, and can progress to advanced liver fibrosis and hepatocellular carcinoma. Genetic factors play an important role in the development of NAFLD, which is a multifactorial disease. Several common naturally occurring variants modulating lipid and retinol metabolism in hepatocytes predispose to NAFLD development and progression, in particular those in PNPLA3, TM6SF2, MBOAT7, and HSD17B13. In addition, genetic variants that protect hepatic cells from oxidative stress modulate the susceptibility to progressive NAFLD. Although the molecular mechanisms linking these genetic variants with liver disease are not yet fully understood, hepatic fat has emerged as a major driver of the disease, while altered retinol metabolism and mitochondrial oxidative stress play a role in determining the development of advanced NAFLD.