New insights into genetic predisposition and novel therapeutic targets for nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the United States affecting 80-100 million Americans. NAFLD encompasses a spectrum of diseases ranging from excess liver fat (nonalcoholic fatty liver or NAFL), to necro-inflammation (nonalcoholic steatohepatitis or NASH), to fibrosis/ cirrhosis, and malignant transformation (hepatocellular carcinoma). Susceptibility to NAFLD is highly variable and it remains unclear why some patients with NAFLD exhibit NASH, whereas patients with known risk factors have NAFL only. The reasons for this variability can be a partially attributed to differences in genetic background. In the last decade, there have been multiple genome wide association studies, which have enriched our understanding of the genetic basis of NAFLD. The I148M PNPLA3 (patatin-like phospholipase domain-containing protein 3) variant has been identified as the major common genetic determinant of NAFLD. Variants with moderate effect size like TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution. New research has uncovered major pathways leading to disease development and progression; therefore, multiple medications are being developed and tested for the treatment of advanced NAFLD. These agents target metabolic mechanisms as well as inflammation and fibrosis pathways. Several randomized clinical trials (RCTs) are evaluating the efficacy of these novel agents on histological improvement of disease severity and decreasing liver-related outcomes. FDA-approved medications for NASH and NASH-related fibrosis are expected by 2020.

Keywords: Nonalcoholic fatty liver disease (NAFLD); clinical trial; nonalcoholic steatohepatitis (NASH); polymorphism; treatment.

Figure 1

Different gene play a role in the development and progression of NAFLD. PNPLA3 gene product plays a role in lipid droplet remodeling; TM6SF2 product is involved in VLDL secretion leading to lipid accumulation in the liver while decreasing cardiovascular risk; GCKR gene is involved in de novo lipogenesis, and MBOAT7 is involved in remodeling of phosphatidylinositol. VLDL, very low-density lipoprotein.

Figure 2

The future of NAFLD management. NAFLD patients will be divided into different disease stages and managed in a similar fashion to the current management of individuals within the type 2 diabetes spectrum. OCA, obeticholic acid; CVC, cenicriviroc; SEL, selonsertib; CAD, coronary artery disease; CKD, chronic kidney disease; HCC, hepatocellular carcinoma; EV, esophageal varices; NAFLD, nonalcoholic fatty liver disease;