Targeting MRG15 for the treatment of nonalcoholic steatohepatitis

Abstract

Non-alcoholic fatty liver disease represents the most common liver disease worldwide and the prevailing cause of liver-related morbidity and mortality. It encompasses a broad clinical spectrum ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and finally hepatocellular carcinoma. There have been many studies about the underlying mechanisms of NASH progression, fueling a solid therapeutic pipeline across a variety of potential targets to resolve steatohepatitis or fibrosis. Unfortunately, no therapeutic agent has been approved so far for NASH. In an interesting study, Wei et al. highlighted the role of MRG15 as a targetable epigenetic remodeller in the rhythmic regulation of hepatic lipid metabolism. Remarkably, a recent study from the same group uncovered a chromatin-binding independent working mechanism of MRG15 in regulating the progression from early liver steatosis to the advanced NASH stage with fibrosis and inflammation. Collectively, these studies have shown that MRG15 constitutes a key factor during different stages of NAFLD development. Nuclear MRG15 is recruited to promoter regions of liver lipogenesis genes by LRH-1, where it activates the rhythmic expression of lipid synthesis genes, leading to liver steatosis; while in mitochondria, MRG15 accelerates TUFM degradation, resulting in the aggravation of inflammation and fibrosis, and NASH progression. Blocking of MRG15 by CRISPR targeting or by the FDA-approved drug argatroban, which is an antagonist to MRG15, may attenuate liver steatosis. Further studies regarding the functional aspects of MRG15 in different cell types and its regulatory signals will shed light on the intriguing functions of MRG15 in lipid metabolism and tissue fibrogenesis.

Keywords

• Fibrosis
• Lipogenesis
• MRG15
• Non-alcoholic fatty liver disease
• Nonalcoholic steatohepatitis
• Steatosis