Lei Yin, MD, PhD
Associate Professor of Molecular and Integrative Physiology, University of Michigan

“The non-canonical ChREBPalpha activity in diet-induced MASLD/MASH”

Abstract

As a central feature of metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis is the result of excessive accumulation of extracellular matrix (ECM). During the progression of MASH, HSCs become persistently activated in response to chronic metabolic and inflammatory stresses, constituting the main source of ECM-producing myofibroblasts. Recent work has highlighted hepatocytes as either pro- or anti-fibrogenic regulators of liver microenvironment, which determine the activation status of HSCs. Yet, the molecules that communicate between hepatocyte and HSCs has not been well studied. ChREBP is a lipogenic transcription factor in response to glucose and fructose influx. Our recent work demonstrated a protective role of hepatocyte ChREBP⍺ against diet-induced liver steatosis, inflammation and fibrosis in part via maintaining fatty acid oxidation. Moreover, we discovered that hepatocyte ChREBP⍺ possesses a previously unrecognized action in monitoring the intrahepatic microenvironment and curbs the overaction of HSCs and the development of liver fibrosis. Our findings underscore the potential of hepatocyte ChREBP⍺ as a drug target for liver fibrosis in response to chronic liver injury.