Regulation of Hepatic Stellate Cell Phenotypes in Metabolic Dysfunction-Associated Steatohepatitis

Abstract

Hepatic stellate cells (HSCs) play a crucial role in the pathogenesis of liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH), a condition characterized by excessive fat accumulation in the hepatocytes, unrelated to alcohol consumption. In a healthy liver, HSCs are quiescent, store vitamin A, and function as pericytes. However, in response to liver injury and inflammation, HSCs become activated. In MASH, HSC activation is driven by metabolic stress, lipotoxicity, and chronic inflammation. Injured hepatocytes, recruited macrophage, capillarized sinusoidal endothelial cells, and permeable intestinal epithelium may each contribute to activating HSCS. This leads to a unique inflammatory environment that promotes fibrosis. MASH HSCs change their metabolism to favor glycolysis, glutaminolysis, and lactate generation. Activated HSCs transform into myofibroblast-like cells, producing excessive extracellular matrix components that result in fibrosis. In addition, HSCs in MASH have inflammatory and intermediate activated phenotypes. This fibrotic process is a key feature of MASH, which can lead to cirrhosis and liver cancer. Understanding the mechanisms of HSC activation and their role in MASH progression is essential for developing targeted therapies to treat and prevent liver fibrosis in affected individuals.

Keywords: Liver Fibrosis; Myofibroblast.