Cellular stress in the pathogenesis of nonalcoholic steatohepatitis and liver fibrosis

The burden of chronic liver disease is rising substantially worldwide. Fibrosis, characterized by excessive deposition of extracellular matrix proteins, is the common pathway leading to cirrhosis, and limited treatment options are available. There is increasing evidence suggesting the role of cellular stress responses contributing to fibrogenesis. This Review provides an overview of studies that analyse the role of cellular stress in different cell types involved in fibrogenesis, including hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells and macrophages. Increasing evidence shows a role of cellular stress responses in nonalcoholic steatohepatitis (NASH) and liver fibrosis pathogenesis. This Review provides a comprehensive overview of the molecular mechanisms involved in cellular stress in fibrogenesis and their role in NASH progression. Chronic activation of endoplasmic reticulum stress in hepatocytes drives nonalcoholic steatohepatitis (ΝASH) pathogenesis, insulin resistance, fat accumulation, inflammation, fibrogenesis and liver fibrosis through inadequate unfolded protein response, cell death and inflammation.Mitochondrial dysfunction and oxidative stress drive NASH and liver fibrosis by causing hepatocyte damage, immune cell activation and inflammation.Cellular stress pathways in hepatocytes also contribute to fibrogenesis independent of NASH.Intracellular reactive oxygen species generation provokes endoplasmic reticulum stress and autophagy that contribute to the activation of hepatic stellate cells.

Automated summary

The burden of chronic liver disease is increasing worldwide, with fibrosis being a common pathway leading to cirrhosis. This review examines the role of cellular stress responses in fibrogenesis, specifically in hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells, and macrophages. It highlights the involvement of cellular stress in nonalcoholic steatohepatitis (NASH) and liver fibrosis progression, particularly through endoplasmic reticulum stress and oxidative stress.