Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) has emerged as a common public health problem in recent decades. However, the underlying mechanisms leading to the development of NAFLD are not fully understood. The endoplasmic reticulum (ER) stress response has recently been proposed to play a crucial role in both the development of steatosis and progression to nonalcoholic steatohepatitis. ER stress is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed due to the accumulation of unfolded or misfolded proteins. However, delayed or insufficient responses to ER stress may turn physiological mechanisms into pathological consequences, including fat accumulation, insulin resistance, inflammation, and apoptosis, all of which play important roles in the pathogenesis of NAFLD. Therefore, understanding the role of ER stress in the pathogenesis of NAFLD has become a topic of intense investigation. This review highlights the recent findings linking ER stress signaling pathways to the pathogenesis of NAFLD.

Keywords: Endoplasmic reticulum stress; Unfolded protein response; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis

Core tip: Nonalcoholic fatty liver disease (NAFLD) is a progressive disorder that can lead to impaired liver function and, ultimately, liver failure. Chronic endoplasmic reticulum stress induces numerous intracellular pathways that can lead to hepatic steatosis, systemic inflammation, and hepatocyte cell death, all of which are keystones of NAFLD. This review highlights the recent findings linking ER stress signaling pathways with the pathogenesis of NAFLD, which may help identify novel therapeutic targets for the prevention and treatment of NAFLD.