Role of endoplasmic reticulum stress in hepatic glucose and lipid metabolism and therapeutic strategies for metabolic liver disease

The endoplasmic reticulum is the most abundant membrane organelle in eukaryotic cells. It is an important site of membrane and secretory protein folding and glycolipid synthesis and transport, and it is responsible for regulating intracellular calcium homeostasis. When the load of protein synthesis and folding exceeds the processing capacity of the endoplasmic reticulum, the excessive accumulation of misfolded proteins leads to endoplasmic reticulum stress and activates the cellular unfolded protein response. Hepatocytes contain an abundance of smooth and rough endoplasmic reticulum, which can sense changes in various nutritional metabolic and external stimuli and mediate the regulation of glucose and lipid metabolism by activating the unfolded protein response signaling pathways. Endoplasmic reticulum stress plays a very important role in metabolic regulation and in the occurrence and development of liver diseases. This review summarizes the recent research progress on the unfolded protein response and hepatic glucose and lipid metabolism and discusses the mechanism linking endoplasmic reticulum stress with glucose and lipid metabolism disorders and related metabolic liver diseases to improve the understanding of the molecular pathological basis of major chronic diseases such as obesity, type II diabetes and nonalcoholic fatty liver disease.