Endoplasmic Reticulum Stress in Hepatic Glucose and Lipid Metabolism and Metabolic Liver Diseases
CHENG Hanbo, LÜ Songya, LIU Yong*
In eukaryotic cells, the ER (endoplasmic reticulum ) is the most abundant membrane network that not only regulates the intracellular Ca2+ homeostasis, but also controls the folding and maturation of secretory and membrane proteins. The ER is also the critical site for the biosynthesis of various carbohydrates and lipids. When the workload of protein synthesis and folding exceeds the ER’s processing capacity, excessive accumulation of unfolded or misfolded proteins results in a state known as ER stress, activating the cellular UPR (unfolded protein response). The ER-localized transmembrane proteins IRE1α, PERK, and ATF6 mediate the three classical UPR signaling pathways, which act to alleviate ER stress to maintain cell functions and survival in mammals. Liver cells possess a great number of both smooth and rough ER, which can sense changes in nutrient availability and metabolic stimuli. Activation of the UPR in the liver has important roles in the regulation of glucose and lipid metabolism. This review will summarize recent advances in our understanding of the UPR regulation of hepatic metabolism as well as its potential connections with the development of metabolic liver diseases. Elucidation of the metabolic actions of hepatic UPR signaling pathways will provide new insights into the UPR physiology/pathophysiology with respect to ER stress-related mechanisms underlying the pathogenesis of obesity, type 2 diabetes and non-alcoholic fatty liver disease.
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