Obesity induced Ext1 reduction mediates the occurrence of NAFLD.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder with intricate etiology. It is closely associated with metabolic syndrome, insulin resistance and endoplasmic reticulum (ER) stress. Exostosin1 (Ext1) is an ER-resident transmembrane glycosyltransferase, which plays an important role in ER homeostasis. Loss-of-function mutations in Ext1 link to hereditary multiple exostosis (HME). The present research was undertaken to identify the effect of Ext1 in the progress of NAFLD. High-fat-diet induced mice obesity, hepatic steatosis and decreased hepatic Ext1 expression. In consistent with evaluation of NAFLD mice possessing down-regulated Ext1 expression, free fatty acid (FFA) treatment blunted Ext1 expression in hepatocytes. In human subjects, HME patients presented elevated fasting blood glucose-one of the criteria that define insulin resistance. In vitro experiments, Ext1 deficiency promoted FFA-induced insulin resistance in hepatocytes by analysis of glycogen storage and hallmarks of gluconeogenesis, ascertaining its association with insulin resistance. Mechanically, Ext1 silencing exacerbated ER stress triggered by FFA, which severely disrupted autophagy in hepatocytes, and thereby accelerated the progression of NAFLD. In conclusion, our study demonstrates a beneficial role for Ext1 during the development of NAFLD, which establishes a novel correlation between Ext1 and ER stress-induced perturbations of autophagy during NAFLD progression.

• Authors: Mengxiao Wang, Bingbing Li, Fujian Qin, Junmei Ye, Liang Jin
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 589 Pg. 123-130 (01 22 2022) ISSN: 1090-2104 [Electronic] United States
• PMID: 34906902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• Fatty Acids, Nonesterified
• N-Acetylglucosaminyltransferases
• exostosin-1

Topics

• Animals
• Autophagy
• Cell Line
• Down-Regulation
• Endoplasmic Reticulum Stress
• Fatty Acids, Nonesterified (metabolism)
• Gene Silencing
• Gluconeogenesis
• Hepatocytes (enzymology, pathology)
• Insulin Resistance
• Liver (pathology)
• Male
• Mice, Inbred C57BL
• Mice, Obese
• N-Acetylglucosaminyltransferases (deficiency, metabolism)
• Non-alcoholic Fatty Liver Disease (enzymology, etiology)
• Obesity (complications)