Endoplasmic Reticulum Stress Induces the Expression of Fetuin-A to Develop Insulin Resistance

• Published in: Endocrinology (Philadelphia) Vol. 153; no. 7; pp. 2974 - 2984
• Main Authors: Ou, Horng-Yih, Wu, Hung-Tsung, Hung, Hao-Chang, Yang, Yi-Ching, Wu, Jin-Shang, Chang, Chih-Jen
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Oxford University Press 01.07.2012; Endocrine Society
• Subjects: Aged; alpha-2-HS-Glycoprotein - biosynthesis; Animals; Biological and medical sciences; Biomarkers; Biomarkers - metabolism; Diabetes; Diabetes mellitus; Diabetes Mellitus - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Fatty liver; Fatty Liver - metabolism; Female; Fetuins - metabolism; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation; Glucose; Glucose - metabolism; Glucose tolerance; Glucose Tolerance Test; Hep G2 Cells; High fat diet; Humans; Hyperglycemia; Insulin; Insulin Resistance; Liver diseases; Male; Metabolic disorders; Mice; Mice, Inbred C57BL; Middle Aged; mRNA; Non-alcoholic Fatty Liver Disease; Palmitic acid; Palmitic Acid - metabolism; Phenylbutyric acid; Steatosis; Streptozocin; Thapsigargin; Vertebrates: endocrinology; Endocrinopathy; Target tissue resistance; Metabolic diseases; Insulin resistance; Fetuin; Endoplasmic reticulum; Stress
• ISSN: 0013-7227; 1945-7170; 1945-7170
• DOI: 10.1210/en.2011-2043

Fetuin-A is a biomarker reported to be important in many metabolic disorders, including obesity, diabetes, and hepatic steatosis. Although it is well known that fetuin-A is increased in diabetes and nonalcoholic fatty liver disease (NAFLD), the levels of fetuin-A in diabetic patients with NAFLD are unknown. Furthermore, the regulation of fetuin-A expression is still obscure. In this study, a total of 180 age- and sex-matched subjects with normal glucose tolerance, NAFLD, newly diagnosed diabetes (NDD), and NDD with NAFLD were recruited. We found that the levels of fetuin-A were significantly increased in NDD with NAFLD as compared with NDD or NAFLD subjects. We further used HepG2 cells to investigate the regulation of fetuin-A. Treatment with endoplasmic reticulum (ER) stress activator, thapsigargin, increased the expression of fetuin-A mRNA and protein in a time- and dose-dependent manner. Pretreatment with ER stress inhibitor, 4-phenylbutyrate, reversed high glucose or palmitate-induced fetuin-A expression. Moreover, treatment with 4-phenylbutyrate in both streptozotocin-induced and high-fat diet-induced diabetic mice not only decreased hepatic fetuin-A levels but also improved hyperglycemia. Taken together, we found that fetuin-A levels were increased in diabetes patients with NAFLD. Moreover, ER stress induced by high glucose and palmitate increased the expression of fetuin-A and further contributed to the development of insulin resistance.