title: Endoplasmic reticulum stress induces the expression of fetuin-A to develop insulin resistance.
abstract: 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.
authors.affiliation: Department of Internal Medicine, National Cheng Kung University Hospital, 138, Sheng-Li Road, Tainan 70403, Taiwan.
authors.forename: Horng-Yih
authors.initials: HY
authors.lastname: Ou
authors.forename: Hung-Tsung
authors.initials: HT
authors.lastname: Wu
authors.forename: Hao-Chang
authors.initials: HC
authors.lastname: Hung
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Yang
authors.forename: Jin-Shang
authors.initials: JS
authors.lastname: Wu
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Chang
mesh_terms: D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism; D005260:Female; D060748:Fetuins / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D019308:Palmitic Acid / Q000378:metabolism; D060749:alpha-2-HS-Glycoprotein / Q000096:biosynthesis*
chemical_list: D015415:Biomarkers; D060748:Fetuins; D060749:alpha-2-HS-Glycoprotein; D019308:Palmitic Acid; D005947:Glucose