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In the present study, metabolomic analysis of 163 serum and stool samples of our metabolic disease cohort was performed, and we identified glycoursodeoxycholic acid (GUDCA), glycine-conjugated bile acid produced from intestinal bacteria, was decreased in both serum and stool samples from patients with hyperglycemia. RNA-sequencing and quantitative PCR results indicated that GUDCA alleviated endoplasmic reticulum (ER) stress in livers of high fat diet (HFD)-fed mice without alteration of liver metabolism. In vitro, GUDCA reduced palmitic acid induced-ER stress and -apoptosis, as well as stabilized calcium homeostasis. In vivo, GUDCA exerted effects on amelioration of HFD-induced insulin resistance and hepatic steatosis. In parallel, ER stress and apoptosis were decreased in GUDCA-treated mice as compared with vehicle-treated mice in liver. These findings demonstrate that reduced GUDCA is an indicator of hyperglycemia. Supplementation of GUDCA could be an option for the treatment of diet-induced metabolic disorders, including insulin resistance and hepatic steatosis, with inhibiting ER stress.<\/jats:p>","DOI":"10.1042\/cs20210198","type":"journal-article","created":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T17:58:31Z","timestamp":1625767111000},"page":"1689-1706","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Glycoursodeoxycholic acid ameliorates diet-induced metabolic disorders with inhibiting endoplasmic reticulum stress"],"prefix":"10.1042","volume":"135","author":[{"given":"Lele","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China"},{"name":"Department of Medical Imaging, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, Shaanxi, China"},{"name":"Key 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