Glycoursodeoxycholic acid ameliorates diet-induced metabolic disorders with inhibiting endoplasmic reticulum stress.
Glycoursodeoxycholic acid ameliorates diet-induced metabolic disorders with inhibiting endoplasmic reticulum stress.
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DOI：
10.1042/cs20210198
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发表时间：
2021-07-30
期刊：
影响因子：
--
通讯作者：
Liu J
中科院分区：
文献类型：
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作者：
Cheng L;Chen T;Guo M;Liu P;Qiao X;Wei Y;She J;Li B;Xi W;Zhou J;Yuan Z;Wu Y;Liu J
近年来的研究表明，在肥胖、2型糖尿病和代谢相关性脂肪肝（MAFLD）等代谢性疾病中，胆汁酸代谢产物的组成和代谢发生了改变，但其作用和机制尚不清楚。在本研究中，我们对代谢性疾病队列的163份血清和粪便样本进行了代谢组学分析，我们发现高血糖患者的血清和粪便样本中的甘氨熊去氧胆酸（GUDCA）（由肠道细菌产生的甘氨酸结合胆汁酸）均减少。RNA测序和定量PCR结果表明，GUDCA减轻了高脂饮食（HFD）喂养小鼠肝脏中的内质网（ER）应激，而不改变肝脏代谢。在体外，GUDCA减少棕榈酸诱导的ER应激和细胞凋亡，以及稳定钙稳态。在体内，GUDCA对HFD诱导的胰岛素抵抗和肝脂肪变性有改善作用。同时，与溶剂处理的小鼠相比，GUDCA处理的小鼠肝脏中的ER应激和细胞凋亡减少。这些发现表明，GUDCA降低是高血糖症的指标。补充GUDCA可能是治疗饮食诱导的代谢紊乱的一种选择，包括胰岛素抵抗和肝脂肪变性，抑制ER应激。
Recent studies reveal that bile acid metabolite composition and its metabolism are changed in metabolic disorders, such as obesity, type 2 diabetes and metabolic associated fatty liver disease (MAFLD), yet its role and the mechanism remain largely unknown. 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.