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应激可通过增加非酒精性脂肪性肝炎小鼠肝内β-鼠胆酸水平来减少肝内脂质堆积。

Stress can attenuate hepatic lipid accumulation via elevation of hepatic β-muricholic acid levels in mice with nonalcoholic steatohepatitis.

机构信息

Department of Anatomy and Regenerative Biology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan.

出版信息

Lab Invest. 2021 Feb;101(2):193-203. doi: 10.1038/s41374-020-00509-x. Epub 2020 Dec 10.

Abstract

Stress can affect our body and is known to lead to some diseases. However, the influence on the development of nonalcohol fatty liver disease (NAFLD) remains unknown. This study demonstrated that chronic restraint stress attenuated hepatic lipid accumulation via elevation of hepatic β-muricholic acid (βMCA) levels in the development of nonalcoholic steatohepatitis (NASH) in mice. Serum cortisol and corticosterone levels, i.e., human and rodent stress markers, were correlated with serum bile acid levels in patients with NAFLD and methionine- and choline-deficient (MCD) diet-induced mice, respectively, suggesting that stress is related to bile acid (BA) homeostasis in NASH. In the mouse model, hepatic βMCA and cholic acid (CA) levels were increased after the stress challenge. Considering that a short stress enhanced hepatic CYP7A1 protein levels in normal mice and corticosterone increased CYP7A1 protein levels in primary mouse hepatocytes, the enhanced Cyp7a1 expression was postulated to be involved in the chronic stress-increased hepatic βMCA level. Interestingly, chronic stress decreased hepatic lipid levels in MCD-induced NASH mice. Furthermore, βMCA suppressed lipid accumulation in mouse primary hepatocytes exposed to palmitic acid/oleic acid, but CA did not. In addition, Cyp7a1 expression seemed to be related to lipid accumulation in hepatocytes. In conclusion, chronic stress can change hepatic lipid accumulation in NASH mice, disrupting BA homeostasis via induction of hepatic Cyp7a1 expression. This study discovered a new βMCA action in the liver, indicating the possibility that βMCA is available for NAFLD therapy.

摘要

压力会影响我们的身体,已知会导致一些疾病。然而,其对非酒精性脂肪性肝病(NAFLD)发展的影响尚不清楚。本研究表明,慢性束缚应激通过增加非酒精性脂肪性肝炎(NASH)小鼠肝脏β-鼠胆酸(βMCA)水平来减轻肝脂质积累。血清皮质醇和皮质酮水平,即人类和啮齿动物应激标志物,与 NAFLD 患者和蛋氨酸-胆碱缺乏(MCD)饮食诱导的小鼠的血清胆汁酸水平相关,提示应激与 NASH 中的胆汁酸(BA)稳态有关。在小鼠模型中,应激后肝脏βMCA 和胆酸(CA)水平增加。考虑到短期应激增强了正常小鼠肝脏 CYP7A1 蛋白水平,皮质酮增加了原代小鼠肝细胞中 CYP7A1 蛋白水平,因此推测增强的 Cyp7a1 表达参与了慢性应激引起的肝脏βMCA 水平升高。有趣的是,慢性应激降低了 MCD 诱导的 NASH 小鼠肝脏的脂质水平。此外,βMCA 抑制了饱食脂肪酸/油酸暴露的小鼠原代肝细胞中的脂质积累,但 CA 没有。此外,Cyp7a1 表达似乎与肝细胞中的脂质积累有关。总之,慢性应激可以改变 NASH 小鼠肝脏的脂质积累,通过诱导肝脏 Cyp7a1 表达破坏 BA 稳态。本研究发现了βMCA 在肝脏中的新作用,表明βMCA 可用于治疗 NAFLD。

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