Glycine-β-muricholic acid antagonizes the intestinal farnesoid X receptor-ceramide axis and ameliorates NASH in mice.
Glycine-β-muricholic acid antagonizes the intestinal farnesoid X receptor-ceramide axis and ameliorates NASH in mice.
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DOI：
10.1002/hep4.2099
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发表时间：
2022-12
影响因子：
5.1
通讯作者：
中科院分区：
文献类型：
--
作者：
非酒精性脂肪性肝炎(NASH)是一种在世界各地迅速发展的病理，可供选择的治疗方法有限。一些法尼类X受体(FXR)激动剂已应用于NASH的临床试验，但已有副作用如瘙痒和低密度脂蛋白升高的报道。肠道FXR被认为是治疗代谢性疾病的有前途的靶点。甘氨酸-β-鼠李酸(Gly-MCA)是一种肠道特异性的FXR拮抗剂，先前被证明对肥胖和胰岛素抵抗有良好的代谢效应。在此，我们确定Gly-MCA在NASH发病机制中的作用，并探讨其潜在的分子机制。在两种不同的NASH模型中，Gly-MCA改善了脂肪堆积、炎症反应和胶原沉积。机制上，Gly-MCA通过减少肠道FXR信号，抑制神经酰胺合成相关基因，从而减少肠源性神经酰胺，从而降低肝脏内质网(ER)应激和促炎细胞因子的产生。胆汁酸代谢和肥胖在Gly-MCA抑制NASH中的作用被排除在外，肠源性神经酰胺与NASH的严重程度相关。Gly-MCA是一种肠道特异性FXR拮抗剂，通过降低肠道FXR信号和神经酰胺的产生，降低循环到肝脏的神经酰胺水平，从而减少肝脏ER应激和NASH进展，从而对NASH产生有益的影响。肠道FXR是一个很有前途的药物靶点，Gly-MCA是一种防治NASH的新型药物。
Nonalcoholic steatohepatitis (NASH) is a rapidly developing pathology around the world, with limited treatment options available. Some farnesoid X receptor (FXR) agonists have been applied in clinical trials for NASH, but side effects such as pruritus and low‐density lipoprotein elevation have been reported. Intestinal FXR is recognized as a promising therapeutic target for metabolic diseases. Glycine‐β‐muricholic acid (Gly‐MCA) is an intestine‐specific FXR antagonist previously shown to have favorable metabolic effects on obesity and insulin resistance. Herein, we identify a role for Gly‐MCA in the pathogenesis of NASH, and explore the underlying molecular mechanism. Gly‐MCA improved lipid accumulation, inflammatory response, and collagen deposition in two different NASH models. Mechanistically, Gly‐MCA decreased intestine‐derived ceramides by suppressing ceramide synthesis–related genes via decreasing intestinal FXR signaling, leading to lower liver endoplasmic reticulum (ER) stress and proinflammatory cytokine production. The role of bile acid metabolism and adiposity was excluded in the suppression of NASH by Gly‐MCA, and a correlation was found between intestine‐derived ceramides and NASH severity. This study revealed that Gly‐MCA, an intestine‐specific FXR antagonist, has beneficial effects on NASH by reducing ceramide levels circulating to liver via lowering intestinal FXR signaling, and ceramide production, followed by decreased liver ER stress and NASH progression. Intestinal FXR is a promising drug target and Gly‐MCA a novel agent for the prevention and treatment of NASH.
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影响因子：
9.8
作者：
Buzzetti, Elena;Pinzani, Massimo;Tsochatzis, Emmanuel A.
通讯作者：
Tsochatzis, Emmanuel A.
影响因子：
29.4
作者：
Koo, Ja Hyun;Lee, Hyo Ju;Kim, Sang Geon
通讯作者：
Kim, Sang Geon
肠道选择性法尼醇 X 受体抑制可改善肥胖相关的代谢功能障碍。
影响因子：
16.6
作者：
Jiang C;Xie C;Lv Y;Li J;Krausz KW;Shi J;Brocker CN;Desai D;Amin SG;Bisson WH;Liu Y;Gavrilova O;Patterson AD;Gonzalez FJ
通讯作者：
Gonzalez FJ
DOI：
10.1111/j.1872-034x.2011.00934.x
发表时间：
2012-04
期刊：
Hepatology research : the official journal of the Japan Society of Hepatology
影响因子：
--
作者：
Longato L;Tong M;Wands JR;de la Monte SM
通讯作者：
de la Monte SM
影响因子：
5.9
作者：
Kitade H;Chen G;Ni Y;Ota T
通讯作者：
Ota T