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学科主题: 基础医学
题名:
Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease
作者: Jiang, Changtao1,2; Xie, Cen1; Li, Fei1; Zhang, Limin3,4,5; Nichols, Robert G.3,4; Krausz, Kristopher W.1; Cai, Jingwei3,4; Qi, Yunpeng1; Fang, Zhong-Ze1; Takahashi, Shogo; Tanaka, Naold1; Desai, Dhimant1,6; Amin, Shantu G.1,6; Albert, Istvan7; Patterson, Andrew D.3,4; Gonzalez, Frank J.1
刊名: JOURNAL OF CLINICAL INVESTIGATION
发表日期: 2015
DOI: 10.1172/JCI76738
卷: 125, 期:1, 页:386-402
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Medicine, Research & Experimental
研究领域[WOS]: Research & Experimental Medicine
关键词[WOS]: INDUCED INSULIN-RESISTANCE ; BILE-ACID-HOMEOSTASIS ; HUMAN GUT MICROBIOTA ; DIET-INDUCED OBESITY ; CHOLESTEROL 7-ALPHA-HYDROXYLASE ; HEPATIC STEATOSIS ; GENE-EXPRESSION ; MICE ; FXR ; METABOLISM
英文摘要:

Nonalcoholic fatty liver disease (NAFLD) is a major worldwide health problem. Recent studies suggest that the gut microbiota influences NAFLD pathogenesis. Here, a murine model of high-fat diet-induced (HFD-induced) NAFLD was used, and the effects of alterations in the gut microbiota on NAFLD were determined. Mice treated with antibiotics or tempol exhibited altered bile acid composition, with a notable increase in conjugated bile acid metabolites that inhibited intestinal farnesoid X receptor (FXR) signaling. Compared with control mice, animals with intestine-specific Fxr disruption had reduced hepatic triglyceride accumulation in response to a HFD. The decrease in hepatic triglyceride accumulation was mainly due to fewer circulating ceramides, which was in part the result of lower expression of ceramide synthesis genes. The reduction of ceramide levels in the ileum and serum in tempol- or antibiotic-treated mice fed a HFD resulted in downregulation of hepatic SREBP1C and decreased de novo lipogenesis. Administration of C16:0 ceramide to antibiotic-treated mice fed a HFD reversed hepatic steatosis. These studies demonstrate that inhibition of an intestinal FXR/ceramide axis mediates gut microbiota-associated NAFLD development, linking the microbiome, nuclear receptor signaling, and NAFLD. This work suggests that inhibition of intestinal FXR is a potential therapeutic target for NAFLD treatment.

语种: 英语
所属项目编号: ES022186
项目资助者: Intramural Research Program of the Center for Cancer Research, NCI, NIH ; National Institutes of Environmental Health Sciences ; Pennsylvania Department of Health using Tobacco CURE Funds
WOS记录号: WOS:000347747300040
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/60717
Appears in Collections:基础医学院_期刊论文

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作者单位: 1.NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
2.Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Key Lab Mol Cardiovasc Sci,Minist Educ, Beijing 100871, Peoples R China
3.Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA
4.Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA
5.Chinese Acad Sci, Wuhan Inst Phys & Math, State Key Lab Magnet Resonance, CAS Key Lab Magnet Resonance Biol Syst, Wuhan, Peoples R China
6.Penn State Univ, Coll Med, Dept Pharmacol, Hershey, PA USA
7.Penn State Univ, Bioinformat Consulting Ctr, University Pk, PA 16802 USA

Recommended Citation:
Jiang, Changtao,Xie, Cen,Li, Fei,et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease[J]. JOURNAL OF CLINICAL INVESTIGATION,2015,125(1):386-402.
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