Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease
Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease
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DOI：
10.1172/jci76738
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发表时间：
2015-01-01
影响因子：
15.9
通讯作者：
Gonzalez, Frank J.
中科院分区：
文献类型：
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作者：
Jiang, Changtao;Xie, Cen;Gonzalez, Frank J.
非酒精性脂肪性肝病（NAFLD）是世界性的主要健康问题。最近的研究表明，肠道微生物群影响NAFLD的发病机制。本研究使用了高脂肪饮食诱导（hfd诱导）NAFLD的小鼠模型，并确定了肠道微生物群改变对NAFLD的影响。用抗生素或tempol处理的小鼠表现出胆汁酸组成的改变，结合胆汁酸代谢物显著增加，抑制肠道法内甾体X受体（FXR）信号传导。与对照组小鼠相比，肠道特异性Fxr紊乱的动物对HFD的反应减少了肝脏甘油三酯积累。肝脏甘油三酯积累的减少主要是由于循环神经酰胺减少，这部分是神经酰胺合成基因表达降低的结果。经天酚或抗生素治疗的小鼠饲喂HFD后，回肠和血清中神经酰胺水平降低，导致肝脏SREBP1C下调，并减少新生脂肪生成。C16:0神经酰胺给喂食HFD的抗生素治疗小鼠逆转肝脂肪变性。这些研究表明，肠道FXR/神经酰胺轴的抑制介导了肠道微生物群相关的NAFLD的发展，将微生物群、核受体信号和NAFLD联系起来。这项工作表明，抑制肠道FXR是治疗NAFLD的潜在治疗靶点。
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.