Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease
Changtao Jiang, … , Andrew D. Patterson, Frank J. Gonzalez
Changtao Jiang, … , Andrew D. Patterson, Frank J. Gonzalez
Published December 15, 2014
Citation Information: J Clin Invest. 2015;125(1):386-402. https://doi.org/10.1172/JCI76738.
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Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

Abstract

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.

Authors

Changtao Jiang, Cen Xie, Fei Li, Limin Zhang, Robert G. Nichols, Kristopher W. Krausz, Jingwei Cai, Yunpeng Qi, Zhong-Ze Fang, Shogo Takahashi, Naoki Tanaka, Dhimant Desai, Shantu G. Amin, Istvan Albert, Andrew D. Patterson, Frank J. Gonzalez

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Figure 9

NMR metabolomic analysis of mouse cecal content extracts.

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NMR metabolomic analysis of mouse cecal content extracts. (A) OPLS-DA sc...
(A) OPLS-DA scores (left) and correlation coefficient–coded loadings plots for the models (right) from NMR spectra of cecal content aqueous extracts from vehicle-treated Fxrfl/fl mice and tempol-treated Fxrfl/fl mice fed a HFD for 16 weeks. n = 5 mice per group. (B) OPLS-DA scores (left) and correlation coefficient–coded loadings plots for the models (right) from NMR spectra of cecal content aqueous extracts from vehicle-treated FxrΔIE mice and tempol-treated FxrΔIE mice fed a HFD for 16 weeks. n = 4–5 mice per group. (C) OPLS-DA scores (left) and correlation coefficient–coded loadings plots for the models (right) from NMR spectra of cecal content aqueous extracts from vehicle-treated and antibiotic-treated mice fed a HFD for 7 weeks. The correlation coefficient values indicating significantly changed metabolites are shown in Supplemental Table 3. |r| cutoff value is 0.755, n = 5, P < 0.05; CV-ANOVA: P = 0.04, 0.02 and 1.18 × 10–4, respectively. n = 4–5 mice per group. (D) Relative abundance of SCFAs (acetate, propionate, and butyrate) and oligosaccharides in cecal content extracts from vehicle-treated Fxrfl/fl mice and tempol-treated Fxrfl/fl mice fed a HFD for 16 weeks, vehicle-treated FxrΔIE mice and tempol-treated FxrΔIE mice fed a HFD for 16 weeks, and vehicle-treated and antibiotic-treated mice fed a HFD for 7 weeks. n = 4–5 mice per group. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01 (2-tailed Student’s t test) compared with vehicle-treated mice.