Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease
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
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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Research Article Hepatology

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 2

Gut microbiota regulate bile acid composition.

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Gut microbiota regulate bile acid composition. (A) Individual taurine-co...
(A) Individual taurine-conjugated bile acid levels in the ileum of HFD-fed mice after 7 weeks of antibiotic treatment. n = 4–5 mice per group. (B) Proportion of individual taurine-conjugated bile acids, expressed as a percentage of the total bile acid pool, in ileum from the vehicle- and antibiotic-treated groups fed a HFD for 7 weeks. n = 4–5 mice per group. (C) mRNA levels for FXR signaling–related genes in the liver after 7 weeks of antibiotic treatment in mice fed a HFD. n = 4–5 mice per group. (D) mRNA levels of Shp and Fgf15 in ileum after 7 weeks of antibiotic treatment in HFD-fed mice. n = 5 mice per group. (C and D) Expression was normalized to 18S RNA. (A–D) Data are presented as the mean ± SD. **P < 0.01 (2-tailed Student’s t test) compared with vehicle-treated mice. (E) mRNA levels of Shp and Fgf15 in ileum after 24 hours of T-β-MCA with TCA treatment in HFD-fed mice. mRNA expression was normalized to 18S RNA. n = 6 mice per group. Data are presented as the mean ± SD. One-way ANOVA with Tukey’s correction. **P < 0.01 compared with vehicle; ##P < 0.01 compared with TCA treatment.