Intestinal Farnesoid X Receptor Signaling Modulates Metabolic Disease

Abstract

Farnesoid X receptor (FXR) regulates the synthesis, transport and enterohepatic circulation of bile acids (BA) by modulating the expression of related genes in the liver and small intestine. The composition of the gut microbiota is correlated with metabolic diseases, notably obesity and non-alcoholic fatty acid disease (NAFLD). Recent studies revealed that bacterial metabolism of BA can modulate FXR signaling in the intestine by altering the composition and concentrations of FXR agonist and antagonist. FXR agonist enhances while FXR antagonist suppresses obesity, NAFLD and insulin resistance. The role of intestinal FXR in metabolic disease was firmly established by the analysis of mice lacking FXR that are metabolic resistant to HFD-induced metabolic disease. This is mediated by FXR modulating in part the expression of genes involved in ceramide synthesis in the small intestine. In ileum of obese mice due to the presence of endogenous FXR agonists produced in the liver, these genes are activated, while in mice with altered levels of specific gut bacteria, levels of an FXR antagonist, tauro-β-muricholic acid (T-β-MCA) increase and FXR signaling and ceramide synthesis are repressed. T-β-MCA, which is metabolized in wild-type mice, led to the discovery of glycine-β-muricholic acid (Gly-MCA) that is stable in the intestine and a potent inhibitor of FXR signaling. These studies reveal that ceramides produced in the ileum under the control of FXR, influence metabolic disease, and suggest that novel FXR antagonist such as Gly-MCA that specifically inhibit intestine FXR, could serve as potential drug for the treatment of metabolic disease.

Fig. 1.

Roles of FXR signaling in the enterohepatic circulation of BA. BA are synthesized from cholesterol (Chol) with CYP7A1, a cholesterol 7α-hydroxylase as the rate-limiting enzyme. BA activates FXR, which through control of a number of genes, accelerates BA export from liver through direct induction of BSEP expression, and decreases BA uptake to liver by the suppression of NTCP expression via hepatic FXR-SHP signaling. FXR decreased BA synthesis by the SHP-mediated suppression of the gene encoding CYP7A1. In the intestinal epithelia cells, BA activation of FXR decreases BA absorption at the intestine through the suppression of ASBT via FXRSHP signaling, and stimulated BA transport to the blood by induction of the gene encoding OSTα/β. Transport across the enterocyte is facilitated by I-BABP, which is also induced by FXR. FXR also induces the expression of FGF15/19, which upon binding to FGFR4-βKlotho complex on the plasma membrane, suppresses the expression of CYP7A1 in the liver. FGF15/19 also stimulates filling of the GB through binding to FGFR3. Thus, when hepatic and ileal BA levels increase, FXR is activated, leading to decreased BA pool size.

Fig. 2.

Modulation of FXR signaling in the ileum and metabolic disease. a In untreated mice, BA metabolites produced in the liver enter the enterocyte. Most of these metabolites are FXR agonists that activate FXR resulting in increased serum ceramides. The FXR antagonist T-β-MCA is rapidly hydrolyzed by bacterial BSH. Ceramides induce endoplasmic reticulum stress in the adipocytes and liver resulting in decreased rates of metabolism through suppression of adipose beiging and increased fatty liver through the activation of fatty acid synthesis pathways. b When mice are treated with tempol or antibiotics, gut bacteria populations are altered including lower levels of bacterial species like Lactobacillus spp. that express BSH resulting in the accumulation of the FXR antagonist T-β-MCA. Inhibition of FXR results in lower levels of serum ceramides, increased adipose beiging and decreased fatty acid synthesis and the associated deleterious phenotypes found in HFD-fed wild-type mice.