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Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice.

ABSTRACT: Bile acids are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR), and pharmacological FXR modulators are under development for the treatment of several liver disorders. The inositol-requiring enzyme 1?/X-box binding protein 1 (IRE1?/XBP1) pathway of the unfolded protein response (UPR) is a protective cellular signaling pathway activated in response to endoplasmic reticulum (ER) stress. We investigated the role of FXR signaling in activation of the hepatic XBP1 pathway. Mice were treated with deoxycholic acid (DCA), cholestyramine, GW4064, or underwent bile duct ligation (BDL), and hepatic UPR activation was measured. Huh7-Ntcp and HepG2 cells were treated with FXR agonists, inhibitor, small interfering RNA (siRNA), or small heterodimer partner (SHP) siRNA to determine the mechanisms of IRE1?/XBP1 pathway activation. DCA feeding and BDL increased and cholestyramine decreased expression of hepatic XBP1 spliced (XBP1s). XBP1 pathway activation increased in Huh7-Ntcp and HepG2 cells treated with bile acids, 6?-ethyl-chenodeoxycholic acid (6-ECDCA) or GW4064. This effect decreased with FXR knockdown and treatment with the FXR inhibitor guggulsterone. FXR agonists increased XBP1 splicing and phosphorylated IRE1? (p-IRE1?) expression. Overexpression of SHP similarly increased XBP1 splicing, XBP1s, and p-IRE1? protein expression. SHP knockdown attenuated FXR agonist-induced XBP1s and p-IRE1? protein expression. Co-immunoprecipitation (Co-IP) assays demonstrate a physical interaction between overexpressed green fluorescent protein (GFP)-SHP and FLAG-IRE1? in HEK293T cells. Mice treated with GW4064 had increased, and FXR and SHP null mice had decreased, basal Xbp1s gene expression. CONCLUSION:FXR signaling activates the IRE1?/XBP1 pathway in vivo and in vitro. FXR pathway activation increases XBP1 splicing and enhances p-IRE1? expression. These effects are mediated, at least in part, by SHP. IRE1?/XBP1 pathway activation by bile acids and pharmacological FXR agonists may be protective during liver injury and may have therapeutic implications for liver diseases. (Hepatology 2018;68:304-316).

SUBMITTER: Liu X

PROVIDER: S-EPMC6033648 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice.

Liu Xiaoying X Guo Grace L GL Kong Bo B Hilburn David B DB Hubchak Susan C SC Park Seong S LeCuyer Brian B Hsieh Antony A Wang Li L Fang Deyu D Green Richard M RM

Hepatology (Baltimore, Md.) 20180510 1

Bile acids are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR), and pharmacological FXR modulators are under development for the treatment of several liver disorders. The inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the unfolded protein response (UPR) is a protective cellular signaling pathway activated in response to endoplasmic reticulum (ER) stress. We investigated the role of FXR signaling in activation of the hepatic XBP1 pathway. Mice ...[more]

PMID: 29377207

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Project description:The gut microbiota modulates obesity and associated metabolic phenotypes in part through intestinal farnesoid X receptor (FXR) signaling. Glycine-β-muricholic acid (Gly-MCA), an intestinal FXR antagonist, has been reported to prevent or reverse high-fat diet (HFD)-induced and genetic obesity, insulin resistance, and fatty liver; however, the mechanism by which these phenotypes are improved is not fully understood. The current study investigated the influence of FXR activity on the gut microbiota community structure and function and its impact on hepatic lipid metabolism. Predictions about the metabolic contribution of the gut microbiota to the host were made using 16S rRNA-based PICRUSt (phylogenetic investigation of communities by reconstruction of unobserved states), then validated using 1H nuclear magnetic resonance-based metabolomics, and results were summarized by using genome-scale metabolic models. Oral Gly-MCA administration altered the gut microbial community structure, notably reducing the ratio of Firmicutes to Bacteroidetes and its PICRUSt-predicted metabolic function, including reduced production of short-chain fatty acids (substrates for hepatic gluconeogenesis and de novo lipogenesis) in the ceca of HFD-fed mice. Metabolic improvement was intestinal FXR dependent, as revealed by the lack of changes in HFD-fed intestine-specific Fxr-null (FxrΔIE) mice treated with Gly-MCA. Integrative analyses based on genome-scale metabolic models demonstrated an important link between Lactobacillus and Clostridia bile salt hydrolase activity and bacterial fermentation. Hepatic metabolite levels after Gly-MCA treatment correlated with altered levels of gut bacterial species. In conclusion, modulation of the gut microbiota by inhibition of intestinal FXR signaling alters host liver lipid metabolism and improves obesity-related metabolic dysfunction. IMPORTANCE The farnesoid X receptor (FXR) plays an important role in mediating the dialog between the host and gut microbiota, particularly through modulation of enterohepatic circulation of bile acids. Mounting evidence suggests that genetic ablation of Fxr in the gut or gut-restricted chemical antagonism of the FXR promotes beneficial health effects, including the prevention of nonalcoholic fatty liver disease in rodent models. However, questions remain unanswered, including whether modulation of FXR activity plays a role in shaping the gut microbiota community structure and function and what metabolic pathways of the gut microbiota contribute in an FXR-dependent manner to the host phenotype. In this report, new insights are gained into the metabolic contribution of the gut microbiota to the metabolic phenotypes, including establishing a link between FXR antagonism, bacterial bile salt hydrolase activity, and fermentation. Multiple approaches, including unique mouse models as well as metabolomics and genome-scale metabolic models, were employed to confirm these results.

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Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice.

Publications

Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice.

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