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Differential modulation of farnesoid X receptor signaling pathway by the thiazolidinediones.

ABSTRACT: Thiazolidinediones (TZD), including troglitazone, rosiglitazone, and pioglitazone, are agonists of peroxisome proliferator-activated receptor (PPAR)-gamma and belong to a class of insulin-sensitizing drugs for type 2 diabetes mellitus. However, member-specific, PPARgamma-independent activities and toxicity have been reported, especially for troglitazone. Currently, the underlying mechanisms are not fully understood. In this study, we demonstrated that troglitazone but not rosiglitazone or pioglitazone modulated expression of farnesoid X receptor (FXR) target genes bile salt export pump (BSEP) and small heterodimer partner (SHP) in Huh-7 cells. More specifically, troglitazone acted as a partial agonist of FXR to weakly increase BSEP and SHP expression but functioned as a potent antagonist to significantly suppress bile acid-induced expression. Consistent with the finding, troglitazone partially induced but markedly antagonized bile acid-mediated BSEP promoter transactivation. However, such modulating effects were not detected with rosiglitazone or pioglitazone. Using the crystal structure of ligand-bound FXR ligand binding domain (LBD), molecular docking predicted that troglitazone, but not rosiglitazone or pioglitazone, could form a stable complex with FXR LBD. The specific alpha-tocopherol side chain of troglitazone significantly contributed to the formation of such a stable complex through extensive interactions with FXR LBD. The docking model was further validated by functional analyses of a series of docking-guided FXR mutants. In summary, the data demonstrated that troglitazone, but not rosiglitazone or pioglitazone, was an FXR modulator and potently antagonized bile acid-induced expression of FXR target genes. Such differential modulation of FXR signaling pathway by TZDs may represent one of the mechanisms for member-specific, PPARgamma-independent activities and toxicity.

SUBMITTER: Kaimal R

PROVIDER: S-EPMC2700164 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Differential modulation of farnesoid X receptor signaling pathway by the thiazolidinediones.

Kaimal Rajani R Song Xiulong X Yan Bingfang B King Roberta R Deng Ruitang R

The Journal of pharmacology and experimental therapeutics 20090415 1

Thiazolidinediones (TZD), including troglitazone, rosiglitazone, and pioglitazone, are agonists of peroxisome proliferator-activated receptor (PPAR)-gamma and belong to a class of insulin-sensitizing drugs for type 2 diabetes mellitus. However, member-specific, PPARgamma-independent activities and toxicity have been reported, especially for troglitazone. Currently, the underlying mechanisms are not fully understood. In this study, we demonstrated that troglitazone but not rosiglitazone or piogli ...[more]

PMID: 19369578

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Project description: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).

Dataset Information

Differential modulation of farnesoid X receptor signaling pathway by the thiazolidinediones.

Publications

Differential modulation of farnesoid X receptor signaling pathway by the thiazolidinediones.

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