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Obeticholic Acid Induces Hepatoxicity Via FXR in the NAFLD Mice.

ABSTRACT: Objective: Obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, is a promising drug for nonalcoholic fatty liver disease (NAFLD); however, it can cause liver injury, especially at high doses. Here, we investigated the role of FXR in the high-dose OCA-induced hepatoxicity in the condition of the NAFLD mouse model. Methods: Wild-type (WT) mice and FXR^-/- mice were administered with over-dose OCA (0.40%) and high-dose OCA (0.16%), in a high-fat diet. RNA-seq on liver samples of mice fed with high-dose OCA was performed to dig out the prominent biological events contributing to hepatic fibrosis. Results: Over-dose OCA induced liver injury and shortened survival in WT mice, but not FXR^-/- mice. High-dose OCA caused hepatic stellate cell activation and liver fibrosis in the presence of FXR. Furthermore, high-dose OCA induced cholesterol accumulation in livers via the upregulation of genes involved in cholesterol acquisition and downregulation of genes regulating cholesterol degradation in liver, leading to the production of interleukin -1β and an FXR-mediated inflammatory response. Conclusion: The high-dose OCA induced FXR-dependent hepatic injury via cholesterol accumulation and interleukin -1β pathway in the NAFLD mice.

SUBMITTER: Lin C

PROVIDER: S-EPMC9124937 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Obeticholic Acid Induces Hepatoxicity Via FXR in the NAFLD Mice.

Lin Chuangzhen C Yu Bingqing B Chen Lixin L Zhang Zhaohui Z Ye Weixiang W Zhong Hui H Bai Wenke W Yang Yuping Y Nie Biao B

Frontiers in pharmacology 20220509

Objective: Obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, is a promising drug for nonalcoholic fatty liver disease (NAFLD); however, it can cause liver injury, especially at high doses. Here, we investigated the role of FXR in the high-dose OCA-induced hepatoxicity in the condition of the NAFLD mouse model. Methods: Wild-type (WT) mice and FXR-/- mice were administered with over-dose OCA (0.40%) and high-dose OCA (0.16%), in a high-fat diet. RNA-seq ...[more]

PMID: 35614939

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Project description:Cholangiocarcinoma (CCA) is an aggressive cancer with high resistance to chemotherapeutics. CCA is enriched in cancer stem cells, which correlate with aggressiveness and prognosis. FXR, a member of the metabolic nuclear receptor family, is markedly down-regulated in human CCA. Our aim was to evaluate, in primary cultures of human intrahepatic CCA (iCCA), the effects of the FXR agonist obeticholic acid (OCA), a semisynthetic bile acid derivative, on their cancerogenic potential. Primary human iCCA cell cultures were prepared from surgical specimens of mucinous or mixed iCCA subtypes. Increasing concentrations (0-2.5 ?M) of OCA were added to culture media and, after 3-10 days, effects on proliferation (MTS assay, cell population doubling time), apoptosis (annexin V-FITC/propidium iodide), cell migration and invasion (wound healing response and Matrigel invasion assay), and cancerogenic potential (spheroid formation, clonogenic assay, colony formation capacity) were evaluated. Results: FXR gene expression was downregulated (RT-qPCR) in iCCA cells vs normal human biliary tree stem cells (p < 0.05) and in mucinous iCCA vs mixed iCCA cells (p < 0.05) but was upregulated by addition of OCA. OCA significantly (p < 0.05) inhibited proliferation of both mucinous and mixed iCCA cells, starting at a concentration as low as 0.05 ?M. Also, CDCA (but not UDCA) inhibited cell proliferation, although to a much lower extent than OCA, consistent with its different affinity for FXR. OCA significantly induced apoptosis of both iCCA subtypes and decreased their in vitro cancerogenic potential, as evaluated by impairment of colony and spheroid formation capacity and delayed wound healing and Matrigel invasion. In general, these effects were more evident in mixed than mucinous iCCA cells. When tested together with Gemcitabine and Cisplatin, OCA potentiated the anti-proliferative and pro-apoptotic effects of these chemotherapeutics, but mainly in mixed iCCA cells. OCA abolished the capacity of both mucinous and mixed iCCA cells to form colonies when administered together with Gemcitabine and Cisplatin. In subcutaneous xenografts of mixed iCCA cells, OCA alone or combined with Gemcitabine or Cisplatin markedly reduced the tumor size after 5 weeks of treatment by inducing necrosis of tumor mass and inhibiting cell proliferation. In conclusion, FXR is down-regulated in iCCA cells, and its activation by OCA results in anti-cancerogenic effects against mucinous and mixed iCCA cells, both in vitro and in vivo. The effects of OCA predominated in mixed iCCA cells, consistent with the lower aggressiveness and the higher FXR expression in this CCA subtype. These results, showing the FXR-mediated capacity of OCA to inhibit cholangiocarcinogenesis, represent the basis for testing OCA in clinical trials of CCA patients.

Project description:Background & aimsIntestinal bacteria can modify the composition of bile acids and bile acids, which are regulated by the farnesoid X receptor, affect the survival and growth of gut bacteria. We studied the effects of obeticholic acid (OCA), a bile acid analogue and farnesoid X receptor agonist, on the intestinal microbiomes of humans and mice.MethodsWe performed a phase I study in 24 healthy volunteers given OCA (5, 10, or 25 mg/d for 17 days). Fecal and plasma specimens were collected at baseline (day 0) and on days 17 (end of dosing) and 37 (end of study). The fecal specimens were analyzed by shotgun meta-genomic sequencing. A Uniref90 high-stringency genomic analysis was used to assign specific genes to the taxonomic signature of bacteria whose abundance was associated with OCA. Male C57BL/6 mice were gavage fed daily with water, vehicle, or OCA (10 mg/kg) for 2 weeks. Small intestine luminal contents were collected by flushing with saline and fecal pellets were collected at baseline and day 14. Mouse samples were analyzed by 16S-tagged sequencing. Culture experiments were performed to determine the taxonomic-specific effects of bile acids and OCA on bacterial growth.ResultsSuppression of endogenous bile acid synthesis by OCA in subjects led to a reversible induction of gram-positive bacteria that are found in the small intestine and are components of the diet and oral microbiota. We found that bile acids decreased proliferation of these bacteria in minimum inhibitory concentration assays. In these organisms, there was an increase in the representation of microbial genomic pathways involved in DNA synthesis and amino acid metabolism with OCA treatment of subjects. Consistent with these findings, mice fed OCA had lower endogenous bile acid levels and an increased proportion of Firmicutes, specifically in the small intestine, compared with mice fed water or vehicle.ConclusionsIn studying the effects of OCA in humans and mice, we found evidence for interactions between bile acids and features of the small intestinal microbiome. These findings indicate that farnesoid X receptor activation alters the intestinal microbiota and could provide opportunities for microbiome biomarker discovery or new approaches to engineering the human microbiome. ClinicalTrials.gov, NCT01933503.

Project description:The farnesoid X receptor (FXR) is known to regulate the gene expression of SR‑BI, which mediates plasma high‑density lipoprotein (HDL)‑cholesterol uptake. Our previous study demonstrated that the activation of FXR by obeticholic acid (OCA) lowered plasma HDL‑cholesterol levels and increased the hepatic mRNA and protein expression levels of SR‑BI in hypercholesterolemic hamsters, but not in normolipidemic hamsters, suggesting that dietary cholesterol may be involved in the OCA‑induced transcription of SR‑BI. In the present study, a functional 90‑base‑pair regulatory region was identified in the first intron of the SR‑BI gene of hamster and mouse that contains a FXR response element (IR‑1) and an adjacent liver X receptor (LXR) response element (LXRE). By in vitro DNA binding and luciferase reporter gene assays, it was demonstrated that FXR and LXR bind to their recognition sequences within this intronic region and transactivate the SR‑BI reporter gene in a synergistic manner. It was also shown that mutations at either the IR‑1 site or the LXRE site eliminated OCA‑mediated gene transcription. Utilizing chow‑fed hamsters as an in vivo model, it was demonstrated that treating normolipidemic hamsters with OCA or GW3965 alone did not effectively induce levels of SR‑BI, whereas their combined treatment significantly increased the mRNA and protein levels of SR‑BI in the liver. The study further investigated effects of FXR and LXR coactivation on the gene expression of SR‑BI in human liver cells. The intronic FXRE and LXRE regulatory region was not conserved in the human SR‑BI genomic sequence, however, higher mRNA expression levels of SR‑BI were observed in human primary hepatocytes and HepG2 cells exposed to combined treatments of FXR and LXR agonists, compared with those in cells exposed to individual ligand treatment. Therefore, these results suggest that human SR‑BI gene transcription may also be subject to concerted activation by FXR and LXR, mediated via currently unidentified regulatory sequences.

Dataset Information

Obeticholic Acid Induces Hepatoxicity Via FXR in the NAFLD Mice.

Publications

Obeticholic Acid Induces Hepatoxicity Via FXR in the NAFLD Mice.

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