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Obeticholic Acid Induces Hepatoxicity Via FXR in the NAFLD Mice
Chuangzhen Lin1, Bingqing Yu1, Lixin Chen1
1Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China.
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.
Insights
High-dose obeticholic acid (OCA) causes liver injury in nonalcoholic fatty liver disease (NAFLD) models by activating the farnesoid X receptor (FXR). This leads to cholesterol buildup and inflammation, highlighting FXR
Area of Science:
- Hepatology
- Pharmacology
- Molecular Biology
Background:
- Obeticholic acid (OCA) is a promising drug for nonalcoholic fatty liver disease (NAFLD).
- High doses of OCA can cause liver injury, particularly in NAFLD contexts.
- The role of the farnesoid X receptor (FXR) in OCA-induced hepatotoxicity requires further investigation.
Purpose of the Study:
- To investigate the role of FXR in high-dose OCA-induced hepatotoxicity.
- To elucidate the mechanisms underlying OCA-induced liver injury in a NAFLD mouse model.
Main Methods:
- Utilized wild-type (WT) and FXR knockout (FXR-/-) mice fed a high-fat diet.
- Administered varying doses of OCA (0.16% and 0.40%) to mice.
- Performed RNA sequencing on liver samples to identify key biological pathways.
Main Results:
- Over-dose OCA induced liver injury and mortality in WT mice, but not FXR-/- mice.
- High-dose OCA promoted hepatic stellate cell activation and liver fibrosis, dependent on FXR presence.
- OCA led to hepatic cholesterol accumulation by altering cholesterol metabolism genes, triggering interleukin-1β production and an FXR-mediated inflammatory response.
Conclusions:
- High-dose OCA induces FXR-dependent liver injury in NAFLD mice.
- Cholesterol accumulation and the interleukin-1β pathway are key mediators of OCA-induced hepatotoxicity.
- FXR activation is critical for OCA-induced liver damage in this model.
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