KMID : 0614620210770030123
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Korean Journal of Gastroenterology 2021 Volume.77 No. 3 p.123 ~ p.131
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Atorvastatin Induces FXR and CYP7A1 Activation as a Result of the Sequential Action of PPAR¥ã/PGC-1¥á/HNF-4¥á in Hep3B Cells
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Lee Jin
Hong Eun-Mi Jung Jang-Han Park Se-Woo Lee Sang-Pyo Koh Dong-Hee Jang Hyun-Joo Kae Sea-Hyub
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Abstract
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Background/Aims: PPAR¥ã, farnesoid X receptor (FXR) and CYP7A1 are associated with solubility of bile. This study was performed to understand a mechanism and interactions of statin-induced PPAR¥ã, PGC-1¥á and HNF-4¥á related to the statin-induced activation of FXR and CYP7A1, and verify whether the mevalonate pathway is involved in the mechanism.
Methods: MTT assays were performed using cultured human Hep3B cells to determine the effect of atorvastatin on the cell proliferation. Expression levels of indicated proteins were measured using Western blotting assays by inhibiting the protein expression or not.
Results: Atorvastatin increased expression of PPAR¥ã, PGC-1¥á, HNF-4¥á, FXR, and CYP7A1 in Hep3B cells. PPAR¥ã ligand of troglitazone upregulated the expression of PGC-1¥á, HNF-4¥á, FXR, and CYP7A1 in Hep3B cells. Silencing of PPAR¥ã, PGC1¥á, and HNF4¥á using respective siRNA demonstrated that atorvastatin-induced FXR and CYP7A1 activation required sequential action of PPAR¥ã /PGC-1¥á/HNF-4¥á. The silencing of PPAR¥ã completely inhibited atorvastatin-induced PGC-1¥á expression, and the PGC1¥á silencing partially inhibited atorvastatin-induced PPAR¥ã expression. The inhibition of HNF4¥á did not affect atorvastatin-induced PPAR¥ã expression, but partially inhibited atorvastatin-induced PGC-1¥á expression. Besides, mevalonate completely reversed the effect of atorvastatin on PPAR¥ã, PGC-1¥á, HNF-4¥á, FXR, and CYP7A1.
Conclusions: Atorvastatin induces FXR and CYP7A1 activation as a result of sequential action of PPAR¥ã/PGC-1¥á/HNF-4¥á in human hepatocytes. We propose that atorvastatin enhances solubility of cholesterol in bile by simultaneously activating of FXR and CYP7A1.
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KEYWORD
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Gallstones, Statin, PGC-1¥á, HNF-4¥á, FXR, CYP7A1
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