Atorvastatin Induces FXR and CYP7A1 Activation as a Result of the Sequential Action of PPARγ/PGC-1α/HNF-4α in Hep3B Cells

Background/Aims: PPAR., 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 gamma, PGC-1 alpha and HNF-4 alpha 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 gamma, PGC-1 alpha, HNF-4 alpha, FXR, and CYP7A1 in Hep3B cells. PPAR. ligand of troglitazone upregulated the expression of PGC-1 alpha, HNF-4 alpha, FXR, and CYP7A1 in Hep3B cells. Silencing of PPAR gamma, PGC1 alpha, and HNF4 alpha using respective siRNA demonstrated that atorvastatin-induced FXR and CYP7A1 activation required sequential action of PPAR. /PGC-1 alpha/HNF-4 alpha. The silencing of PPAR. completely inhibited atorvastatin-induced PGC-1 alpha expression, and the PGC1 alpha silencing partially inhibited atorvastatin-induced PPAR. expression. The inhibition of HNF4 alpha did not affect atorvastatin-induced PPAR. expression, but partially inhibited atorvastatin-induced PGC-1 alpha expression. Besides, mevalonate completely reversed the effect of atorvastatin on PPAR gamma, PGC-1 alpha, HNF-4 alpha, FXR, and CYP7A1. Conclusions: Atorvastatin induces FXR and CYP7A1 activation as a result of sequential action of PPAR gamma/PGC-1 alpha/HNF-4 alpha in human hepatocytes. We propose that atorvastatin enhances solubility of cholesterol in bile by simultaneously activating of FXR and CYP7A1. (Korean J Gastroenterol 2021;77:123-131)