Pitavastatin, a potent hydroxymethylglutaryl coenzyme a reductase inhibitor, increases cholesterol 7 alpha-hydroxylase gene expression in HepG2 cells.
BACKGROUND
The effect of pitavastatin on the mRNA levels of apolipoprotein (apo) A-I, peroxisome proliferator-activated receptor alpha (PPARalpha), cholesterol 7alpha-hydroxylase (CYP7A1), and farnesoid X receptor (FXR) in HepG2 cells was examined to establish whether pitavastatin affects bile acid synthesis and if so, to determine a possible molecular mechanism.


RESULTS
HepG2 cells were cultured in serum-free Dulbecco's modified Eagle medium for 18 h before drug treatment. Total RNA was extracted at set times and mRNA levels were quantified by reverse transcription-real time polymerase chain reaction. Pitavastatin at 0.1, 1, 5, and 10 micromol/L increased the mRNA levels of apo A-I, PPARalpha, CYP7A1, and FXR in a dose-dependent manner. The mRNA levels of apo A-I, PPAR alpha, CYP7A1, and FXR similarly increased with increasing doses of pitavastatin. Coincubation of mevalonate (4 mmol/L) with pitavastatin (5 micromol/L) reversed the inductive effects of pitavastatin on the mRNA levels of these genes, indicating that the inductive effects of pitavastatin were related to its inhibition of HMG-CoA reductase.


CONCLUSIONS
Pitavastatin increased the mRNA levels of CYP7A1 in HepG2 cells, suggesting that increased conversion of cholesterol to bile acids may be the mechanism for its potent low-density lipoprotein cholesterol-lowering effects.
Fan
Ping
P
Department of Cardiology, Fukuoka University School of Medicine, , 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Zhang
Bo
B
Kuroki
Syoji
S
Saku
Keijiro
K
D016632:Apolipoprotein A-I / Q000235:genetics; D045744:Cell Line, Tumor; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D047493:PPAR alpha / Q000235:genetics; D011804:Quinolines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
D016632:Apolipoprotein A-I; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008798:Mevalonic Acid; D047493:PPAR alpha; D011804:Quinolines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C108475:pitavastatin