Effects of pravastatin on the expression of ATP-binding cassette transporter A1.
In vitro inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase causes the suppression of liver X receptor (LXR) activity. Because LXR regulates the expression of ATP-binding cassette transporter (ABC) A1, which is involved in the high-density lipoprotein-related reverse cholesterol transport pathway, we examined the effects of an HMG-CoA reductase inhibitor pravastatin on ABCA1 expression in vitro and in vivo. Pravastatin (10 microM) significantly reduced the transcript levels of murine ABCA1 gene by 35% in RAW264.7 macrophages under a lipoprotein-deficient condition. The inhibition was due to the decreased mevalonic acid production because addition of exogenous mevalonic acid restored ABCA1 mRNA levels. In addition, cholesterol and 22(R)-hydroxycholesterol thoroughly blunted the inhibition. Furthermore, pravastatin did not decrease ABCA1 mRNA and protein levels in HepG2 hepatocytes even in the absence of exogenous LXR agonists. Oral dosing of pravastatin (0.1% concentration in drinking water) for 24 h or 2 weeks to mice did not decrease ABCA1 mRNA and protein levels in the liver and leukocytes. Interestingly, pravastatin significantly increased both hepatic and leukocyte LXRalpha mRNA levels. Thus, although HMG-CoA reductase inhibitors suppress ABCA1 mRNA expression in the absence of LXR agonists, in vivo inhibition of HMG-CoA reductase is unlikely to cause such suppression.
Ando
Hitoshi
H
Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical School, Tochigi 329-0498, Japan.
Tsuruoka
Shuichi
S
Yamamoto
Hisashi
H
Takamura
Toshinari
T
Kaneko
Shuichi
S
Fujimura
Akio
A
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001692:Biological Transport; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017035:Pravastatin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D012333:RNA, Messenger; D017035:Pravastatin