RT Journal Article
SR Electronic
T1 Effects of Pravastatin on the Expression of ATP-Binding Cassette Transporter A1
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 420
OP 425
DO 10.1124/jpet.104.068213
VO 311
IS 1
A1 Hitoshi Ando
A1 Shuichi Tsuruoka
A1 Hisashi Yamamoto
A1 Toshinari Takamura
A1 Shuichi Kaneko
A1 Akio Fujimura
YR 2004
UL http://jpet.aspetjournals.org/content/311/1/420.abstract
AB 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 μM) 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 LXRα 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. The American Society for Pharmacology and Experimental Therapeutics