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TRANSCRIPTIONAL REGULATION OF THE RAT PHOSPHOLIPID TRANSLOCASE MDR 2 GENE EXPRESSION BY CHOLESTEROL SYNTHESIS INHIBITORS AND STEROL REGULATORY ELEMENT-BINDING PROTEINS

We have been shown in rats that the hepatic expression of the phosphatidylcholine translocase Mdr2 is induced by statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Statins are known to activate sterol regulatory element-binding proteins (SREBPs), transcription factors that control key enzymes of the cholesterol and fatty acid biosynthetic pathways. Here, we investigated the effects of three different statins on the steady-state mRNA levels of Mdr2 and of SREBP family members in cultured primary rat hepatocytes. In addition, the effects of statins and overexpression of nuclear SREBP-1a and SREBP-2 on Mdr2 promoter activity were studied in human HepG2 hepatoma cells. Simvastatin, lovastatin as well as atorvastatin equally induced Mdr2 and Srebp-2 mRNA levels in cultured hepatocytes, whereas the expression levels of Srebp-1a and –1c transcripts were reduced. The three statins induced (6 to 8-fold) the activity of a 1572 base pair Mdr2 promoter fragment of the Mdr2 promoter in HepG2 cells, as did nuclear SREBP-1a. Nuclear SREBP-2 did not stimulate promoter activity. This does not rule out involvement of Srebp-2 in Mdr2 induction but rather indicate that other transcription factors must play a role. Mutations introduced into a 10 bp G+C-rich region, previously identified as potential sterol regulatory element, resulted in dramatically decreased basal activity of the Mdr2 promoter, but did not abolish the response to nuclear SREBP-1a. We conclude that statins increase steady-state Mdr2 mRNA levels in rat hepatocytes as a result of enhanced gene transcription. SREBP-1a, but not SREBP-2, stimulates transcription of the Mdr2 gene in HepG2 cells.