Abstract
The human multidrug resistance gene MDR3 encodes a P-glycoprotein that belongs to the ATP-binding cassette transporter family (ABCB4). MDR3 is a critical trans-locator for phospholipids across canalicular membranes of hepatocytes, evidenced by the fact that human MDR3 deficiencies result in progressive familial intrahepatic cholestasis type III. It has been reported previously that MDR3 expression is modulated by hormones, cellular stress, and xenobiotics. Here we show that the MDR3 gene is trans-activated by the farnesoid X receptor (FXR) via a direct binding of FXR/retinoid X receptor alpha heterodimers to a highly conserved inverted repeat element (a FXR response element) at the distal promoter (-1970 to -1958). In FXR trans-activation assays, both the endogenous FXR agonist chenodeoxycholate and the synthetic agonist GW4064 activated the MDR3 promoter. Deletion or mutation of this inverted repeat element abolished FXR-mediated MDR3 promoter activation. Consistent with these data, MDR3 mRNA was significantly induced by both chenodeoxycholate and GW4064 in primary human hepatocytes in time- and dose-dependent fashions. In conclusion, we demonstrate that MDR3 expression is directly up-regulated by FXR. These results, together with the previous report that the bile salt export pump is a direct FXR target, suggest that FXR coordinately controls secretion of bile salts and phospholipids. Results of this study further support the notion that FXR is a master regulator of lipid metabolism.
Highlights
ATP-binding cassette (ABC)1 transporters constitute a large family of proteins, and many have been shown to be involved in lipid transport
Endogenous Expression of MDR3 Is Increased by farnesoid X receptor (FXR) Agonists in Primary Human Hepatocytes—To determine whether MDR3 expression is regulated by FXR, primary human hepatocytes were treated with the endogenous FXR agonist CDCA (60 M) and the synthetic FXR agonist GW4064 (5 M) for 3, 6, 12, 24, and 48 h, and the endogenous expression of MDR3 was determined by real time PCR (TaqMan)
Activated FXR suppresses the expression of Naϩ-dependent taurocholate-co-transporting polypeptide [24], a transporter that is located at the basal membrane for hepatic uptake of bile salts and organic anions
Summary
ATP-binding cassette (ABC) transporters constitute a large family of proteins, and many have been shown to be involved in lipid transport. We demonstrate that the bile acid receptor FXR directly regulates expression of MDR3. FXR is a nuclear receptor for bile acids and regulates expression of a number of genes in which products are critically important for bile acid and cholesterol homeostasis (8 –11). FXR functions as a heterodimer with the 9-cis-retinoic acid receptor (RXR␣) [12, 13], and the FXR/RXR␣ heterodimer activates gene transcription via binding to a specific DNA sequence comprised of two inverted hexamer repeats separated by one nucleotide (IR-1) in the target promoter. Previous studies [15, 16] have shown that agonist-bound FXR directly regulates expression of the bile salt export pump (BSEP), an ABC transporter (ABCB11) in which deficiencies cause progressive familial intrahepatic cholestasis (type II) [3]. We hypothesized that FXR might regulate expression of MDR3 to coordinately control secretion of bile acids and phospholipids
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