Resveratrol promotes degradation of the human bile acid transporter ASBT (SLC10A2).
The sodium/bile acid co-transporter ASBT [apical sodium-dependent bile acid transporter; SLC10A2 (solute carrier family 10 member 2)] plays a key role in the enterohepatic recycling of the bile acids and indirectly contributes to cholesterol homoeostasis. ASBT inhibitors reportedly lower plasma triglyceride levels and increase HDL (high-density lipoprotein) cholesterol levels. RSV (resveratrol), a major constituent of red wine, is known to lower LDL (low-density lipoprotein) cholesterol levels, but its mechanism of action is still unclear. In the present study, we investigated the possible involvement of ASBT in RSV-mediated cholesterol-lowering effects. We demonstrate that RSV inhibits ASBT protein expression and function via a SIRT1 (sirtuin 1)-independent mechanism. The effect was specific to ASBT since other transporters involved in cholesterol homoeostasis, NTCP (SLC10A1), OSTα (SLC51A) and ABCG1 (ATP-binding cassette G1), remained unaffected. ASBT inhibition by RSV was reversed by proteasome inhibitors (MG-132 and lactacystin) and the ubiquitin inhibitor LDN57444, suggesting involvement of the ubiquitin-proteasome pathway. Immunoprecipitation revealed high levels of ubiquitinated ASBT after RSV treatment. Phosphorylation at Ser335 and Thr339 was shown previously to play a role in proteosomal degradation of rat ASBT. However, mutation at corresponding residues in rat ASBT revealed that phosphorylation does not contribute to RSV-mediated degradation of ASBT. Combined, our data indicate that RSV promotes ASBT degradation via the ubiquitin-proteasome pathway without requiring phosphorylation. We conclude that regulation of ASBT expression by RSV may have clinical relevance with regard to the observed cholesterol-lowering effects of RSV.
*Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201, U.S.A.
Paresh P
PP
Chothe
*Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201, U.S.A.
Peter W
PW
Swaan
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D027981:Symporters / Q000235:genetics / Q000378:metabolism*
D029363:Organic Anion Transporters, Sodium-Dependent; D013267:Stilbenes; D027981:Symporters; C071908:sodium-bile acid cotransporter; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol