Resveratrol promotes degradation of the human bile acid transporter ASBT (SLC10A2)

Abstract

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.

Resveratrol Attenuates Trimethylamine- N -Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota

“…Recently, it was found that ASBT plays a key role in the enterohepatic recycling of BAs and indirectly contributes to cholesterol homoeostasis ( 26 ). RSV promotes the degradation of ASBT in vitro , which might have some clinical relevance with regard to the observed cholesterol-lowering effects of RSV ( 44 ). We found that RSV reduced ileal BA levels, with no effect on ASBT expression.…”

Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans

“…Although its function is best understood in the small intestine [45], SLC10A2 also is expressed in brain [46]. Resveratrol, a chief constituent of red wine, inhibits SLC10A2 expression and function through a Sirt1 (sirtuin 1)–independent manner [47]. Potentially an exciting therapy for LOAD, resveratrol reduces amyloid plaque pathology in AD animal models [48] and has been shown to be safe and well-tolerated in a large phase 2 LOAD clinical trial [49].…”

Sirtuin 1 activation alleviates cholestatic liver injury in a cholic acid–fed mouse model of cholestasis

“…Lack of intestinal Sirt1 down‐regulates dimerization cofactor of HNF1α, pterin 4α carbinolamine dehydratase 2/dimerization cofactor of HNF1α 2 (DCoH2)‐Hnf1α‐Fxr signaling and decreases hepatic BA levels as well as ileal BA metabolic genes, such as organic solute transporter α (Ostα), apical sodium dependent bile acid transporter (Asbt), and ileal bile acid binding protein . However, Sirt1 activator resveratrol degrades Asbt expression in vitro . Sirt1 increases hepatic Fxr messenger RNA (mRNA) expression, thus increasing Pgc1α/Hnf1α binding to the FXR promoter .…”

“…(15) However, Sirt1 activator resveratrol degrades Asbt expression in vitro. (16) Sirt1 increases hepatic Fxr messenger RNA (mRNA) expression, thus increasing Pgc1a/ Hnf1a binding to the FXR promoter. (3) Sirt1 increases hepatic Fxr/Rxr heterodimerization at FXRE by deacetylating Fxr, primarily at Lys-217, and activates Shp and bile salt export pump (Bsep) mRNA expression.…”