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.
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RSV promotes degradation of ASBT in vitro.
“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).”
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- Authors
- Chothe, P. P., & Swaan, P. W.
- Affiliations
- University of Maryland, Baltimore (US)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2014-03-28
- Volume
- 459
- Issue
- 2
- Pages
- 301-312
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2107561401
- Cited by
- 29
- References
- 45
- Citations by year
- 2023: 3 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 5 · 2018: 2 · 2017: 2 · 2016: 5 · 2014: 1
- FWCI
- 1.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 56631, R01DK056631)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- resveratrol, ASBT, SLC10A2, bile acid transporters, protein degradation, ubiquitin-proteasome system, cholesterol homeostasis, cholesterol-lowering effect, proteasome inhibitors, HDL cholesterol
- MeSH terms
- Resveratrol, Animals, Cell Line, Gene Expression Regulation, Humans, Phosphorylation, Stilbenes, Protein Transport, Symporters, Organic Anion Transporters, Sodium-Dependent, Sirtuin 1, Proteolysis
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