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

The sodium/bile acid cotransporter ASBT (SLC10A2) plays a key role in the enterohepatic recycling of the bile acids and indirectly contributes to cholesterol homeostasis. ASBT inhibitors reportedly lower plasma triglyceride levels and increase HDL cholesterol levels. Resveratrol (RSV), a major constituent of red wine, is known to lower LDL cholesterol levels, but its mechanism of action is still unclear. Here, we studied the possible involvement of ASBT in RSV-mediated cholesterol lowering effects. We demonstrate that RSV inhibits ASBT protein expression and function via a SIRT1-independent mechanism. The effect was specific to ASBT since other transporters involved in cholesterol homeostasis NTCP, OSTα and ABCG1 remained unaffected. ASBT inhibition by RSV was reversed by proteasome inhibitors (MG132 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 residues Ser335 and Thr339 was previously shown 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 ubiquitin-proteasome pathway without requiring phosphorylation. We conclude that regulation of ASBT expression by RSV may have clinical relevance with...
Source: BJ Cell - Category: Biochemistry Authors: Tags: BJ Metabolism Source Type: research