Resveratrol promotes degradation of the human bile acid transporter ASBT (SLC10A2)
Resveratrol promotes degradation of the human bile acid transporter ASBT (SLC10A2)
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DOI：
10.1042/bj20131428
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发表时间：
2014-04-15
影响因子：
4.1
通讯作者：
Swaan, Peter W.
中科院分区：
文献类型：
--
作者：
Chothe, Paresh P.;Swaan, Peter W.
钠/胆汁酸共转运体ASBT[钠依赖性胆汁酸转运体；SLC10A2（溶质载体家族10成员2）]在胆汁酸的肠肝循环中起关键作用，并间接促进胆固醇稳态。据报道，ASBT抑制剂可降低血浆甘油三酯水平并增加高密度脂蛋白胆固醇水平。RSV（白藜芦醇）是红酒的主要成分，已知可以降低低密度脂蛋白（低密度脂蛋白）胆固醇水平，但其作用机制尚不清楚。在本研究中，我们调查了ASBT可能参与rsv介导的降胆固醇作用。我们证明RSV通过SIRT1 （sirtuin 1）不依赖的机制抑制ASBT蛋白的表达和功能。由于其他参与胆固醇平衡的转运蛋白NTCP （SLC10A1）、OST α (SLC51A)和ABCG1 （atp结合盒G1）未受影响，因此这种影响仅针对ASBT。RSV对ASBT的抑制被蛋白酶体抑制剂（MG-132和lactacystin）和泛素抑制剂LDN57444逆转，提示泛素蛋白酶体途径参与其中。免疫沉淀显示RSV治疗后ASBT泛素化水平高。先前已证明Ser（335）和Thr（339）的磷酸化在大鼠ASBT的蛋白体降解中起作用。然而，大鼠ASBT中相应残基的突变表明，磷酸化并不参与rsv介导的ASBT降解。综上所述，我们的数据表明RSV通过泛素蛋白酶体途径促进ASBT降解，而不需要磷酸化。我们得出结论，RSV对ASBT表达的调节可能与观察到的RSV降胆固醇作用具有临床相关性。
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), OST alpha (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 Ser(335) and Thr(339) 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.