7-Dehydrocholesterol (7-DHC), But Not Cholesterol, Causes Suppression of Canonical TGF-β Signaling and Is Likely Involved in the Development of Atherosclerotic Cardiovascular Disease (ASCVD).
7-Dehydrocholesterol (7-DHC), But Not Cholesterol, Causes Suppression of Canonical TGF-β Signaling and Is Likely Involved in the Development of Atherosclerotic Cardiovascular Disease (ASCVD).
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DOI：
10.1002/jcb.25797
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发表时间：
2017-06
影响因子：
4
通讯作者：
Huang JS
中科院分区：
文献类型：
--
作者：
Huang SS;Liu IH;Chen CL;Chang JM;Johnson FE;Huang JS
几十年来，胆固醇一直被认为是导致ASCVD的原因。建议限制饮食中胆固醇的摄入量以降低疾病的风险。然而，最近的几项流行病学研究并不支持饮食胆固醇和/或血液胆固醇与ASCVD之间的关系。因此，胆固醇在动脉粥样硬化形成中的作用现在还不确定。许多证据表明，TGF-β（一种抗炎细胞因子）可预防ASCVD，并且经典TGF-β信号传导（Smad 2依赖性）的抑制参与动脉粥样硬化形成。我们假设胆固醇通过抑制血管内皮中典型的TGF-β信号传导而导致ASCVD。为了验证这一假设，我们确定了胆固醇、7-脱氢胆固醇（7-DHC;胆固醇的生物合成前体）和其他固醇对典型TGF-β信号传导的影响。我们使用稳定表达Smad 2依赖性荧光素酶报告基因的Mv 1 Lu细胞（用于研究TGF-β活性的模型细胞系统）。我们证明7-DHC（而不是胆固醇或其他固醇）有效地抑制TGF-β刺激的荧光素酶活性。我们还证明，7-DHC通过促进脂筏/小窝形成并随后将细胞表面TGF-β受体从非脂筏微结构域募集到脂筏/小窝来抑制TGF-β刺激的荧光素酶活性，其中TGF-β受体在转导经典信号传导中变得无活性并在TGF-β结合后经历快速降解。我们通过细胞表面125 I-TGF-β-交联和蔗糖密度梯度超离心来确定这一点。我们进一步证明，甲基-β-环糊精（MβCD），甾醇螯合剂，逆转7-DHC诱导的抑制TGF-β刺激的荧光素酶活性的挤出7-DHC从居民脂筏/小窝。这些结果表明，7-DHC，而不是胆固醇，促进脂筏/小窝形成，导致典型的TGF-β信号转导和动脉粥样硬化的抑制。J.细胞。118：1387-1400，2017.© 2016 Wiley Periodicals，Inc.
For several decades, cholesterol has been thought to cause ASCVD. Limiting dietary cholesterol intake has been recommended to reduce the risk of the disease. However, several recent epidemiological studies do not support a relationship between dietary cholesterol and/or blood cholesterol and ASCVD. Consequently, the role of cholesterol in atherogenesis is now uncertain. Much evidence indicates that TGF-β, an anti-inflammatory cytokine, protects against ASCVD and that suppression of canonical TGF-β signaling (Smad2-dependent) is involved in atherogenesis. We had hypothesized that cholesterol causes ASCVD by suppressing canonical TGF-β signaling in vascular endothelium. To test this hypothesis, we determine the effects of cholesterol, 7-dehydrocholesterol (7-DHC; the biosynthetic precursor of cholesterol), and other sterols on canonical TGF-β signaling. We use Mv1Lu cells (a model cell system for studying TGF-β activity) stably expressing the Smad2-dependent luciferase reporter gene. We demonstrate that 7-DHC (but not cholesterol or other sterols) effectively suppresses the TGF-β-stimulated luciferase activity. We also demonstrate that 7-DHC suppresses TGF-β-stimulated luciferase activity by promoting lipid raft/caveolae formation and subsequently recruiting cell-surface TGF-β receptors from non-lipid raft microdomains to lipid rafts/caveolae where TGF-β receptors become inactive in transducing canonical signaling and undergo rapid degradation upon TGF-β binding. We determine this by cell-surface 125I-TGF-β-cross-linking and sucrose density gradient ultracentrifugation. We further demonstrate that methyl-β-cyclodextrin (MβCD), a sterol-chelating agent, reverses 7-DHC-induced suppression of TGF-β-stimulated luciferase activity by extrusion of 7-DHC from resident lipid rafts/caveolae. These results suggest that 7-DHC, but not cholesterol, promotes lipid raft/caveolae formation, leading to suppression of canonical TGF-β signaling and atherogenesis. J. Cell. Biochem. 118: 1387–1400, 2017. © 2016 Wiley Periodicals, Inc.
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