Contribution of Accelerated Degradation to Feedback Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Cholesterol Metabolism in the Liver
Contribution of Accelerated Degradation to Feedback Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Cholesterol Metabolism in the Liver
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DOI：
10.1074/jbc.m116.728469
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发表时间：
2016-06-24
影响因子：
4.8
通讯作者：
DeBose-Boyd, Russell A.
中科院分区：
文献类型：
--
作者：
Hwang, Seonghwan;Hartman, Isamu Z.;DeBose-Boyd, Russell A.
固醇在内质网膜中的积累刺激3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）的泛素化，其催化胆固醇合成中的限速步骤。这种泛素化标志着HMGCR的蛋白酶体介导的降解，并构成了胆固醇合成的反馈控制的几种机制之一。通过对培养的哺乳动物细胞的研究，已经阐明了甾醇加速HMGCR泛素化和降解的机制。然而，这些反应在多大程度上调节HMGCR并有助于控制整个动物的胆固醇代谢尚不清楚。在这里，我们研究了转基因小鼠在肝脏中表达的HMGCR（HMGCR（TM 1 -8）），一个区域的必要和足够的甾醇加速降解的膜结构域，和基因敲入小鼠内源性HMGCR窝藏突变，防止甾醇诱导的泛素化。转基因小鼠的表征显示，在喂食高胆固醇饮食或补充有HMGCR抑制剂洛伐他汀的普通饲料的小鼠的肝脏中，HMGCR（TM 1 -8）被适当地调节。泛素化抗性HMGCR蛋白在肝脏和其他组织中的积累与其mRNA不成比例，表明甾醇加速降解显著有助于体内HMGCR的反馈调节。这些研究的结果表明，HMGCR在肝脏中通过与培养细胞中建立的机制相似的机制进行甾醇加速降解。此外，这些研究将HMGCR的甾醇加速降解指定为预防动脉粥样硬化和相关心血管疾病的潜在治疗靶点。
Accumulation of sterols in endoplasmic reticulum membranes stimulates the ubiquitination of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which catalyzes a rate-limiting step in synthesis of cholesterol. This ubiquitination marks HMGCR for proteasome-mediated degradation and constitutes one of several mechanisms for feedback control of cholesterol synthesis. Mechanisms for sterol-accelerated ubiquitination and degradation of HMGCR have been elucidated through the study of cultured mammalian cells. However, the extent to which these reactions modulate HMGCR and contribute to control of cholesterol metabolism in whole animals is unknown. Here, we examine transgenic mice expressing in the liver the membrane domain of HMGCR (HMGCR (TM1-8)), a region necessary and sufficient for sterol-accelerated degradation, and knock-in mice in which endogenous HMGCR harbors mutations that prevent sterol-induced ubiquitination. Characterization of transgenic mice revealed that HMGCR (TM1-8) is appropriately regulated in the liver of mice fed a high cholesterol diet or chow diet supplemented with the HMGCR inhibitor lovastatin. Ubiquitination-resistant HMGCR protein accumulates in the liver and other tissues disproportionately to its mRNA, indicating that sterol-accelerated degradation significantly contributes to feedback regulation of HMGCR in vivo. Results of these studies demonstrate that HMGCR is subjected to sterol-accelerated degradation in the liver through mechanisms similar to those established in cultured cells. Moreover, these studies designate sterol-accelerated degradation of HMGCR as a potential therapeutic target for prevention of atherosclerosis and associated cardiovascular disease.