Cholesterol synthesis inhibition elicits an integrated molecular response in human livers including decreased ACAT2.
Cholesterol synthesis inhibition elicits an integrated molecular response in human livers including decreased ACAT2.
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胆固醇合成抑制会引起人类肝脏中的综合分子反应，包括 ACAT2 减少。
DOI：
10.1161/atvbaha.107.157172
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Eriksson,Mats
中科院分区：
文献类型：
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作者：
Parini,Paolo;Gustafsson,Ulf;Davis,MattA;Larsson,Lilian;Einarsson,Curt;Wilson,Martha;Rudling,Mats;Tomoda,Hiroshi;Omura,Satoshi;Sahlin,Staffan;Angelin,Bo;Rudel,LawrenceL;Eriksson,Mats
目的——本研究的目的是确定不同程度的胆固醇合成抑制如何影响人类肝脏胆固醇代谢。方法和结果——对 37 名胆固醇正常的胆结石患者随机接受安慰剂、20 毫克/天氟伐他汀或 80 毫克/天阿托伐他汀治疗，为期 4 周。根据血清 Lathosterol 测定结果，接受他汀类药物治疗的 2 组胆固醇合成分别减少了 42% 和 70%。 VLDL 胆固醇降低了 20% 和 55%。在胆结石手术期间，进行了肝活检，并测定了胆固醇代谢限速步骤的肝蛋白和 mRNA 表达，并与血清脂蛋白相关。 LDL 受体和 3-羟基-3-甲基戊二酰 (HMG) 辅酶 A (CoA) 还原酶的显着诱导与胆固醇合成抑制 (ChSI) 的程度呈正相关。在 ChSI 期间，ACAT2 的活性、蛋白质和 mRNA 均降低，apoE mRNA 也是如此。高 ChSI 导致的 HDL 胆固醇降低不能用 HDL 受体 CLA-1、ABCA1 或 apoA-I 表达的改变来解释。结论——他汀类药物治疗可降低人肝脏中的 ACAT2 活性，这种效应与 Apo E 表达减少相结合，除了在他汀类药物治疗期间降低 LDL 外，还可能有助于有利地降低 VLDL 胆固醇。
Objective—The purpose of this study was to identify how different degrees of cholesterol synthesis inhibition affect human hepatic cholesterol metabolism.Methods and Results—Thirty-seven normocholesterolemic gallstone patients randomized to treatment with placebo, 20 mg/d fluvastatin, or 80 mg/d atorvastatin for 4 weeks were studied. Based on serum lathosterol determinations, cholesterol synthesis was reduced by 42% and 70% in the 2 groups receiving statins. VLDL cholesterol was reduced by 20% and 55%. During gallstone surgery, a liver biopsy was obtained and hepatic protein and mRNA expression of rate-limiting steps in cholesterol metabolism were assayed and related to serum lipoproteins. A marked induction of LDL receptors and 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase was positively related to the degree of cholesterol synthesis inhibition (ChSI). The activity, protein, and mRNA for ACAT2 were all reduced during ChSI, as was apoE mRNA. The lowering of HDL cholesterol in response to high ChSI could not be explained by altered expression of the HDL receptor CLA-1, ABCA1, or apoA-I.Conclusions—Statin treatment reduces ACAT2 activity in human liver and this effect, in combination with a reduced Apo E expression, may contribute to the favorable lowering of VLDL cholesterol seen in addition to the LDL lowering during statin treatment.