Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis
Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis
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DOI：
10.1016/j.cmet.2007.11.013
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发表时间：
2008-02-01
期刊：
影响因子：
29
通讯作者：
Kahn, C. Ronald
中科院分区：
文献类型：
--
作者：
Biddinger, Sudha B.;Hernandez-Ono, Antonio;Kahn, C. Ronald
胰岛素抵抗在代谢综合征的发展中起着核心作用，但它与心血管疾病的关系仍然存在争议。肝脏胰岛素受体敲除（LIRKO）小鼠具有纯肝脏胰岛素抵抗。在标准食物饮食中，LIRKO小鼠具有促动脉粥样硬化脂蛋白谱，具有降低的高密度脂蛋白（HDL）胆固醇和显著富含胆固醇的极低密度脂蛋白（VLDL）颗粒。这是由于含载脂蛋白B的脂蛋白的分泌增加和清除减少，再加上继发于Pgc-1 β（Ppargc-1b）表达增加的甘油三酯分泌减少，Pgc-1 β（Ppargc-1b）促进VLDL分泌，但Srebp-1c（Srebf 1）、Srebp-2（Srebf 2）及其靶点、脂肪生成酶和LDL受体的表达减少。在致动脉粥样硬化饮食的12周内，LIRKO小鼠显示出明显的高胆固醇血症，并且100%的LIRKO小鼠，但对照组的0%，发展为严重的动脉粥样硬化。因此，肝脏水平的胰岛素抵抗足以产生血脂异常和与代谢综合征相关的动脉粥样硬化风险增加。
Insulin resistance plays a central role in the development of the metabolic syndrome, but how it relates to cardiovascular disease remains controversial. Liver insulin receptor knockout (LIRKO) mice have pure hepatic insulin resistance. On a standard chow diet, LIRKO mice have a proatherogenic lipoprotein profile with reduced high-density lipoprotein (HDL) cholesterol and very low-density lipoprotein (VLDL) particles that are markedly enriched in cholesterol. This is due to increased secretion and decreased clearance of apolipoprotein B-containing lipoproteins, coupled with decreased triglyceride secretion secondary to increased expression of Pgc-1 beta (Ppargc-1b), which promotes VLDL secretion, but decreased expression of Srebp-1c (Srebf1), Srebp-2 (Srebf2), and their targets, the lipogenic enzymes and the LDL receptor. Within 12 weeks on an atherogenic diet, LIRKO mice show marked hypercholesterolemia, and 100% of LIRKO mice, but 0% of controls, develop severe atherosclerosis. Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome.