Biddinger Sudha B, Hernandez-Ono Antonio, Rask-Madsen Christian, Haas Joel T, Alemán José O, Suzuki Ryo, Scapa Erez F, Agarwal Chhavi, Carey Martin C, Stephanopoulos Gregory, Cohen David E, King George L, Ginsberg Henry N, Kahn C Ronald
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Cell Metab. 2008 Feb;7(2):125-34. doi: 10.1016/j.cmet.2007.11.013.
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.
胰岛素抵抗在代谢综合征的发生发展中起核心作用，但它与心血管疾病的关系仍存在争议。肝脏胰岛素受体敲除（LIRKO）小鼠具有单纯的肝脏胰岛素抵抗。在标准普通饮食下，LIRKO小鼠具有致动脉粥样硬化的脂蛋白谱，高密度脂蛋白（HDL）胆固醇降低，极低密度脂蛋白（VLDL）颗粒显著富含胆固醇。这是由于含载脂蛋白B的脂蛋白分泌增加和清除减少，以及由于促进VLDL分泌的Pgc-1β（Ppargc-1b）表达增加导致甘油三酯分泌减少，同时Srebp-1c（Srebf1）、Srebp-2（Srebf2）及其靶标、生脂酶和低密度脂蛋白受体的表达降低。在致动脉粥样硬化饮食的12周内，LIRKO小鼠出现明显的高胆固醇血症，100%的LIRKO小鼠发生严重动脉粥样硬化，而对照组为0%。因此，肝脏水平的胰岛素抵抗足以产生与代谢综合征相关的血脂异常和动脉粥样硬化风险增加。
