Insulin resistance and cardiovascular disease
Insulin resistance and cardiovascular disease
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DOI：
10.1172/jci10762
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发表时间：
2000-08-01
影响因子：
15.9
通讯作者：
Ginsberg, HN
中科院分区：
文献类型：
--
作者：
Ginsberg, HN
454临床研究杂志|八月2000|容积106|脂肪细胞的4号摄取和储存，如脂肪敏感脂肪酶（HSL）（9）、脂蛋白脂肪酶（LPL）（10）和补体成分C3 a（其蛋白水解产物是酰化刺激蛋白[ASP][参考文献11]）以及各种脂肪酸转运蛋白和结合蛋白。尽管一些研究者认为HSL、LPL和ASP与胰岛素抵抗/肥胖综合征或混合型高脂血症（有些人认为这也是胰岛素抵抗的结果）之间存在联系，但还没有确凿的证据将这些重要的蛋白质与胰岛素抵抗综合征联系起来。事实上，对ASP基因缺失的小鼠的单独研究导致了关于其在脂质代谢中的作用的矛盾结果（11，12）。另一方面，最近从携带脂肪酸转运蛋白CD 36基因无效突变的小鼠获得的数据非常揭示了脂肪细胞不能将脂肪酸储存为TG的后果。这些动物的血浆游离脂肪酸水平升高，并出现高胆固醇血症，表明肝脏对来自外周的能量通量增加的反应（13）。令人感兴趣的是，CD 36基因敲除的小鼠在脂肪和肌肉组织中都缺乏脂肪酸转运蛋白，因此没有胰岛素抵抗。事实上，他们似乎对胰岛素更敏感，可能是由于肌肉对脂肪酸的摄取减少。该模型中胰岛素抵抗和TG代谢的分离表明，血浆脂肪酸流入肝脏的增加在高甘油三酯血症的发生中起着直接和关键的作用。这一结论得到了在肌肉中过表达CD 36的转基因小鼠的研究的支持（14）：这些动物的脂肪酸和TG血浆水平均较低，但具有胰岛素抗性。在基因修饰的小鼠模型中的这些发现被观察到的自发性高血压大鼠（SHR）的品系具有似乎与胰岛素抵抗相关的CD 36突变所证实（15，16）。然而，最近的一份报告表明，胰岛素抵抗的原始SHR系在其CD 36基因中没有缺陷（17）。总之，胰岛素抵抗性脂肪细胞不能储存TG很可能是胰岛素抵抗性血脂异常发展的第一步。重要的是，在小鼠模型中，脂肪细胞和肝脏产生VLDL之间的这种联系似乎不一定与肌肉水平的胰岛素抵抗有关。没有候选基因与人类血脂异常或胰岛素抵抗明确相关。事实上，尽管CD 36基因似乎是一个重要的候选者，但来自CD 36敲除小鼠的数据向我表明，任何CD 36缺陷都必须是脂肪组织特异性的，才能引起高脂血症和胰岛素抵抗。
454 The Journal of Clinical Investigation| August 2000| Volume 106| Number 4 uptake and storage by adipocytes, such as those for hormone-sensitive lipase (HSL)(9), lipoprotein lipase (LPL)(10), and complement component C3a (whose proteolytic product is the acylation-stimulating protein [ASP][ref. 11]), as well as for various fatty acid transporters and binding proteins. Although some investigators have suggested links between HSL, LPL, and ASP, and either the insulin resistance/obesity syndrome or combined hyperlipidemia (which some believe is also the result of insulin resistance), no firm evidence yet exists linking these important proteins to the insulin resistance syndrome. Indeed, separate studies of a mouse in which the gene for ASP was deleted have resulted in contradictory results regarding its role in lipid metabolism (11, 12). On the other hand, recent data from mice carrying null mutations in the gene for the fatty acid transporter CD36 are quite revealing as to the consequences of the inability of fat cells to store fatty acids as TG. These animals had increased levels of plasma FFAs and hypertriglyceridemia, indicative of the response of the liver to an increased flux of energy from the periphery (13). Of interest, CD36 knock-out mice, which lack the fatty acid transporter in both adipose and muscle tissue, are not insulin-resistant. Indeed, they seem to be more insulin-sensitive, possibly as a result of diminished uptake of fatty acids by muscle. The dissociation of insulin resistance and TG metabolism in this model suggests a direct and critical role of increased plasma fatty acid flux to the liver in the genesis of hypertriglyceridemia. This conclusion is supported by work with transgenic mice overexpressing CD36 in muscle (14): these animals have low plasma levels of both fatty acids and TG but are insulin-resistant. These findings in gene-modified mouse models were paralleled by the observation that a strain of the spontaneously hypertensive rat (SHR) had mutations in CD36 that appeared to be associated with insulin resistance (15, 16). However, a very recent report indicated that the original SHR line, which is insulin-resistant, has no defects in its CD36 gene (17). Further developments in this area of investigation are eagerly awaited.In summary, the inability of insulin-resistant fat cells to store TG is very likely the initial step in the development of the dyslipidemia characteristic of insulin resistance. Importantly, this link between the fat cell and hepatic production of VLDL does not seem to be necessarily linked, in mouse models, to insulin resistance at the level of muscle. No candidate genes have been linked unequivocally to either the dyslipidemia or the insulin resistance in humans. Indeed, although the CD36 gene appears to be an important candidate, the data from the CD36 knock-out mice indicate to me that any CD36 defect would have to be specific to adipose tissue to cause both hypertriglyceridemia and insulin resistance.