Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance
Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance
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DOI：
10.1074/jbc.m611550200
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发表时间：
2007-05-18
影响因子：
4.8
通讯作者：
Coleman, Rosalind A.
中科院分区：
文献类型：
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作者：
Nagle, Cynthia A.;An, Jie;Coleman, Rosalind A.
脂肪肝通常与胰岛素抵抗和2型糖尿病相关，但目前尚不清楚在没有遗传或饮食诱导的肥胖的情况下，三酰甘油积累或三酰甘油合成途径中脂质中间体的过量流量是否足以引起胰岛素抵抗。为了确定增加的甘油脂流量本身是否会引起肝脏胰岛素抵抗，我们使用腺病毒构建体过表达甘油-sn-3-磷酸酰基转移酶-1（Ad-GPAT 1），这是从头合成三酰甘油的关键步骤。5-7天后，Ad-GPAT 1和Ad-增强绿色荧光蛋白对照组大鼠的摄食量、体重和脂肪垫重量没有差异，但饲料喂养的Ad-GPAT 1大鼠出现脂肪肝、高脂血症和胰岛素抵抗。肝脏是胰岛素抵抗的主要部位; Ad-GPAT 1大鼠在高胰岛素-正葡萄糖钳夹期间的肝葡萄糖输出比对照组高2.5倍。Ad-GPAT 1大鼠肝脏甘油二酯和溶血磷脂酸升高，提示这些脂质代谢产物在肝脏胰岛素抵抗的发展中起作用，肝脏蛋白激酶C是被激活的一个元件，为胰岛素抵抗提供了潜在的机制。Ad-GPAT 1治疗的大鼠肝脏NF-κ B活性降低50%，肿瘤坏死因子-α和白细胞介素-β的表达无差异，这与肝脏炎症不增加时的肝脏胰岛素抵抗一致。骨骼肌糖原合成和2-脱氧葡萄糖摄取减少，提示轻度外周胰岛素抵抗与骨骼肌三酰甘油含量较高有关。这些结果表明，通过肝脏从头三酰甘油合成途径的流量增加，可导致肝脏和全身胰岛素抵抗，在没有肥胖或脂肪生成饮食。
Fatty liver is commonly associated with insulin resistance and type 2 diabetes, but it is unclear whether triacylglycerol accumulation or an excess flux of lipid intermediates in the pathway of triacyglycerol synthesis are sufficient to cause insulin resistance in the absence of genetic or diet-induced obesity. To determine whether increased glycerolipid flux can, by itself, cause hepatic insulin resistance, we used an adenoviral construct to overexpress glycerol-sn-3-phosphate acyltransferase-1 (Ad-GPAT1), the committed step in de novo triacylglycerol synthesis. After 5-7 days, food intake, body weight, and fat pad weight did not differ between Ad-GPAT1 and Ad-enhanced green fluorescent protein control rats, but the chow-fed Ad-GPAT1 rats developed fatty liver, hyperlipidemia, and insulin resistance. Liver was the predominant site of insulin resistance; Ad-GPAT1 rats had 2.5-fold higher hepatic glucose output than controls during a hyperinsulinemic-euglycemic clamp. Hepatic diacylglycerol and lysophosphatidate were elevated in Ad-GPAT1 rats, suggesting a role for these lipid metabolites in the development of hepatic insulin resistance, and hepatic protein kinase C is an element of was activated, providing a potential mechanism for insulin resistance. Ad-GPAT1-treated rats had 50% lower hepatic NF-kappa B activity and no difference in expression of tumor necrosis factor-alpha and interleukin-beta, consistent with hepatic insulin resistance in the absence of increased hepatic inflammation. Glycogen synthesis and uptake of 2-deoxyglucose were reduced in skeletal muscle, suggesting mild peripheral insulin resistance associated with a higher content of skeletal muscle triacylglycerol. These results indicate that increased flux through the pathway of hepatic de novo triacylglycerol synthesis can cause hepatic and systemic insulin resistance in the absence of obesity or a lipogenic diet.