Mordier Sylvie, Iynedjian Patrick B
Department of Cell Physiology and Metabolism, University of Geneva School of Medicine, CMU, 1 Rue Michel-Servet, CH-1211 Geneva 4, Switzerland.
Department of Cell Physiology and Metabolism, University of Geneva School of Medicine, CMU, 1 Rue Michel-Servet, CH-1211 Geneva 4, Switzerland.
Biochem Biophys Res Commun. 2007 Oct 12;362(1):206-211. doi: 10.1016/j.bbrc.2007.08.004. Epub 2007 Aug 9.
Excessive supply of fatty acids to the liver might be a contributing factor to hepatic insulin resistance associated with obesity and type 2 diabetes mellitus. The aim of this study was to investigate direct effects of palmitate on insulin signaling in hepatocytes. The ability of metformin to reverse changes induced by palmitate was also studied. Rat hepatocytes in primary culture exhibited a rightward shift of the insulin dose-response curve for PKB phosphorylation during culture with palmitate. The insulin-stimulated phosphorylation of GSK-3beta, a metabolic substrate of PKB, was diminished in palmitate hepatocytes. By contrast, the mTOR protein kinase was overstimulated in cells incubated with palmitate. Hepatocytes cultured with palmitate displayed hyperphosphorylation of IRS-1 at Ser residues 632/635, known to be phosphorylated by mTOR. Metformin treatment of the hepatocytes resulted in activation of the AMP-activated kinase, attenuation of the mTOR/S6K1 pathway, reduction of IRS-1 phosphorylation, and a leftward shift in the insulin dose-response curve for PKB activation. These data suggest a link between an oversupply of fatty acid to hepatocytes, a disproportionate stimulation of mTOR/S6K1, and resistance to insulin.
肝脏中脂肪酸供应过多可能是肥胖和2型糖尿病相关的肝脏胰岛素抵抗的一个促成因素。本研究的目的是调查棕榈酸酯对肝细胞胰岛素信号传导的直接影响。还研究了二甲双胍逆转棕榈酸酯诱导变化的能力。原代培养的大鼠肝细胞在与棕榈酸酯共培养期间，PKB磷酸化的胰岛素剂量反应曲线向右移动。胰岛素刺激的PKB代谢底物GSK-3β的磷酸化在棕榈酸酯处理的肝细胞中减少。相比之下，在与棕榈酸酯孵育的细胞中mTOR蛋白激酶受到过度刺激。用棕榈酸酯培养的肝细胞在已知由mTOR磷酸化的Ser632/635残基处显示IRS-1的过度磷酸化。用二甲双胍处理肝细胞导致AMP激活的激酶活化、mTOR/S6K1途径减弱、IRS-1磷酸化减少以及PKB激活的胰岛素剂量反应曲线向左移动。这些数据表明肝细胞脂肪酸供应过多、mTOR/S6K1的过度刺激与胰岛素抵抗之间存在联系。
