Selective hepatic insulin resistance in a murine model heterozygous for a mitochondrial trifunctional protein defect.
Selective hepatic insulin resistance in a murine model heterozygous for a mitochondrial trifunctional protein defect.
复制标题
DOI：
10.1002/hep.26285
复制
发表时间：
2013-06
期刊：
影响因子：
13.5
通讯作者：
Ibdah, Jamal A.
中科院分区：
文献类型：
--
作者：
Rector, R. Scott;Morris, E. Matthew;Ridenhour, Suzanne;Meers, Grace M.;Hsu, Fong-Fu;Turk, John;Ibdah, Jamal A.
早期的报告表明线粒体功能障碍与肝脏胰岛素抵抗的发生有关。在这里，我们使用了线粒体三功能蛋白(MTP)基因缺陷的小鼠模型杂合子(HET)来确定线粒体长链脂肪酸氧化的主要缺陷是否扰乱了肝脏的胰岛素作用。为评估全身和肝脏的胰岛素抵抗/信号，进行了高胰岛素-正常血糖钳夹和信号研究。此外，利用从HET和野生型(WT)小鼠分离的原代肝细胞，在体外评估了肝脏脂肪酸氧化和肝脏胰岛素的作用。在肝脏线粒体和分离的原代肝细胞中，MTP的杂合性导致线粒体脂肪酸氧化减少~50%，显著损害了胰岛素钳夹期间的葡萄糖处置，并显著降低了胰岛素刺激的肝脏葡萄糖生成的抑制。HET小鼠也表现出胰岛素信号转导受损，肝组织和分离的原代肝细胞中IRS2的磷酸化增加(Ser731)，Akt的磷酸化减少(Ser473)。对胰岛素刺激的FOXO1/磷酸化FOXO1蛋白含量和PEPCK/G6Pase mRNA表达的评估没有发现HET和WT小鼠之间的差异。然而，胰岛素诱导的GSK3β的磷酸化在热休克小鼠中被显著钝化。肝脏胰岛素抵抗与蛋白磷酸酶2A催化亚单位(PP2A-C)甲基化状态增加有关，但与肝脏DAG含量、活化的PKC-ε、IKK-β、JNK或磷酸化JNK蛋白含量的差异无关。令人惊讶的是，与WT相比，HET组小鼠的肝脏神经酰胺显著降低。我们的数据表明，线粒体脂肪酸β氧化的主要缺陷导致肝脏胰岛素抵抗，选择性地与肝糖原代谢有关，这与甲基化PP2A-C相关，但独立于通常被认为导致胰岛素抵抗的其他机制。
Earlier reports suggest a link between mitochondrial dysfunction and development of hepatic insulin resistance. Here we used a murine model heterozygous (HET) for a mitochondrial trifunctional protein (MTP) gene defect to determine if a primary defect in mitochondrial long-chain fatty acid oxidation disrupts hepatic insulin action. Hyperinsulinemic-euglycemic clamps and signaling studies were performed for assessment of whole-body and hepatic insulin resistance/signaling. In addition, hepatic fatty acid oxidation and hepatic insulin action were assessed in vitro utilizing primary hepatocytes isolated from HET and wild-type (WT) mice. In both hepatic mitochondria and isolated primary hepatocytes, heterozygosity of MTP caused a ~50% reduction in mitochondrial fatty acid oxidation, a significantly impaired glucose disposal during the insulin clamp, and a markedly lower insulin-stimulated suppression of hepatic glucose production. HET mice also exhibited impaired insulin signaling, with increased hepatic phosphorylation of IRS2 (ser731) and reduced Akt phosphorylation (ser473) in both hepatic tissue and isolated primary hepatocytes. Assessment of insulin-stimulated FOXO1/phospho-FOXO1 protein content and PEPCK/G6Pase mRNA expression did not reveal differences between HET and WT mice. However, insulin-induced phosphorylation of GSK3β was significantly blunted in HET mice. Hepatic insulin resistance was associated with an increased methylation status of the catalytic subunit of protein phosphatase 2A (PP2A-C), but was not associated with differences in hepatic DAG content, activated PKC-ε, IKK-β, JNK, or phospho-JNK protein contents. Surprisingly, hepatic ceramides were significantly lower in the HET mice compared with WT. Our data document that a primary defect in mitochondrial fatty acid β-oxidation causes hepatic insulin resistance selective to hepatic glycogen metabolism that is associated with elevated methylated PP2A-C, but independent of other mechanisms commonly considered to be responsible for insulin resistance.
登录
查看更多内容
影响因子：
29
作者：
Farese RV Jr;Zechner R;Newgard CB;Walther TC
通讯作者：
Walther TC
DOI：
10.1152/ajpendo.2000.278.3.e553
发表时间：
2000-03-01
影响因子：
5.1
作者：
Cortright, RN;Azevedo, JL;Dohm, GL
通讯作者：
Dohm, GL
影响因子：
7.7
作者：
Boden, G;She, PX;Ruderman, N
通讯作者：
Ruderman, N
影响因子：
3.7
作者：
Galbo T;Olsen GS;Quistorff B;Nishimura E
通讯作者：
Nishimura E
影响因子：
15.9
作者：
Ibdah, JA;Paul, H;Strauss, AW
通讯作者：
Strauss, AW