Free fatty acid-induced PP2A hyperactivity selectively impairs hepatic insulin action on glucose metabolism.
Free fatty acid-induced PP2A hyperactivity selectively impairs hepatic insulin action on glucose metabolism.
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DOI：
10.1371/journal.pone.0027424
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Nishimura E
中科院分区：
文献类型：
--
作者：
Galbo T;Olsen GS;Quistorff B;Nishimura E
在2型糖尿病（T2D）中，血浆中的游离脂肪酸（FFA）增加，并且肝胰岛素抵抗是“选择性的”，在胰岛素介导的葡萄糖产生的减少被钝化的意义上，同时维持胰岛素对刺激脂肪生成的作用。我们研究了这种致病悖论的分子机制。原代大鼠肝细胞暴露于棕榈酸酯20小时。为了建立体外研究结果的生理相关性，我们还研究了胰岛素抵抗的Zucker糖尿病脂肪（ZDF）大鼠。虽然胰岛素受体磷酸化不受影响，但在棕榈酸暴露的细胞中，Akt的激活和下游靶点糖原合成酶激酶3α（Gsk 3 α）和Forkhead box O1（FoxO1）的失活受到抑制。因此，胰岛素介导的FoxO1诱导的促胰岛素生成基因的抑制和从头葡萄糖产生的剂量反应曲线右移，胰岛素刺激的葡萄糖氧化和糖原合成受损。相反，与人T2D中的发现相似，胰岛素诱导甘油三酯（TG）蓄积和催化从头脂肪生成和TG组装的酶转录的能力不受影响。然而，这些基因的胰岛素诱导可以通过抑制非典型PKCs（aPKCs）来阻断。Akt失活蛋白磷酸酶2A（PP2A）的活性在胰岛素抵抗细胞中增加。此外，通过特异性抑制剂抑制PP2A可增加胰岛素刺激的Akt活化以及FoxO1和Gsk 3 α的磷酸化。最后，在胰岛素抵抗的ZDF大鼠中，肝脏、肌肉和脂肪组织中PP2A mRNA水平增加，而肝脏和肌肉组织中PP2A活性增加。总之，我们的研究结果表明，游离脂肪酸可能会导致一个选择性损害胰岛素的行动后，肝脏葡萄糖代谢的PP2A活性增加。
In type 2 Diabetes (T2D) free fatty acids (FFAs) in plasma are increased and hepatic insulin resistance is “selective”, in the sense that the insulin-mediated decrease of glucose production is blunted while insulin's effect on stimulating lipogenesis is maintained. We investigated the molecular mechanisms underlying this pathogenic paradox. Primary rat hepatocytes were exposed to palmitate for twenty hours. To establish the physiological relevance of the in vitro findings, we also studied insulin-resistant Zucker Diabetic Fatty (ZDF) rats. While insulin-receptor phosphorylation was unaffected, activation of Akt and inactivation of the downstream targets Glycogen synthase kinase 3α (Gsk3α and Forkhead box O1 (FoxO1) was inhibited in palmitate-exposed cells. Accordingly, dose-response curves for insulin-mediated suppression of the FoxO1-induced gluconeogenic genes and for de novo glucose production were right shifted, and insulin-stimulated glucose oxidation and glycogen synthesis were impaired. In contrast, similar to findings in human T2D, the ability of insulin to induce triglyceride (TG) accumulation and transcription of the enzymes that catalyze de novo lipogenesis and TG assembly was unaffected. Insulin-induction of these genes could, however, be blocked by inhibition of the atypical PKCs (aPKCs). The activity of the Akt-inactivating Protein Phosphatase 2A (PP2A) was increased in the insulin-resistant cells. Furthermore, inhibition of PP2A by specific inhibitors increased insulin-stimulated activation of Akt and phosphorylation of FoxO1 and Gsk3α. Finally, PP2A mRNA levels were increased in liver, muscle and adipose tissue, while PP2A activity was increased in liver and muscle tissue in insulin-resistant ZDF rats. In conclusion, our findings indicate that FFAs may cause a selective impairment of insulin action upon hepatic glucose metabolism by increasing PP2A activity.
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DOI：
10.1152/ajpendo.00549.2003
发表时间：
2004-07-01
影响因子：
5.1
作者：
Basu, R;Schwenk, WF;Rizza, RA
通讯作者：
Rizza, RA
影响因子：
64.5
作者：
Padmanabhan S;Mukhopadhyay A;Narasimhan SD;Tesz G;Czech MP;Tissenbaum HA
通讯作者：
Tissenbaum HA
影响因子：
29
作者：
Biddinger, Sudha B.;Hernandez-Ono, Antonio;Kahn, C. Ronald
通讯作者：
Kahn, C. Ronald
影响因子：
4.8
作者：
Kuo, Yi-Chun;Huang, Kai-Yun;Chiang, Chi-Wu
通讯作者：
Chiang, Chi-Wu
影响因子：
8.2
作者：
Cozzone, D.;Froejdoe, S.;Vidal, H.
通讯作者：
Vidal, H.