Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism.
Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism.
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DOI：
10.1038/s41467-017-01969-4
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发表时间：
2017-11-27
影响因子：
16.6
通讯作者：
Vanhaesebroeck B
中科院分区：
文献类型：
--
作者：
Bilanges B;Alliouachene S;Pearce W;Morelli D;Szabadkai G;Chung YL;Chicanne G;Valet C;Hill JM;Voshol PJ;Collinson L;Peddie C;Ali K;Ghazaly E;Rajeeve V;Trichas G;Srinivas S;Chaussade C;Salamon RS;Backer JM;Scudamore CL;Whitehead MA;Keaney EP;Murphy LO;Semple RK;Payrastre B;Tooze SA;Vanhaesebroeck B
Vps 34 PI 3 K被认为是磷脂酰肌醇-3-单磷酸的主要生产者，磷脂酰肌醇-3-单磷酸是一种控制细胞内囊泡运输的脂质。Vps 34激酶活性的全身性抑制对生物体的影响尚未完全了解。在这里，我们表明，杂合子Vps 34激酶死亡小鼠是健康的，并显示出强劲增强的胰岛素敏感性和葡萄糖耐量，表型模仿的选择性Vps 34抑制剂在野生型小鼠。胰岛素增敏的潜在机制是多因素的，而不是通过经典的胰岛素/Akt途径。Vps 34抑制改变细胞能量代谢，激活肝脏和肌肉中的AMPK通路。在肝脏中，Vps 34失活轻度抑制自噬，限制线粒体呼吸的底物可用性并减少线粒体异生。在肌肉中，Vps 34失活触发了从氧化磷酸化到糖酵解的代谢转换，并增强了葡萄糖摄取。我们的研究将Vps 34确定为2型糖尿病胰岛素抵抗的新药物靶点，其中未满足的治疗需求仍然很大。Vps 34是一种从酵母到人类都保守的脂质激酶，参与细胞内囊泡运输和自噬。Bilanges等人在本文中表明，抑制小鼠中的这种激酶可通过调节线粒体呼吸和代谢来改善葡萄糖耐量和饮食诱导的脂肪变性。
Vps34 PI3K is thought to be the main producer of phosphatidylinositol-3-monophosphate, a lipid that controls intracellular vesicular trafficking. The organismal impact of systemic inhibition of Vps34 kinase activity is not completely understood. Here we show that heterozygous Vps34 kinase-dead mice are healthy and display a robustly enhanced insulin sensitivity and glucose tolerance, phenotypes mimicked by a selective Vps34 inhibitor in wild-type mice. The underlying mechanism of insulin sensitization is multifactorial and not through the canonical insulin/Akt pathway. Vps34 inhibition alters cellular energy metabolism, activating the AMPK pathway in liver and muscle. In liver, Vps34 inactivation mildly dampens autophagy, limiting substrate availability for mitochondrial respiration and reducing gluconeogenesis. In muscle, Vps34 inactivation triggers a metabolic switch from oxidative phosphorylation towards glycolysis and enhanced glucose uptake. Our study identifies Vps34 as a new drug target for insulin resistance in Type-2 diabetes, in which the unmet therapeutic need remains substantial. Vps34 is a lipid kinase conserved from yeast to humans and involved in in intracellular vesicular trafficking and autophagy. Here Bilanges et al. show that inhibition of this kinase in mice improves glucose tolerance and diet-induced steatosis by modulating mitochondrial respiration and metabolism.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
Beclin 2在自噬中功能，G蛋白偶联受体的降解和代谢。
影响因子：
64.5
作者：
He C;Wei Y;Sun K;Li B;Dong X;Zou Z;Liu Y;Kinch LN;Khan S;Sinha S;Xavier RJ;Grishin NV;Xiao G;Eskelinen EL;Scherer PE;Whistler JL;Levine B
通讯作者：
Levine B
影响因子：
4.5
作者：
Carpentier, Sarah;N'Kuli, Francisca;Courtoy, Pierre J.
通讯作者：
Courtoy, Pierre J.
DOI：
10.1042/bj20090428
发表时间：
2009-07-29
期刊：
The Biochemical journal
影响因子：
--
作者：
Hammond GR;Schiavo G;Irvine RF
通讯作者：
Irvine RF
影响因子：
8.2
作者：
Alliouachene S;Bilanges B;Chaussade C;Pearce W;Foukas LC;Scudamore CL;Moniz LS;Vanhaesebroeck B
通讯作者：
Vanhaesebroeck B