Cochran Blake J, Bisoendial Radjesh J, Hou Liming, Glaros Elias N, Rossy Jérémie, Thomas Shane R, Barter Philip J, Rye Kerry-Anne
From the Lipid Research Group, Centre for Vascular Research (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.) and Redox Cell Signaling Group, School of Medical Sciences (E.N.G., S.R.T.), University of New South Wales, Sydney, Australia; Lipid Research Group, Heart Research Institute, Sydney, Australia (B.J.C., R.J.B., L.H., P.J.B., K.-A.R.); Australian Centre for Nanomedicine, Sydney, Australia (J.R.); Immune Imaging, Centenary Institute, Sydney, Australia (R.J.B.); and Faculty of Medicine, University of Sydney, Sydney, Australia (P.J.B., K.-A.R.).
Arterioscler Thromb Vasc Biol. 2014 Oct;34(10):2261-7. doi: 10.1161/ATVBAHA.114.304131. Epub 2014 Aug 21.
Therapeutic interventions that increase plasma levels of high-density lipoproteins and apolipoprotein A-I (apoA-I) A-I, the major high-density lipoprotein apolipoprotein, improve glycemic control in people with type 2 diabetes mellitus. High-density lipoproteins and apoA-I also enhance insulin synthesis and secretion in isolated pancreatic islets and clonal β-cell lines. This study identifies the signaling pathways that mediate these effects.
Incubation with apoA-I increased cAMP accumulation in Ins-1E cells in a concentration-dependent manner. The increase in cAMP levels was inhibited by preincubating the cells with the cell-permeable, transmembrane adenylate cyclase inhibitor, 2'5' dideoxyadenosine, but not with KH7, which inhibits soluble adenylyl cyclases. Incubation of Ins-1E cells with apoA-I resulted in colocalization of ATP-binding cassette transporter A1 with the Gαs subunit of a heterotrimeric G-protein and a Gαs subunit-dependent increase in insulin secretion. Incubation of Ins-1E cells with apoA-I also increased protein kinase A phosphorylation and reduced the nuclear localization of forkhead box protein O1 (FoxO1). Preincubation of Ins-1E cells with the protein kinase A-specific inhibitors, H89 and PKI amide, prevented apoA-I from increasing insulin secretion and mediating the nuclear exclusion of FoxO1. Transfection of Ins-1E cells with a mutated FoxO1 that is restricted to the nucleus confirmed the requirement for FoxO1 nuclear exclusion by blocking insulin secretion in apoA-I-treated Ins-1E cells. ApoA-I also increased Irs1, Irs2, Ins1, Ins2, and Pdx1 mRNA levels.
ApoA-I increases insulin synthesis and secretion via a heterotrimeric G-protein-cAMP-protein kinase A-FoxO1-dependent mechanism that involves transmembrane adenylyl cyclases and increased transcription of key insulin response and β-cell survival genes.
提高血浆高密度脂蛋白和主要高密度脂蛋白载脂蛋白载脂蛋白A-I（apoA-I）水平的治疗干预措施可改善2型糖尿病患者的血糖控制。高密度脂蛋白和apoA-I还可增强分离的胰岛和克隆β细胞系中的胰岛素合成与分泌。本研究确定了介导这些作用的信号通路。
用apoA-I孵育以浓度依赖的方式增加了Ins-1E细胞中cAMP的积累。用细胞可渗透的跨膜腺苷酸环化酶抑制剂2'5'二脱氧腺苷预孵育细胞可抑制cAMP水平的升高，但用抑制可溶性腺苷酸环化酶的KH7预孵育则无此作用。用apoA-I孵育Ins-1E细胞导致ATP结合盒转运蛋白A1与异源三聚体G蛋白的Gαs亚基共定位，并导致Gαs亚基依赖性胰岛素分泌增加。用apoA-I孵育Ins-1E细胞还增加了蛋白激酶A的磷酸化，并减少了叉头框蛋白O1（FoxO1）的核定位。用蛋白激酶A特异性抑制剂H89和PKI酰胺预孵育Ins-1E细胞可阻止apoA-I增加胰岛素分泌并介导FoxO1的核排除。用限制在细胞核内的突变型FoxO1转染Ins-1E细胞，通过阻断apoA-I处理的Ins-1E细胞中的胰岛素分泌，证实了FoxO1核排除的必要性。apoA-I还增加了Irs1、Irs2、Ins1、Ins2和Pdx1的mRNA水平。
apoA-I通过异源三聚体G蛋白-cAMP-蛋白激酶A-FoxO1依赖性机制增加胰岛素合成与分泌，该机制涉及跨膜腺苷酸环化酶以及关键胰岛素反应和β细胞存活基因转录的增加。
