Baudrand Rene, Gupta Nidhi, Garza Amanda E, Vaidya Anand, Leopold Jane A, Hopkins Paul N, Jeunemaitre Xavier, Ferri Claudio, Romero Jose R, Williams Jonathan, Loscalzo Joseph, Adler Gail K, Williams Gordon H, Pojoga Luminita H
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA Department of Endocrinology, School of Medicine, Pontificia Universidad Catolica De Chile, Santiago, Chile.
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
J Am Heart Assoc. 2016 Sep 28;5(10):e003845. doi: 10.1161/JAHA.116.003845.
Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav-1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav-1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav-1-null mice and humans with a prevalent variant in the CAV1 gene.
In mouse studies, cav-1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high- to low-density lipoprotein (all P<0.001 versus wild type). Moreover, cav-1 knockout mice displayed hypertriglyceridemia and higher mRNA levels for resistin, retinol binding protein 4, NADPH oxidase 4, and aldose reductase in liver and/or fat tissues. MR blockade with eplerenone significantly decreased glycemia (P<0.01), total cholesterol (P<0.05), resistin (P<0.05), and described enzymes, with no effect on insulin or triglycerides. In the human study, we analyzed the CAV1 gene polymorphism rs926198 in 556 white participants; 58% were minor allele carriers and displayed higher odds of insulin resistance (odds ratio 2.26 [95% CI 1.40-3.64]) and low high-density lipoprotein (odds ratio 1.54 [95% CI 1.01-3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high-density lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cav-1 expression in adipose tissues by the rs926198 minor allele.
Our findings in mice and humans suggested that decreased cav-1 expression may activate the effect of aldosterone/MR signaling on several pathways of glycemia, dyslipidemia, and resistin. In contrast, hyperinsulinemia and hypertriglyceridemia are likely mediated by MR-independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype-mediated cav-1 deficiency.
醛固酮和盐皮质激素受体（MR）信号通路过度激活与高血糖和血脂异常有关。小窝蛋白1（cav-1）参与葡萄糖/脂质稳态调节，可能调控MR信号传导。我们研究了cav-1与醛固酮信号传导之间的相互作用，以探讨其在调节cav-1基因缺失小鼠以及携带CAV1基因常见变异的人类胰岛素抵抗和血脂异常中的作用。
在小鼠研究中，cav-1基因敲除小鼠的胰岛素抵抗、胆固醇和抵抗素的稳态模型评估水平较高，高密度脂蛋白与低密度脂蛋白的比值较低（与野生型相比，均P<0.001）。此外，cav-1基因敲除小鼠表现出高甘油三酯血症，肝脏和/或脂肪组织中抵抗素、视黄醇结合蛋白4、NADPH氧化酶4和醛糖还原酶的mRNA水平较高。依普利酮阻断MR可显著降低血糖（P<0.01）、总胆固醇（P<0.05）、抵抗素（P<0.05）以及上述酶的水平，但对胰岛素或甘油三酯无影响。在人类研究中，我们分析了556名白人参与者的CAV1基因多态性rs926198；58%为次要等位基因携带者，其胰岛素抵抗（比值比2.26 [95%可信区间1.40 - 3.64]）和低高密度脂蛋白（比值比1.54 [95%可信区间1.01 - 3.37]）的几率更高。仅在次要等位基因携带者中，醛固酮水平与更高的胰岛素抵抗和抵抗素稳态模型评估以及更低的高密度脂蛋白相关。CAV1基因表达数量性状位点数据显示，rs926198次要等位基因使脂肪组织中的cav-1表达降低。
我们在小鼠和人类中的研究结果表明，cav-1表达降低可能激活醛固酮/MR信号传导对血糖、血脂异常和抵抗素多条信号通路的影响。相比之下，高胰岛素血症和高甘油三酯血症可能由不依赖MR的机制介导。未来的人体研究将阐明MR阻断在基因型介导的cav-1缺乏患者中的临床意义。
