Spironolactone Improves Glucose and Lipid Metabolism by Ameliorating Hepatic Steatosis and Inflammation and Suppressing Enhanced Gluconeogenesis Induced by High-Fat and High-Fructose Diet
Spironolactone Improves Glucose and Lipid Metabolism by Ameliorating Hepatic Steatosis and Inflammation and Suppressing Enhanced Gluconeogenesis Induced by High-Fat and High-Fructose Diet
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DOI：
10.1210/en.2009-0869
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发表时间：
2010-05-01
期刊：
影响因子：
4.8
通讯作者：
Sasaoka, Toshiyasu
中科院分区：
文献类型：
--
作者：
Wada, Tsutomu;Kenmochi, Hiroki;Sasaoka, Toshiyasu
最近的证据表明，盐皮质激素受体拮抗剂治疗抑制血管组织或心肌细胞的局部炎症，因此，我们研究了螺内酯对饮食诱导的糖尿病和非酒精性脂肪肝小鼠模型的葡萄糖和脂质代谢的影响。C57 BL/6小鼠分别饲喂对照饲料、60%脂肪饲料加30%果糖水（HFFD）或HFFD加螺内酯8周。HFFD小鼠表现出明显的代谢综合征表型，包括胰岛素抵抗、高血压、血脂异常和脂肪肝。虽然螺内酯治疗不影响HFFD引起的热量摄入和体重增加，但附睾脂肪重量、血压、血清甘油三酯、游离脂肪酸、瘦素和总胆固醇水平的增加受到显著抑制。螺内酯可显著降低HFFD小鼠在葡萄糖和胰岛素耐量试验期间的血糖升高。值得注意的是，HFFD小鼠中丙酮酸耐受性试验期间增加的葡萄糖水平通过治疗几乎完全改善至对照水平。苏木精-伊红（HE）和油红-O染色显示HFFD小鼠肝小叶中心部分甘油三酯明显蓄积，螺内酯可有效改善这些蓄积。同时，HFFD喂养显著上调了促炎细胞因子（TNF α、IL-6和单核细胞趋化蛋白-1）、促炎基因磷酸烯醇丙酮酸羧激酶、转录因子碳水化合物反应元件结合蛋白及其下游脂肪生成酶的肝脏mRNA表达，所有这些酶均被螺内酯显著抑制。这些结果表明，抑制盐皮质激素受体可能是一种有益的治疗方法，饮食诱导的代谢综合征和脂肪肝的表型。（内分泌学151：2040-2049，2010）
Recent evidence suggests that treatment with mineralocorticoid receptor antagonist suppressed local inflammation in vascular tissues or cardiomyocytes; therefore, we examined the effect of spironolactone on glucose and lipid metabolism in a mouse model with diet-induced diabetes and nonalcoholic fatty liver disease. C57BL/6 mice were fed either the control diet, 60% fat diet with 30% fructose water (HFFD), or HFFD with spironolactone for 8 wk. HFFD mice demonstrated apparent phenotypes of metabolic syndrome, including insulin resistance, hypertension, dyslipidemia, and fatty liver. Although treatment with spironolactone did not affect the increased calorie intake and body weight by HFFD, the increments of epididymal fat weight, blood pressure, serum triglyceride, free fatty acids, leptin, and total cholesterol levels were significantly suppressed. Elevation of blood glucose during glucose and insulin tolerance tests in HFFD mice was significantly lowered by spironolactone. Notably, increased glucose levels during pyruvate tolerance test in HFFD mice were almost completely ameliorated to control levels by the treatment. Staining with hematoxylin-eosin (HE) and Oil-red-O demonstrated marked accumulation of triglycerides in the centrilobular part of the hepatic lobule in HFFD mice, and these accumulations were effectively improved by spironolactone. Concomitantly HFFD feeding markedly up-regulated hepatic mRNA expression of proinflammatory cytokines (TNF alpha, IL-6, and monocyte chemoattractant protein-1), gluconeogenic gene phosphoenolpyruvate carboxykinase, transcription factor carbohydrate response element binding protein, and its downstream lipogenic enzymes, all of which were significantly suppressed by spironolactone. These results indicate that inhibition of mineralocorticoid receptor might be a beneficial therapeutic approach for diet-induced phenotypes of metabolic syndrome and fatty liver. (Endocrinology 151: 2040-2049, 2010)