11β-HSD1 inhibition improves triglyceridemia through reduced liver VLDL secretion and partitions lipids toward oxidative tissues
11β-HSD1 inhibition improves triglyceridemia through reduced liver VLDL secretion and partitions lipids toward oxidative tissues
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DOI：
10.1152/ajpendo.00276.2007
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发表时间：
2007-10-01
影响因子：
5.1
通讯作者：
Deshaies, Yves
中科院分区：
文献类型：
--
作者：
Berthiaume, Magalie;Laplante, Mathieu;Deshaies, Yves
11 β-羟基类固醇脱氢酶（HSD）1型活性的组织特异性改变（其放大糖皮质激素的作用）被认为是导致肥胖的一些代谢并发症的原因。本研究通过研究11 β-HSD 1抑制剂（化合物A，3 mg中心点/kg（-1）中心点/天（-1），21天）对饮食诱导的肥胖大鼠模型中甘油三酯（TG）代谢的影响来测试高甘油三酯血症是否是一种这样的并发症。所用化合物A的剂量不影响食物摄入或最终体重。化合物A通过肝脏TG分泌速率的稳健降低（~ 41%）改善空腹甘油三酯血症（~ 42%），而血浆TG清除速率没有变化。然而，氧化组织（包括红色腓肠肌（+47%）、心脏（+39%）和棕色脂肪组织（BAT，+46%））中TG衍生脂肪酸的摄取增加，肝脏受损，同时质膜脂肪酸结合蛋白增加。红色腓肠肌（+35%）和心脏（+33%）的脂质氧化产物增加，BAT（+48%）中解偶联蛋白1 mRNA的水平也增加，一些氧化组织中肉毒碱棕榈酰转移酶1的活性趋于增加。这些发现表明，在不影响食物摄入的剂量下药理学抑制11 β-HSD 1通过减少肝脏极低密度脂蛋白-TG分泌来改善脂蛋白血症，其中TG衍生的脂肪酸摄取模式向氧化组织转变，其中通过增加脂质氧化来防止脂质蓄积。
Tissue-specific alterations in 11 beta-hydroxysteroid dehydrogenase (HSD) type 1 activity, which amplifies glucocorticoid action, are thought to contribute to some of the metabolic complications of obesity. The present study tested whether hypertriglyceridemia is one such complication by investigating the effects of an 11 beta-HSD1 inhibitor (compound A, 3 mg center dot kg(-1)center dot day(-1), 21 days) on triglyceride (TG) metabolism in a rat model of diet-induced obesity. The dose of compound A used did not affect food intake or final body weight. Compound A improved fasting triglyceridemia (-42%) through a robust reduction (-41%) in hepatic TG secretion rate, without change in plasma TG clearance rate. Uptake of TG-derived fatty acids was, however, increased in oxidative tissues, including red gastrocnemius (+47%), heart (+39%), and brown adipose tissue (BAT, +46%) at the expense of the liver, with a concomitant increase in plasma membrane fatty acid-binding protein. Lipid oxidation products were increased in red gastrocnemius (+35%) and heart (+33%), as were levels of uncoupling protein 1 mRNA in BAT (+48%), and carnitine palmitoyltransferase 1 activity tended to be increased in some oxidative tissues. These findings demonstrate that pharmacological inhibition of 11 beta-HSD1 at a dose that does not affect food intake improves triglyceridemia by reducing hepatic very low density lipoprotein-TG secretion, with a shift in the pattern of TG-derived fatty acid uptake toward oxidative tissues, in which lipid accumulation is prevented by increased lipid oxidation.