Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11β-hydroxysteroid dehydrogenase type 1 null mice.
Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11β-hydroxysteroid dehydrogenase type 1 null mice.
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DOI：
10.1074/jbc.m103676200
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发表时间：
2001-11-02
影响因子：
4.8
通讯作者：
Seckl, JR
中科院分区：
文献类型：
--
作者：
Morton, NM;Holmes, MC;Seckl, JR
过量的组织糖皮质激素作用可能是代谢综合征的血脂异常、胰岛素抵抗和糖耐量受损的基础。11 β-羟基类固醇脱氢酶1型（11 β-HSD-1）催化循环惰性11-脱氢皮质酮转化为活性皮质酮，从而放大局部细胞内糖皮质激素作用，特别是在肝脏中。11 β-HSD-1（-/-）小鼠在应激或肥胖时对高血糖症的抗性表明了11 β-HSD-1在葡萄糖稳态中的重要性，这是由于减弱的促血管生成反应.本研究进一步研究了11 β-HSD-1缺乏的代谢后果，重点是脂质和脂蛋白谱。自由进食11 β-HSD-1（-/-）小鼠具有显著较低的血浆甘油三酯水平。这似乎是由脂肪分解酶（肉毒碱棕榈酰转移酶-I、酰基辅酶A氧化酶和解偶联蛋白-2）及其协调转录因子过氧化物酶体增殖物激活受体-a（PPAR α）的肝脏表达增加驱动的。11 β-HSD-1（-/-）小鼠也具有增加的HDL胆固醇，肝脏mRNA和血清载脂蛋白Al水平升高.相反，肝脏A α-纤维蛋白原mRNA水平降低.禁食后，11 β-HSD-1（-/-）小鼠中过氧化物酶体增殖物激活受体-α mRNA的正常升高丢失，与减弱的糖皮质激素诱导一致。尽管如此，关键的氧化反应禁食保持;肉毒碱棕榈酰转移酶-I诱导和葡萄糖水平与野生型相似。在11 β-HSD-1（-/-）小鼠中，再喂养显示编码脂肪生成酶的基因的过度诱导和脂肪催化剂基因的更显著抑制，这意味着肝脏胰岛素敏感性增加。与此一致的是，24小时再喂养的11 β-HSD-1（-/-）小鼠具有较高的甘油三酯但较低的葡萄糖水平。此外，11只β-HSD-1（-/-）小鼠具有改善的葡萄糖耐量。这些数据表明，11 β-HSD-1缺乏产生改善的脂质分布、肝胰岛素增敏和潜在的动脉粥样硬化保护表型。
Excess tissue glucocorticoid action may underlie the dyslipidemia, insulin resistance, and impaired glucose tolerance of the metabolic syndrome. 11 beta -Hydroxy-steroid dehydrogenase type 1 (11 beta -HSD-1) catalyzes conversion of circulating inert 11-dehydrocorticosterone into active corticosterone, thus amplifying local intracellular glucocorticoid action, particularly in liver. The importance of 11 beta -HSD-1 in glucose homeostasis is suggested by the resistance of 11 beta -HSD-1(-/-) mice to hyperglycemia upon stress or obesity, due to attenuated gluconeogenic responses. The present study further investigates the metabolic consequences of 11 beta -HSD-1 deficiency, focusing on the lipid and lipoprotein profile. Ad lib fed 11 beta -HSD-1(-/-) mice have markedly lower plasma triglyceride levels. This appears to be driven by increased hepatic expression of enzymes of fat catabolism (carnitine palmitoyltransferase-I, acyl-CoA oxidase, and uncoupling protein-2) and their coordinating transcription factor, peroxisome proliferator-activated receptor-a (PPAR alpha). 11 beta -HSD-1(-/-) mice also have increased HDL cholesterol, with elevated liver mRNA and serum levels of apolipoprotein Al. Conversely, liver A alpha -fibrinogen mRNA levels are decreased. Upon fasting, the normal elevation of peroxisome proliferator-activated receptor-a mRNA is lost in 11 beta -HSD-1(-/-) mice, consistent with attenuated glucocorticoid induction. Despite this, crucial oxidative responses to fasting are maintained; carnitine palmitoyltransferase-I induction and glucose levels are similar to wild type. Refeeding shows exaggerated induction of genes encoding lipogenic enzymes and a more marked suppression of genes for fat catabolism in 11 beta -HSD-1(-/-) mice, implying increased liver insulin sensitivity. Concordant with this, 24-h refed 11 beta -HSD-1(-/-) mice have higher triglyceride but lower glucose levels. Further, 11 beta -HSD-1(-/-) mice have improved glucose tolerance. These data suggest that 11 beta -HSD-1 deficiency produces an improved lipid profile, hepatic insulin sensitization, and a potentially atheroprotective phenotype.