Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11β-hydroxysteroid dehydrogenase type 1.
Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11β-hydroxysteroid dehydrogenase type 1.
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在11β-羟基甾体脱氢酶1型的小鼠中缺乏明显的代谢异常。
DOI：
10.1210/en.2012-1019
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发表时间：
2012-07
期刊：
影响因子：
4.8
通讯作者：
Stewart PM
中科院分区：
文献类型：
--
作者：
Lavery GG;Zielinska AE;Gathercole LL;Hughes B;Semjonous N;Guest P;Saqib K;Sherlock M;Reynolds G;Morgan SA;Tomlinson JW;Walker EA;Rabbitt EH;Stewart PM
糖皮质激素(GC)与代谢综合征的发生有关，糖皮质激素过多的患者有许多临床特征，如中心性肥胖和糖耐量减低。在肥胖或2型糖尿病患者中，全身GC浓度似乎总是正常的。组织GC浓度由下丘脑-垂体-肾上腺(HPA)轴和局部皮质醇(小鼠为皮质酮)通过11β-羟基类固醇脱氢酶1型(11β-HSD1)酶再生皮质醇(小鼠为11脱氢皮质酮)决定，主要在肝脏表达。转基因小鼠已经证明了11个β-HSD1在调节代谢综合征的各个方面以及HPA轴控制方面的重要性。为了阐明肝脏11β-HSD1在调节代谢和HPA轴中的首要地位，我们建立了肝脏特异的11β-HSD1基因敲除小鼠，评估了GC代谢的生物标志物，并检测了对高脂饮食的反应。LKO小鼠能够从对照组的40%的皮质醇再生皮质醇，并且在尿液代谢物标记物11β-hsd1活性方面没有明显的差异。虽然循环皮质酮没有改变，但肾上腺大小增加，表明慢性HPA刺激。糖耐量略有改善，但胰岛素敏感性基本未受影响。肥胖和体重没有受到影响，肝脏脂肪平衡、甘油三酯积聚和血清脂质也没有受到影响。此外，参与糖或脂平衡的基因的表达没有变化。肝脏特异性缺失11β-hsd1减少了皮质酮的再生，可能是重要的设置方面的下丘脑轴张力，而不会影响尿类固醇代谢产物谱。这些不一致的数据对这些11个β-HSD1活性的生物标志物在临床研究中的使用具有重要意义。肝外11β-HSD1的表达具有重要的代偿作用，突显了GC靶组织间的串扰在决定代谢表型中的作用。
Glucocorticoids (GC) are implicated in the development of metabolic syndrome, and patients with GC excess share many clinical features, such as central obesity and glucose intolerance. In patients with obesity or type 2 diabetes, systemic GC concentrations seem to be invariably normal. Tissue GC concentrations determined by the hypothalamic-pituitary-adrenal (HPA) axis and local cortisol (corticosterone in mice) regeneration from cortisone (11-dehydrocorticosterone in mice) by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, principally expressed in the liver. Transgenic mice have demonstrated the importance of 11β-HSD1 in mediating aspects of the metabolic syndrome, as well as HPA axis control. In order to address the primacy of hepatic 11β-HSD1 in regulating metabolism and the HPA axis, we have generated liver-specific 11β-HSD1 knockout (LKO) mice, assessed biomarkers of GC metabolism, and examined responses to high-fat feeding. LKO mice were able to regenerate cortisol from cortisone to 40% of control and had no discernible difference in a urinary metabolite marker of 11β-HSD1 activity. Although circulating corticosterone was unaltered, adrenal size was increased, indicative of chronic HPA stimulation. There was a mild improvement in glucose tolerance but with insulin sensitivity largely unaffected. Adiposity and body weight were unaffected as were aspects of hepatic lipid homeostasis, triglyceride accumulation, and serum lipids. Additionally, no changes in the expression of genes involved in glucose or lipid homeostasis were observed. Liver-specific deletion of 11β-HSD1 reduces corticosterone regeneration and may be important for setting aspects of HPA axis tone, without impacting upon urinary steroid metabolite profile. These discordant data have significant implications for the use of these biomarkers of 11β-HSD1 activity in clinical studies. The paucity of metabolic abnormalities in LKO points to important compensatory effects by HPA activation and to a crucial role of extrahepatic 11β-HSD1 expression, highlighting the contribution of cross talk between GC target tissues in determining metabolic phenotype.
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影响因子：
4.8
作者：
Gomez-Sanchez, Elise P.;Romero, Damian G.;Gomez-Sanchez, Celso E.
通讯作者：
Gomez-Sanchez, Celso E.
影响因子：
8.2
作者：
Alberts, P;Engblom, L;Abrahmsén, L
通讯作者：
Abrahmsén, L
影响因子：
15.9
作者：
Masuzaki, H;Yamamoto, H;Flier, JS
通讯作者：
Flier, JS
影响因子：
4.8
作者：
Lavery, Gareth G.;Hauton, David;Stewart, Paul M.
通讯作者：
Stewart, Paul M.
下丘脑 - 垂体 - 肾上腺轴异常，响应于11BETA-HSD1的缺失是应变依赖性的。
影响因子：
3.2
作者：
Carter RN;Paterson JM;Tworowska U;Stenvers DJ;Mullins JJ;Seckl JR;Holmes MC
通讯作者：
Holmes MC