Contribution of local regeneration of glucocorticoids to tissue steroid pools.
Contribution of local regeneration of glucocorticoids to tissue steroid pools.
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DOI：
10.1530/joe-23-0034
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发表时间：
2023-09-01
期刊：
影响因子：
--
通讯作者：
Andrew R
中科院分区：
文献类型：
--
作者：
Khan S;Livingstone DEW;Zielinska A;Doig CL;Cobice DF;Esteves CL;Man JTY;Homer NZM;Seckl JR;MacKay CL;Webster SP;Lavery GG;Chapman KE;Walker BR;Andrew R
11β-羟基类固醇脱氢酶1(11βHSD1)是一种减轻慢性糖皮质激素过量不良反应的药物靶点。它催化大脑、肝脏和脂肪组织(与己糖-6-磷酸脱氢酶偶联，H6PDH)等组织中活性糖皮质激素的细胞内再生。11β热休克蛋白1在单个组织中的活性被认为对这些部位的糖皮质激素水平有显著贡献，但其局部对通过循环输送糖皮质激素的贡献尚不清楚。在这里，我们假设肝脏11βhsd1将对循环池有显著贡献。这是在Cre介导的肝脏Hsd11b1破坏(ALAC-Cre)与脂肪组织(aP2-Cre)或H6pdh全身破坏的小鼠身上进行的研究。在[9，12，12，12-2H4]-皮质醇(D4F)注射后的稳态条件下，测定了[9，12，12-2H3]-皮质醇(D3F)由[9，12，12-2H3]-皮质醇(D3E)再生的11βHSD1还原酶活性。采用基质辅助激光解吸电离或液相色谱联用质谱仪测定血浆中类固醇的浓度以及肝脏、脂肪组织和脑中的类固醇含量。肝脏中d3F的含量高于脑和脂肪组织。在H6pdh−/−小鼠中，d3F的出现速度慢了约6倍，这表明了全身11βHSD1还原酶活性的重要性。破坏肝脏11β热休克蛋白1可减少肝脏中d3F的含量(约36%)，其他部位未见变化。相比之下，脂肪组织中11βHSD1的破坏降低了循环中d3F的出现率(~67%)，也减少了d3F在肝脏和脑中的再生(均减少~30%)。因此，肝脏11βHSD1对其他组织中循环糖皮质激素水平和数量的贡献小于脂肪组织。
11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) is a drug target to attenuate adverse effects of chronic glucocorticoid excess. It catalyses intracellular regeneration of active glucocorticoids in tissues including brain, liver and adipose tissue (coupled to hexose-6-phosphate dehydrogenase, H6PDH). 11βHSD1 activity in individual tissues is thought to contribute significantly to glucocorticoid levels at those sites, but its local contribution vs glucocorticoid delivery via the circulation is unknown. Here, we hypothesised that hepatic 11βHSD1 would contribute significantly to the circulating pool. This was studied in mice with Cre-mediated disruption of Hsd11b1 in liver (Alac-Cre) vs adipose tissue (aP2-Cre) or whole-body disruption of H6pdh. Regeneration of [9,12,12-2H3]-cortisol (d3F) from [9,12,12-2H3]-cortisone (d3E), measuring 11βHSD1 reductase activity was assessed at steady state following infusion of [9,11,12,12-2H4]-cortisol (d4F) in male mice. Concentrations of steroids in plasma and amounts in liver, adipose tissue and brain were measured using mass spectrometry interfaced with matrix-assisted laser desorption ionisation or liquid chromatography. Amounts of d3F were higher in liver, compared with brain and adipose tissue. Rates of appearance of d3F were ~6-fold slower in H6pdh−/− mice, showing the importance for whole-body 11βHSD1 reductase activity. Disruption of liver 11βHSD1 reduced the amounts of d3F in liver (by ~36%), without changes elsewhere. In contrast disruption of 11βHSD1 in adipose tissue reduced rates of appearance of circulating d3F (by ~67%) and also reduced regenerated of d3F in liver and brain (both by ~30%). Thus, the contribution of hepatic 11βHSD1 to circulating glucocorticoid levels and amounts in other tissues is less than that of adipose tissue.
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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。
影响因子：
4.8
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
通讯作者：
Stewart PM
影响因子：
4.8
作者：
Paterson JM;Holmes MC;Kenyon CJ;Carter R;Mullins JJ;Seckl JR
通讯作者：
Seckl JR
DOI：
10.1210/jc.2013-2049
发表时间：
2014-03
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
--
作者：
Iqbal J;Andrew R;Cruden NL;Kenyon CJ;Hughes KA;Newby DE;Hadoke PW;Walker BR
通讯作者：
Walker BR
影响因子：
7.7
作者：
Hughes KA;Manolopoulos KN;Iqbal J;Cruden NL;Stimson RH;Reynolds RM;Newby DE;Andrew R;Karpe F;Walker BR
通讯作者：
Walker BR