SEXUAL DIMORPHISM OF HEPATIC 11-BETA-HYDROXYSTEROID DEHYDROGENASE IN THE RAT - THE ROLE OF GROWTH-HORMONE PATTERNS
SEXUAL DIMORPHISM OF HEPATIC 11-BETA-HYDROXYSTEROID DEHYDROGENASE IN THE RAT - THE ROLE OF GROWTH-HORMONE PATTERNS
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DOI：
10.1677/joe.0.1430541
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发表时间：
1994-12-01
影响因子：
4
通讯作者：
SECKL, JR
中科院分区：
文献类型：
--
作者：
LOW, SC;CHAPMAN, KE;SECKL, JR
11 β-羟基类固醇脱氢酶（11 β-HSD）催化皮质酮可逆代谢为惰性11-脱氢皮质酮。至少存在两种同种型。11 β-HSD-1是第一个被鉴定的，也是唯一一个分离出cDNA的同种型，在肝脏、肾脏和海马体中高度表达。雄性大鼠肝脏中11 β-HSD的活性较高，这是由于雌性大鼠中雌激素抑制11 β-HSD-1基因转录所致。啮齿类动物肝脏蛋白质的性二态性通常通过GH释放的性别特异性模式（雌性中为连续，雄性中为脉冲）间接介导。我们现在已经调查了这是否适用于11 β-HSD，使用侏儒大鼠（先天缺乏生长激素）和垂体切除动物。11 β-HSD活性和11 β-HSD-1 mRNA在肝脏中的表达显着低于对照组雌性大鼠（50%和72%的雄性水平分别）。在侏儒大鼠中，肝脏中的这些性别差异减弱，雄性和雌性大鼠的11 β-HSD活性水平与对照组雄性大鼠相似。给侏儒雄性大鼠连续（雌性模式）给予GH可降低肝脏11 β-HSD活性（下降30%）和mRNA表达（下降77%），而在雄性（脉冲式）模式中给予相同总日剂量的GH对雌性侏儒大鼠肝脏11 β-HSD无影响。连续GH也减弱了垂体切除动物的肝脏11 β-HSD活性（下降25%）和11 β-HSD-1 mRNA表达（下降82%）。然而，雌二醇本身抑制了垂体切除大鼠肝脏11 β-HSD活性（下降25%）和11 β-HSD-1 mRNA表达（下降60%）。肾脏11 β-HSD活性在对照组或侏儒大鼠中没有表现出性别二型性，尽管侏儒动物的总体活性较低。相比之下，11 β-HSD-1 mRNA的表达在雄性比雌性肾在对照和侏儒株。两种GH模式对侏儒大鼠肾脏中的11 β-HSD活性或11 β-HSD-1 mRNA水平都没有任何影响，尽管连续GH减弱了垂体切除动物肾脏中的11 β-HSD活性（下降28%）和11 β-HSD-1 mRNA表达（下降47%）。雌二醇减弱了垂体切除大鼠肾脏11 β-HSD-1 mRNA的表达（下降74%），但增加了肾脏中的酶活性（上升62%）。这些操作对海马11 β-HSD活性或基因表达没有任何影响。(i)肝脏11 β-HSD的性别二型性部分通过作用于11 β-HSD-1基因表达的GH分泌的性别特异性模式介导。(ii)雌激素对肝脏11 β-HSD-1有额外的直接抑制作用。(iii)其他组织特异性因子参与调节11 β-HSD-1，因为外周GH和雌激素对海马11 β-HSD-1都没有影响。(iv)肾脏中11 β-HSD-1 mRNA表达的调节与肝脏大致平行。11 β-HSD-1基因的表达变化与肾11 β-HSD活性之间缺乏相关性，反映了肾脏中存在额外的基因产物，其表达在很大程度上与GH无关。
11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the reversible metabolism of corticosterone to inert 11-dehydrocorticosterone. At least two isoforms exist. 11 beta-HSD-1, the first to be characterised and the only isoform for which a cDNA has been isolated, is highly expressed in liver, kidney and hippocampus. The activity of 11 beta-HSD in rat liver is higher in males, due to oestrogen repression of 11 beta-HSD-1 gene transcription in females. Sexual dimorphism in rodent liver proteins is frequently mediated indirectly via sex-specific patterns of GH release (continuous in females, pulsatile in males). We have now investigated whether this applies to 11 beta-HSD, using dwarf rats (congenitally deficient in GH) and hypophysectomised animals.11 beta-HSD activity and 11 beta-HSD-1 mRNA expression in liver was significantly lower in control female than male rats (50% and 72% of male levels respectively). These sex differences in the liver were attenuated in dwarf rats, with both males and females showing similar levels of 11 beta-HSD activity to control males. Administration of continuous (female pattern) GH to dwarf male rats decreased hepatic 11 beta-HSD activity (30% fall) and mRNA expression (77% fall), whereas the same total daily dose of GH given in the male (pulsatile) pattern had no effect on hepatic 11 beta-HSD in female dwarf rats. Continuous GH also attenuated hepatic 11 beta-HSD activity (25% fall) and 11 beta-HSD-1 mRNA expression (82% fall) in hypophysectomised animals. However, oestradiol itself suppressed hepatic 11 beta-HSD activity (25% fall) and 11 beta-HSD-1 mRNA expression (60% fall) in hypophysectomised rats.Renal 11 beta-HSD activity showed no sexual dimorphism in control or dwarf rats, although overall activity was lower in dwarf animals. By contrast, 11 beta-HSD-1 mRNA expression was higher in male than female kidney in both control and dwarf strains. Neither GH pattern had any effect on 11 beta-HSD activity or 11 beta-HSD-1 mRNA levels in the kidney of dwarf rats, although continuous GH attenuated 11 beta-HSD activity (28% fall) and 11 beta-HSD-1 mRNA expression in kidney (47% decrease) in hypophysectomised animals. Oestradiol attenuated renal 11 beta-HSD-1 mRNA expression (74% fall) in hypophysectomised rats, but increased enzyme activity (62% rise) in the kidney. None of the manipulations had any effect on hippocampal 11 beta-HSD activity or gene expression.These data demonstrate the following. (i) Sexual dimorphism of hepatic 11 beta-HSD is mediated, in part, via sex-specific patterns of GH secretion acting on 11 beta-HSD-1 gene expression. (ii) There is an additional direct repressive effect of oestrogen on hepatic 11 beta-HSD-1. (iii) Other tissue-specific factors are involved in regulating 11 beta-HSD-1, as neither peripheral GH nor oestrogen have effects upon hippocampal 11 beta-HSD-1. (iv) The regulation of 11 beta-HSD-1 mRNA expression in the kidney broadly parallels the Liver. The lack of correlation between changes in expression of the 11 beta-HSD-1 gene and renal 11 beta-HSD activity reflects the presence of an additional gene product(s) in the kidney, the expression of which is largely independent of GH.