Estrogen replacement reverses the hepatic steatosis phenotype in the male aromatase knockout mouse
Estrogen replacement reverses the hepatic steatosis phenotype in the male aromatase knockout mouse
复制标题
DOI：
10.1210/en.2003-1369
复制
发表时间：
2004-04-01
期刊：
影响因子：
4.8
通讯作者：
Simpson, ER
中科院分区：
文献类型：
--
作者：
Hewitt, KN;Pratis, K;Simpson, ER
由于 Cyp19 基因被破坏，芳香酶敲除 (ArKO) 小鼠无法合成内源性雌激素。此前，我们已经证明雄性和雌性 ArKO 小鼠均具有年龄渐进性肥胖表型，并且肝脏胆固醇和甘油三酯稳态存在性别二态性破坏。只有 ArKO 雄性的肝脏甘油三酯水平升高，导致肝脏脂肪变性，部分原因是参与从头脂肪生成的酶和参与脂肪酸摄取的转运蛋白的表达增加。在这项研究中，ArKO 雄性在 18 周龄时接受 17β-雌二醇（3 杯/kg.d）治疗，持续 6 周。野生型对照未经处理，ArKO 对照接受载体油注射。雌激素替代疗法可逆转先前报道的肥胖和脂肪肝表型；这是通过减少性腺、内脏和棕色脂肪组织重量以及显着降低肝脏甘油三酯水平来实现的。雌激素缺乏导致肝脂肪酸合酶表达显着上调，17β-雌二醇替代后可降低肝脂肪酸合酶表达，但尚未达到显着效果。乙酰辅酶A羧化酶α mRNA表达没有表现出显着变化。在雌激素缺乏的男性中，编码脂肪细胞分化调节蛋白（一种脂肪酸转运蛋白）的转录物的表达显着升高，而 17β-雌二醇替代则显着降低了这些水平。 1 型 b 类清道夫受体没有显示出显着变化。这项研究表明，先前报道的雌激素缺乏男性中甘油三酯稳态的破坏可以通过 17β-雌二醇治疗来逆转，这表明雌激素在维持男性甘油三酯和脂肪酸稳态中发挥着重要作用。
The aromatase knockout (ArKO) mouse cannot synthesize endogenous estrogens due to a disruption to the Cyp19 gene. Previously we have shown both male and female ArKO mice have an age progressive obese phenotype and a sexually dimorphic disruption to hepatic cholesterol and triglyceride homeostasis. Only ArKO males have elevated hepatic triglyceride levels leading to hepatic steatosis partly due to an increase in expression of enzymes involved in de novo lipogenesis and transporters involved in fatty acid uptake. In this study ArKO males were treated with 17beta-estradiol ( 3 mug/kg.d) at 18 wk old for 6 wk. Wild-type controls were not treated, and ArKO controls received vehicle oil injections. Estrogen replacement reverses the previously reported obese and fatty liver phenotypes; this was achieved by reductions in gonadal, visceral, and brown adipose tissue weights and significantly decreased hepatic triglyceride levels. Estrogen deficiency led to a significant up-regulation of hepatic fatty acid synthase expression, which was reduced with 17beta-estradiol replacement, although not quite reaching significance. Acetyl Coenzyme A carboxylase alpha mRNA expression showed no significant changes. Expression of transcripts encoding adipocyte differentiated regulatory protein, a fatty acid transporter, was significantly elevated in estrogen-deficient males, and 17beta-estradiol replacement significantly reduced these levels. Scavenger receptor class b type 1 showed no significantly changes. This study reveals that the previously reported disruption to triglyceride homeostasis in estrogen-deficient males can be reversed with 17beta-estradiol treatment, indicating an important role for estrogen in maintaining triglyceride and fatty acid homeostasis in males.