Hewitt Kylie N, Pratis Kyriakos, Jones Margaret E E, Simpson Evan R
Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia.
Endocrinology. 2004 Apr;145(4):1842-8. doi: 10.1210/en.2003-1369. Epub 2003 Dec 18.
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 microg/ kg x 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.
芳香化酶基因敲除（ArKO）小鼠由于Cyp19基因的破坏而无法合成内源性雌激素。此前我们已经表明，雄性和雌性ArKO小鼠都有随年龄增长的肥胖表型，以及肝脏胆固醇和甘油三酯稳态的性别差异破坏。只有ArKO雄性小鼠肝脏甘油三酯水平升高，导致肝脏脂肪变性，部分原因是从头脂肪生成相关酶的表达增加以及脂肪酸摄取相关转运蛋白的增加。在本研究中，18周龄的ArKO雄性小鼠接受17β-雌二醇（3μg/kg×d）治疗6周。野生型对照组未接受治疗，ArKO对照组接受赋形剂油注射。雌激素替代可逆转先前报道的肥胖和脂肪肝表型；这是通过降低性腺、内脏和棕色脂肪组织重量以及显著降低肝脏甘油三酯水平来实现的。雌激素缺乏导致肝脏脂肪酸合酶表达显著上调，17β-雌二醇替代可使其降低，尽管未达到显著水平。乙酰辅酶A羧化酶α mRNA表达无显著变化。编码脂肪细胞分化调节蛋白（一种脂肪酸转运蛋白）的转录本表达在雌激素缺乏的雄性小鼠中显著升高，17β-雌二醇替代可显著降低这些水平。清道夫受体B1类无显著变化。本研究表明，先前报道的雌激素缺乏雄性小鼠甘油三酯稳态破坏可通过17β-雌二醇治疗逆转，表明雌激素在维持雄性甘油三酯和脂肪酸稳态中起重要作用。
