Hewitt Kylie N, Boon Wah Chin, Murata Yoko, Jones Margaret E E, Simpson Evan R
Prince Henry's Institute of Medical Research and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Endocrinology. 2003 Sep;144(9):3895-903. doi: 10.1210/en.2003-0244.
The aromatase knockout (ArKO) mouse cannot synthesize endogenous estrogens due to disruption of the Cyp19 gene. We have shown previously, that ArKO mice present with age-progressive obesity and hepatic steatosis, and by 1 yr of age both male and female ArKO mice develop hypercholesterolemia. In this present study 10- to 12-wk-old ArKO mice were challenged for 90 d with high cholesterol diets. Our results show a sexually dimorphic response to estrogen deficiency in terms of cholesterol homeostasis in the liver. ArKO females presented with elevated serum cholesterol; conversely, ArKO males had elevated hepatic cholesterol levels. In response to dietary cholesterol, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase transcript levels were significantly reduced in females, whereas males showed more modest changes. Neither low density lipoprotein nor sterol regulatory element-binding protein expression levels were significantly altered by diet or genotype. The expression of Cyp7a, which encodes cholesterol 7 alpha-hydroxylase, was significantly reduced in ArKO females compared with wild-type females and was increased by cholesterol feeding. Cyp7a expression was significantly elevated in the wild-type males on the high cholesterol diet, although no difference was seen between genotypes on the control diet. The ATP-binding cassette G5 and ATP-binding cassette G8 transporters do not appear to be regulated by estrogen. The expression of acyl-coenzyme A:cholesterol acyltransferase 2 showed a sexually dimorphic response, where estrogen appeared to have a stimulatory effect in females, but not males. This study reveals a sexually dimorphic difference in mouse hepatic cholesterol homeostasis and roles for estrogen in the regulation of cholesterol uptake, biosynthesis, and catabolism in the female, but not in the male.
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。我们之前已经表明，ArKO小鼠会出现年龄增长导致的肥胖和肝脂肪变性，到1岁时，雄性和雌性ArKO小鼠都会出现高胆固醇血症。在本研究中，对10至12周龄的ArKO小鼠用高胆固醇饮食进行了90天的挑战。我们的结果显示，在肝脏胆固醇稳态方面，对雌激素缺乏存在性别差异反应。ArKO雌性小鼠血清胆固醇升高；相反，ArKO雄性小鼠肝脏胆固醇水平升高。对于饮食中的胆固醇，雌性小鼠3-羟基-3-甲基戊二酰辅酶A还原酶转录水平显著降低，而雄性小鼠变化较小。饮食或基因型均未显著改变低密度脂蛋白或固醇调节元件结合蛋白的表达水平。与野生型雌性小鼠相比，ArKO雌性小鼠中编码胆固醇7α-羟化酶的Cyp7a表达显著降低，且胆固醇喂养可使其增加。高胆固醇饮食时，野生型雄性小鼠Cyp7a表达显著升高，尽管对照饮食时各基因型之间未见差异。ATP结合盒转运体G5和ATP结合盒转运体G8似乎不受雌激素调节。酰基辅酶A：胆固醇酰基转移酶2的表达呈现性别差异反应，雌激素似乎对雌性有刺激作用，而对雄性没有。这项研究揭示了小鼠肝脏胆固醇稳态中的性别差异，以及雌激素在雌性而非雄性中对胆固醇摄取、生物合成和分解代谢的调节作用。
