Aims

The prevalence of nonalcoholic fatty liver disease (NAFLD) is higher in women with polycystic ovarian syndrome (PCOS) than that in healthy women. This association can be explained in part by the resistance to insulin and the prevalence of obesity, which are fueled by high androgen levels. However, there is little evidence of the involvement of endogenous testosterone in hepatic steatosis in women with PCOS. Here, we treated Sprague Dawley rats with the aromatase inhibitor, letrozole, to increase the endogenous testosterone level and to decrease the estradiol levels. We also quantified the testosterone levels in human serum specimens and HepG2 cells to investigate the effects of androgens on hepatic steatosis and liver dysfunction.

Results

Twenty-nine PCOS patients and twenty healthy women were enrolled. Alanine transaminase and aspartate transaminase (AST) levels were increased in women with PCOS, and a strong correlation between testosterone and AST levels was observed. After letrozole treatment for 90 days, rats were significantly more obese, with animals developing hepatic steatosis and moderate insulin resistance. Additional experiments revealed that excess androgen inhibited the AMP-activated protein kinase alpha pathway in letrozole-treated livers and dihydrotestosterone (DHT)-treated HepG2 cells, thereby causing steatosis.

Innovation and conclusion

Our results show that an elevated endogenous testosterone level can induce hepatic steatosis. Decreasing the endogenous testosterone level in hepatocytes may represent a new approach in the treatment of NAFLD in PCOS patients.

中文翻译：

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内源性睾丸激素参与多囊卵巢综合征妇女的肝脂肪变性

目的

多囊卵巢综合征（PCOS）妇女的非酒精性脂肪肝疾病（NAFLD）患病率高于健康妇女。这种关联可以部分解释为对胰岛素的抵抗力和肥胖症的流行，而雄激素水平高则助长了肥胖。但是，几乎没有证据表明内源性睾丸激素参与了PCOS妇女的肝脂肪变性。在这里，我们用芳香酶抑制剂来曲唑治疗Sprague Dawley大鼠，以增加内源性睾丸激素水平并降低雌二醇水平。我们还量化了人类血清标本和HepG2细胞中的睾丸激素水平，以研究雄激素对肝脂肪变性和肝功能障碍的影响。

结果

招募了29名PCOS患者和20名健康女性。患有PCOS的女性的丙氨酸转氨酶和天冬氨酸转氨酶（AST）水平升高，并且睾丸激素和AST水平之间存在很强的相关性。来曲唑治疗90天后，大鼠明显肥胖，动物发展为肝脂肪变性和中度胰岛素抵抗。其他实验表明，过量的雄激素会抑制来曲唑治疗的肝脏和二氢睾丸激素（DHT）治疗的HepG2细胞中AMP激活的蛋白激酶α途径，从而导致脂肪变性。

创新与结论

我们的结果表明，内源性睾丸激素水平升高可诱发肝脂肪变性。降低肝细胞内源性睾丸激素水平可能代表了PCOS患者NAFLD治疗的新方法。