Objective

Among obesity-associated metabolic diseases, non-alcoholic fatty liver disease (NAFLD) represents an increasing public health issue due to its emerging association with atherogenic dyslipidemia and cardiovascular diseases (CVDs). The lower prevalence of NAFLD in pre-menopausal women compared with men or post-menopausal women led us to hypothesize that the female-inherent ability to counteract this pathology might strongly rely on estrogen signaling.

In female mammals, estrogen receptor alpha (ERα) is highly expressed in the liver, where it acts as a sensor of the nutritional status and adapts the metabolism to the reproductive needs. As in the male liver this receptor is little expressed, we here hypothesize that hepatic ERα might account for sex differences in the ability of males and females to cope with an excess of dietary lipids and counteract the accumulation of lipids in the liver.

Methods

Through liver metabolomics and transcriptomics we analyzed the relevance of hepatic ERα in the metabolic response of males and females to a diet highly enriched in fats (HFD) as a model of diet-induced obesity.

Results

The study shows that the hepatic ERα strongly contributes to the sex-specific response to an HFD and its action accounts for opposite consequences for hepatic health in males and females.

Conclusion

This study identified hepatic ERα as a novel target for the design of sex-specific therapies against fatty liver and its cardio-metabolic consequences.

中文翻译：

---

肝ERα导致性别上的差异，以应付饮食中过多的脂质。

客观的

在肥胖相关的代谢性疾病中，非酒精性脂肪肝疾病（NAFLD）由于其与动脉粥样硬化血脂异常和心血管疾病（CVD）的关系而日益成为一种日益严重的公共健康问题。与男性或绝经后女性相比，NAFLD在绝经前女性中的患病率较低，这使我们推测，女性固有的抵抗这种病理的能力可能强烈依赖于雌激素信号传导。

在雌性哺乳动物中，雌激素受体α（ERα）在肝脏中高表达，在肝脏中它可以作为营养状况的传感器，并使新陈代谢适应生殖需求。由于在男性肝脏中该受体很少表达，因此我们在此假设肝ERα可能解释了男性和女性应对过量饮食脂质和抵消脂质在肝脏中积累的能力中的性别差异。

方法

通过肝脏代谢组学和转录组学，我们分析了肝脏ERα与高脂饮食（HFD）作为饮食诱发肥胖的模型，在男性和女性的代谢反应中的相关性。

结果

研究表明，肝ERα强烈促进了对HFD的性别特异性反应，其作用解释了男性和女性对肝脏健康的相反后果。

结论

这项研究确定了肝ERα作为针对脂肪肝及其心脏代谢后果的性别特异性疗法设计的新靶标。