Hepatic ERα accounts for sex differences in the ability to cope with an excess of dietary lipids

Clara Meda, Mara Barone, Nico Mitro, Federica Lolli, Silvia Pedretti, Donatella Caruso, Adriana Maggi, Sara Della Torre

In female mammals, liver estrogen receptor alpha (ERα) plays a central role in the adaptive response of hepatic metabolism to the energy requirements characterizing the different reproductive stages. Unlike in females, the expression of ERα in the adult male liver is very low. Although obesity is prevalent in females, fertile women are to some extent protected from obesity-associated fatty liver and cardio-metabolic disease, suggesting the involvement of estrogen signaling. Meda and colleagues highlight the essential role of hepatic ERα in the regulation of lipid metabolism in the liver of the two sexes when dietary lipids are in excess. In males, hepatic ERα action contributes to liver lipid accumulation; conversely, in females, ERα prevents the hepatic lipid deposition.

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.