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

Non-alcoholic Fatty Liver Disease as a Canonical Example of Metabolic Inflammatory-Based Liver Disease Showing a Sex-Specific Prevalence: Relevance of Estrogen Signaling

“…NAFLD patients show a low hepatic content of BCAAs, that changes with the progression of the pathology, likely as a consequence of impaired expression of hepatic BCAA-degrading enzymes ( 149 , 150 ). Furthermore, a recent study demonstrates that plasma BCAA levels display sex-dimorphic changes with increasing severity of NAFLD, independently of BMI, insulin resistance and age ( 151 ), suggesting a sex-specific regulation of BCAA metabolism and/or a sex-specific role of BCAAs in NAFLD development, as supported by pre-clinical studies ( 91 ). Indeed, although their causative or associative role has not yet clarified, among AAs and several other metabolites, BCAAs result the pathway most affected in the liver of a mouse model of diet-induced obesity ( 91 ).…”

“…Furthermore, a recent study demonstrates that plasma BCAA levels display sex-dimorphic changes with increasing severity of NAFLD, independently of BMI, insulin resistance and age ( 151 ), suggesting a sex-specific regulation of BCAA metabolism and/or a sex-specific role of BCAAs in NAFLD development, as supported by pre-clinical studies ( 91 ). Indeed, although their causative or associative role has not yet clarified, among AAs and several other metabolites, BCAAs result the pathway most affected in the liver of a mouse model of diet-induced obesity ( 91 ). Notably, the decrease in AAs and, especially, in BCAAs correlates with increased lipid deposition in the liver of male, but not female mice; in fact, when exposed to an excess of dietary lipids, female mice, contrary to males, preserve the hepatic AA homeostasis, an effect associated with the ability to counteract liver lipid deposition ( 91 ), suggesting that the metabolism of BCAAs might have a key role in driving hepatic steatosis in a sex-specific fashion.…”

“…With respect to the female counterparts, men and male rodents show a higher propensity of developing hepatic steatosis/NAFLD that derives from the combination of increased FA import, DNL, and storage of lipids within the liver and lower dietary FA oxidation and secretion ( 91 , 139 ). By comparing control and LERKO (liver-specific Estrogen Receptor alpha KO) mice, a recent study demonstrates that the liver ability of females to cope with the excess of dietary lipids strongly relies on the activity of hepatic ERα, that confers to females a higher metabolic flexibility ( 91 ).…”

“…Indeed, although their causative or associative role has not yet clarified, among AAs and several other metabolites, BCAAs result the pathway most affected in the liver of a mouse model of diet-induced obesity ( 91 ). Notably, the decrease in AAs and, especially, in BCAAs correlates with increased lipid deposition in the liver of male, but not female mice; in fact, when exposed to an excess of dietary lipids, female mice, contrary to males, preserve the hepatic AA homeostasis, an effect associated with the ability to counteract liver lipid deposition ( 91 ), suggesting that the metabolism of BCAAs might have a key role in driving hepatic steatosis in a sex-specific fashion. The female-specific ability to preserve BCAA homeostasis and counteract liver lipid deposition is dependent on hepatic ERα, as it is lost in LERKO female mice ( 91 ), and it is likely a consequence of an higher metabolic flexibility conferred by hepatic ERα, that, in the female liver, adapts the hepatic metabolism to hormonal status and to nutrient availability, amino acids in particular ( 13 , 15 , 152 , 153 ).…”

“…Estrogens can regulate sex differences in the liver through direct and indirect mechanisms, that are both affected by and able to prevail over sex-based genetic background and sexual hormone-dependent regulatory activities. Estrogen activity can contribute to the sexual dimorphism of the liver directly ( 21 , 91 , 152 , 236 , 237 ) and indirectly, by regulating GH action, both in the central nervous system and locally ( 198 , 233 , 238 – 240 ). Several experimental models with impaired/lost estrogen signaling support the involvement of estrogen dependent pathways in the regulation of hepatic metabolism, also in a sexually dimorphic fashion ( 14 , 91 , 152 , 153 , 241 ).…”