Hepatocyte ERα orchestrates sex-specific liver adaptation to fasting and feeding states

Sex differences in hepatic physiology are thought to influence individual susceptibility to chronic liver diseases including Metabolic-Associated Steatotic Liver Disease (MALSD). Previous studies demonstrated the central contribution of estrogens which primarily influence liver biology through the activation of Estrogen Receptor alpha (ER). However, how ER signaling in hepatocyte modulates liver functions according to the nutritional status, a critical determinant of hepatic metabolism, remains to be characterized. The present study first reveals the nycthemeral expression profile of liver ER, which peaks during the feeding period (ZT16) in both male and female mice. ER expression is altered by reprogramming the hepatic circadian clock in response to inverted food intake, highlighting the influence of feeding on liver ER expression patterns. As ER is mainly expressed in hepatocytes both in human and mouse livers, the functional role of hepatocyte ER during fasting or feeding state was then delineated, using mice harboring ER hepatocyte-specific deletion (ERhep-/-) compared with their wild-type littermates (ERhep+/+). Transcriptomic analyses reveal significant sex differences in the adaptation of liver functions to this contrasted nutritional status, as well as the sex-specific regulatory effects of hepatocyte ER. In such physiological settings, hepatocyte ER deletion does not influence liver transcriptomic profiles in males but significantly alters gene expression in female livers, both fed and fasted conditions. Hepatocyte ER more specifically controls genes associated with inflammatory responses and fatty acid metabolic pathways in females, modulating the ChREBP and PPAR pathways in feeding or fasting states, respectively. Thus, hepatocyte ER is integral to liver metabolic adaptations to fasting and feeding in females but not in males, thus exhibiting both sex-specific and diet-dependent actions. Further characterizing sex differences in liver metabolic flexibility, these results provide new information to develop sex-based strategies for the prevention and management of MASLD.