The regulation of intrahepatic fatty acid partitioning within the human liver: the effect of sex

The liver plays a central role in systemic fatty acid (FA) metabolism through the coordinated regulation of hepatic FA uptake, partitioning within, and export. Increasing evidence indicates that hepatic FA metabolism is sexually dimorphic and this may, in part, contribute to sex-specific differences in intrahepatic triglyceride (IHTG) accumulation and susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD). The sex-dependent divergences in hepatic FA metabolism are thought to arise from differences in systemic FA metabolism, adipose tissue distribution, and intrahepatic FA metabolic pathways, mediated by sexually dimorphic hormonal factors. Here, we review the evidence from human studies and, where appropriate, integrate findings from pre-clinical rodent and in vitro cellular models to elucidate how sex influences fatty acid delivery to, synthesis and partitioning with and disposal (through oxidation and secretion as triglyceride in very low-density lipoprotein) from the liver, in a manner that may result in divergent metabolic responses between men and women, potentially leading to dysregulated hepatic metabolism and an altered risk of cardiometabolic disease.