The liver is a pivotal regulator of systemic glucose and lipid levels, serving as a central hub for metabolism. Dysfunctions in hepatic nutrient sensing and processing contribute to the development of metabolic syndrome and progression to non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), two liver pathologies exhibiting sexual dimorphism. The metabolism of iron and of its bioavailable form, heme, are intricately linked to nutrient utilization, responding to nutritional cues such as glucagon during fasting and insulin post-prandially, and influencing the expression of glycolytic and oxidative enzymes.

Our previous works have shown that FLVCR1a, a plasma membrane transporter first recognized as a heme exporter but recently identified as a choline importer, regulates ALAS1-mediated heme synthesis. Our recent findings indicate that deletion of Flvcr1a in hepatocytes (LivKO mice) results in decreased heme biosynthesis and in heme-dependent reduction of glucose uptake and glycolysis, along with elevated fatty acid uptake and oxidation, oxidative phosphorylation and cholesterol production. Based on these results, we hypothesized that the metabolic dysregulation elicited by impaired hepatic heme synthesis in these mice predisposes them to metabolic syndrome. To test this in a gender-specific manner, male and female LivKO mice were subjected to high-fat high-fructose (HFF) diet. Preliminary data indicate exacerbated insulin resistance and compromised gluco-lipid metabolism in LivKO males and females under HFF diet compared to matched controls. These results suggest that rewiring of hepatic heme metabolism contributes to systemic gluco-lipid dysregulation, hinting at heme biosynthesis as a potential target for the prevention/treatment of metabolic syndrome and NAFLD.