Unsolved challenges in metabolic syndrome: the role of heme metabolism in liver and muscle gluco-lipid homeostasis.

The correct sensing and management of carbohydrates and lipids is essential for the maintenance of body homeostasis, and their impairment is integral to the development of serious metabolic disorders, primarily the metabolic syndrome, a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, affecting about one quarter of the world population, with an ensuing enormous economic burden. Although the awareness on mechanisms regulating glucose and lipid uptake, storage and utilization is significantly grown, the true impact of cellular energetic metabolism on systemic glucose and lipid homeostasis, particularly in certain metabolic diseases, remains elusive. Heme is an iron-containing porphyrin with a pivotal role in cellular energetic processes. Our preliminary data indicate that the inhibition of heme synthesis in mouse liver and skeletal muscle, two of the organs most involved in the control of gluco-lipid homeostasis, results in reduced glycolysis, altered mitochondrial functionality and dysregulated lipid synthesis/utilization. Thus, we hypothesize that the rate of heme synthesis in the liver and in skeletal muscle modulates the ability of these tissues to metabolize sugars and lipids, thus contributing to the establishment of metabolic syndrome and to the development of its hepatic manifestation nonalcoholic fatty liver disease (NAFLD). The project is intended to dissect this hypothesis. We will use in vitro and in vivo models to evaluate the effects of dysregulated heme synthesis on liver and muscle control of gluco-lipid homeostasis focusing on both tissue-specific effects and on liver-muscle inter/intra-tissue communication. The relevance of the obtained results for the metabolic syndrome and, particularly, for its hepatic manifestation nonalcoholic fatty liver disease, will be confirmed on patient-derived induced pluripotent stem cells and liver biopsies. The achievement of the project objectives will improve the understanding of the mechanisms underlying the pathogenesis of the metabolic syndrome/nonalcoholic fatty liver disease and open new avenues for the development of strategies to better control gluco-lipid homeostasis.