An emerging interplay between altered human lipid metabolism, lipodystrophy and aging

LMNA -Lipodystrophies are a group of heterogeneous syndromes, with either genetic or acquired origin, characterized by the accumulation of prelamin A, an inmature form of the protein lamin A, one of the major components of the nuclear lamina. Several molecular studies suggest lamin A is involved in adipocyte development, the disruption of which leads to compromised regulation of adipogenesis, adipocyte lipid droplet formation and maintenance, and subsequent secondary dysfunctions in fat metabolism. Moreover, these diseases clinically present with generalized or partial fat atrophy connected with metabolic complications, such as insulin-resistant diabetes and dyslipidemia, in addition to age associated manifestations. There is a real need to increase our understanding regarding these syndromes because of their import in human health and the lack of knowledge of their etiopathology. To gain deeper insights into these metabolic diseases, we have taken advantage of a previously generated “disease in a dish” model of human LMNA -lipodystrophy based on the pathological accumulation of the precursor prelamin A in stem cell derived adipocytes. This experimental model recapitulates phenotypes observed in lipodystrophic patient’s samples and animal models, and it has been critical in elucidating new insights into the molecular mechanisms governing this set of disorders. Recently, we have identified alterations in fundamental processes of lipid homeostasis such as lipolysis, as well as mitochondrial and endoplasmic reticulum functions, similar to what can be observed in some metabolic and aging phenotypes. Additionally, the lipidomic profile of this lipodystrophic experimental model displayed a lipid metabolic signature similar to aging systems, providing new information concerning metabolic pathways affected during the aging process. By clarifying the fundamental mechanisms governing these aging associated diseases, future novel interventions could be developed that will at least delay the appearance of aging phenotypes and thereby increase the healthspan or disease-free time of an individual.