Adaptation to ceramide involves AKT/FOXO regulated novel triglyceride lipases

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

? DESCRIPTION (provided by applicant): Triacylglycerols are a source of fatty acyl CoA and serve as stores of energy in organisms. They are mobilized during conditions of stress and high-energy activity for efficient energy production. Defects in mobilizing triacylglycerol results in several human disorders such as obesity, metabolic syndrome and is a complication of diabetes and cardiovascular disorders. The sphingolipid ceramide affects cellular energy metabolism by interfering with mitochondrial function. In a Drosophila model that accumulates ceramide, we investigated how it adapts to compromised energy levels and discovered AKT/FOXO regulated novel lipases that mobilize and integrate the use of triglycerides for energy consuming processes. Impairment of the function of these lipases leads to elevated triglycerides, increased sensitivity to starvation and cardiac dysfunction. Our data indicate the existence of a lipolytic pathway functioning across different organs that includes the two novel lipases and is active under both physiological and stress conditions. The goal of this proposal is to elucidate the mechanisitic details involved in the complex functioning of these lipases in physiological as well as pathological states that are associated with hypertriglyceridemia. The specific aims of this project are (1). Gain insight into the non-autonomous mode of action of CG8093 and CG6277 lipases (2). Identify components and pathways involved in the regulation of triglycerides by CG8093 and CG6277 through a genetic approach (3). Evaluate the role of CG8093 and G6277 lipases in hypertriglyceridemia associated with obesity and diabetes using Drosophila and mouse models. Upon completion of these aims, we hope to gain considerable insight into the mechanism of action of these lipases and their contribution to energy metabolism in physiological and stress conditions and identify components and pathways involved in the functioning of these lipases.