KLF15 as a Regulator of Cardiac Lipid Metabolism

Case Western Reserve University, Cleveland OH

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Abstract

DESCRIPTION (provided by applicant): Cardiac lipid metabolism involves the coordination of sarcolemmal FA uptake, mitochondrial transport and beta-oxidation. These processes are under robust transcriptional control that is tightly coupled to substrate availability and metabolic demand. Genetic mutations in the genes that are critical regulators of cardiac lipid utilization often give rise to human cardiomyopathies. Therefore, a complete understanding of the transcriptional mechanisms which govern cardiac lipid metabolism is of critical importance. Studies in this proposal investigate a novel transcription factor termed KLF15 that modulates cardiac lipid utilization in vivo. KLF15 is a member of the Kruppel-like family of zinc-finger transcription factors and is known to regulate key aspects of cardiac hypertrophy, hepatic gluconeogenesis, and adipogenesis. However, a specific role for the KLF family in cardiac metabolism has not been reported. Preliminary results demonstrate that systemic deletion of Klf15 attenuates fatty acid oxidation in an isolated working heart preparation and is associated with reduced expression of multiple genes critical for myocardial lipid utilization. Interestingly, gain- and loss-of- function studies suggest KLF15 both regulates the expression of and cooperates with a member of the ligand activated nuclear receptor superfamily termed peroxisomal proliferator activated receptor-1 (PPAR1), a well established regulator of cardiac lipid metabolism. Consistent with these observations, PPAR1-dependent induction of canonical lipid metabolic gene targets is dependent on KLF15. Finally, cardiac restricted Klf15 deficient mice have been successfully generated. These observations underlie the central hypothesis of this application that KLF15 is a novel regulator of cardiac lipid metabolism. The goals of this proposal are: (1) To elucidate the precise molecular mechanism by which KLF15 regulates targets genes in the lipid utilization pathway; (2) To determine the effect of altering KLF15 levels, in a cardiac specific fashion, on lipid metabolism in vivo. These results will provide molecular, cellular, and whole-organ insights regarding the role of KLF15 as a modulator of cardiac lipid metabolism through a mechanism that involves, at least in part, cooperativity with PPAR1.