Mechanisms of Fatty Acid Uptake By Cardiac Muscle

Columbia University Health Sciences, New York NY

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Abstract

DESCRIPTION (provided by applicant): Alterations in cardiac lipid metabolism are associated with heart failure in patients with diabetes and obesity. Excess dietary fat is also thought to be deleterious. Fatty acids (FAs) and glucose supply energy to all tissues of the body, however, the heart is the organ with the greatest FA utilization. This project focuses on how FAs are used for cardiac energetics and why toxicity occurs when excess lipid accumulates. During the first cycle of this grant we created mice with a cardiomyocyte specific deletion of lipoprotein lipase (hLpL0 mice). Hearts from hLpL0 mice have decreased uptake of lipoprotein-derived FAs, normal uptake of albumin-associate FAs, and increased uptake of glucose, but develop cardiac dysfunction with aging. We also studied two models of cardiac lipotoxicity: mice with cardiomyocyte anchored LpL and a newly created model in which the transcription factor PPAR3 is overexpressed in the heart. In Aim 1 of this renewal we propose experiments to assess the role(s) of LpL versus the FA transporter CD36 in heart lipid accumulation and determine how loss of these pathways of FA uptake alters heart function. In Aim 2 we will determine which lipids cause cardiac toxicity by using two newly created genetically modified mice that have reduced production of ceramide or increased conversion of fatty acyl CoAs to triglyceride. In Aim 3, we will determine the primary defects associated with lipotoxicity by studying pre-lipotoxic mice and by replicating the lipotoxic biology in cell culture. The objective will be to define pathways that mediate or exacerbate lipotoxic heart disease. PUBLIC HEALTH RELEVANCE: Heart failure is an increasingly important cause of mortality and morbidity in patients with obesity and diabetes mellitus. This is associated with abnormal use and accumulation of fats within the heart. The experiments in this application seek to understand how fats, including dietary fat, enter the heart and to determine which of these fats are responsible for heart failure.