Abstract 648: Cardiac Lipoprotein Lipase Deficiency Rescues Lipotoxic Cardiomyopathy and Identifies a Distinct Cellular PPARα Signaling Pathway
Recent evidence implicates metabolic abnormalities in the pathogenesis of diabetic cardiac dysfunction. In obese and diabetic states, excessive fatty acid (FA) metabolism contributes to cardiac dysfunction, a problem referred to as ”lipotoxic” cardiomyopathy. Transgenic mice that overexpress the FA-activated transcription factor, peroxisome proliferator-activated receptor alpha (PPARα) in heart (MHC-PPARα mice) model lipotoxic cardiomyopathy. We have recently shown that the cardiomyopathy of MHC-PPARα mice is “rescued” by crossing with mice deficient for the free FA transport protein CD36 (CD36−/ − mice). Lipoprotein lipase functions upstream of CD36 to hydrolyze lipoprotein triglyceride (TG) into free FA. We hypothesized that lipoprotein lipase plays an important role in lipotoxic cardiomyopathy by providing the bulk of FA delivery. MHC-PPARα mice were crossed with mice with heart-specific deletion of the lipoprotein lipase gene (hsLPLko). High fat-fed MHC-PPARα/hsLPLko mice exhibited significant improvement in left ventricular function when compared to the MHC-PPARα mice (LV fractional shortening 52±2.8% vs. 32±2.7%, p<0.01). Furthermore, similar to the MHC-PPARα/CD36−/ − mice, there was a remarkable reduction in cardiac lipid accumulation in the hsLPLko background, based on oil red O staining and tissue TG quantification (16.1±4 vs 2.5±0.6 μg/mg tissue, p<0.01). However, in striking contrast to the MHC-PPARα/CD36−/ − mice, the hsLPLko background resulted in a reversal of the chronic PPARα-driven activation of FA oxidation as measured by palmitate oxidation in the isolated working heart (699±26 vs 215±28 nmol/min/g dry wt, p<0.01), and normalization of mRNA expression for PPARα target genes involved in FA and glucose oxidation. Taken together, these results provide evidence that lipoprotein-derived FA import is required for cardiac lipotoxicity and suggest that activation of the cardiac PPARα pathway requires a lipoprotein-derived ligand that is delivered via a CD36-independent mechanism.