Long Chain Fatty Acid Storage Dynamics and Nuclear Receptor Activation in Failing Hearts

Intramyocardial triglyceride (TG) turnover is reduced in hypertrophied, failing hearts, limiting availability of this rich source of stored long-chain fatty acids (LCFAs) for mitochondrial oxidation and nuclear receptor activation. The two major dietary LCFAs, palmitate and oleate, differentially influence TG turnover in normal and hypertrophied rat hearts with dramatic effects on contractility and transcription. In contrast to palmitate, oleate induced normal TG content and elevated turnover rates in decompensated, hypertrophic hearts. Normalized lipid dynamics with oleate in the hypertrophied heart resulted in normalized peroxisome proliferator-activated receptor-α (PPAR-α) target gene expression and mitochondrial oxidation of TG. Oleate supply to failing hearts also averted an increase in the lipotoxic acyl intermediate C16 ceramide, associated with improved cardiac contractility. The findings link reduced intracellular lipid storage dynamics to impaired PPAR-α signaling and contractility in diseased hearts and indicate a rate-dependent lipolytic activation of PPAR-α. In decompensated hearts, oleate may serve as a beneficial energy substrate versus palmitate, to confer improved TG dynamics and nuclear receptor signaling. As part of an overall programmatic shift in lipid handling enzymes, hypertrophied hearts demonstrate increased cytosolic malic enzyme 1 (ME1) expression which upregulates anaplerotic flux into the second span of the cycle by carboxylating glycolytic pyruvate, forming malate. ME1 is known to be lipogenic in other tissue types, generating NADPH and pyruvate from malate. However, reverse flux that consumes pyruvate and NADPH in hypertrophied myocardium appears to be maladaptive, as this alternative route of entry into the TCA cycle is inefficient compared to pyruvate decarboxylation into acetyl-CoA by pyruvate dehydrogenase complex (PDC). Numerous NADH-producing reactions are bypassed, contributing to a net loss of ATP per glycolytic carbon. Furthermore, the carboxylation reaction consumes NADPH, depleting the cardiomyocyte of a critical cofactor for maintaining TG stores and intracellular redox state. We tested the effects of cardiac-specific knockdown of ME1 in hypertrophied hearts via delivery of adenovirus containing non-native microRNA targeted to ME1 mRNA. Knockdown of ME1 returned anaplerosis to normal low levels and increased glutathione content in hypertrophy.