Dietary Fat Supply to Failing Hearts Determines Dynamic Lipid Signaling for Nuclear Receptor Activation and Oxidation of Stored Triglyceride

Abstract

Background— Intramyocardial triglyceride (TG) turnover is reduced in pressure-overloaded, failing hearts, limiting the availability of this rich source of long-chain fatty acids for mitochondrial β-oxidation and nuclear receptor activation. This study explored 2 major dietary fats, palmitate and oleate, in supporting endogenous TG dynamics and peroxisome proliferator–activated receptor-α activation in sham-operated (SHAM) and hypertrophied (transverse aortic constriction [TAC]) rat hearts. Methods and Results— Isolated SHAM and TAC hearts were provided media containing carbohydrate with either 13 C-palmitate or 13 C-oleate for dynamic 13 C nuclear magnetic resonance spectroscopy and end point liquid chromatography/mass spectrometry of TG dynamics. With palmitate, TAC hearts contained 48% less TG versus SHAM ( P =0.0003), whereas oleate maintained elevated TG in TAC, similar to SHAM. TG turnover in TAC was greatly reduced with palmitate (TAC, 46.7±12.2 nmol/g dry weight per min; SHAM, 84.3±4.9; P =0.0212), as was β-oxidation of TG. Oleate elevated TG turnover in both TAC (140.4±11.2) and SHAM (143.9±15.6), restoring TG oxidation in TAC. Peroxisome proliferator–activated receptor-α target gene transcripts were reduced by 70% in TAC with palmitate, whereas oleate induced normal transcript levels. Additionally, mRNA levels for peroxisome proliferator–activated receptor-γ-coactivator-1α and peroxisome proliferator–activated receptor-γ-coactivator-1β in TAC hearts were maintained by oleate. With these metabolic effects, oleate also supported a 25% improvement in contractility over palmitate with TAC ( P =0.0202). Conclusions— The findings link reduced intracellular lipid storage dynamics to impaired peroxisome proliferator–activated receptor-α signaling and contractility in diseased hearts, consistent with a rate-dependent lipolytic activation of peroxisome proliferator–activated receptor-α. In decompensated hearts, oleate may serve as a beneficial energy substrate versus palmitate by upregulating TG dynamics and nuclear receptor signaling.