Dietary Fat Supply to Failing Hearts Determines Dynamic Lipid Signaling for Nuclear Receptor Activation and Oxidation of Stored Triglyceride
Background—Intramyocardial triglyceride (TG) turnover is reduced in pressure overloaded, failing hearts, limiting availability of this rich source of long-chain fatty acids (LCFAs) for mitochondrial β-oxidation and nuclear receptor activation. This study explored two major dietary fats, palmitate and oleate, in supporting endogenous TG dynamics and peroxisome proliferator-activated receptor-α (PPAR-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 13C-palmitate or 13C-oleate for dynamic 13C NMR spectroscopy and endpoint LC/MS of TG dynamics. With palmitate, TAC hearts contained 48% less TG versus SHAM (P=0.0003), while 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 dw/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. PPAR-α target gene transcripts were reduced by 70% in TAC with palmitate, while oleate induced normal transcript levels. Additionally, mRNA levels for PGC-1α and PGC-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 PPAR-α signaling and contractility in diseased hearts, consistent with a rate-dependent lipolytic activation of PPAR-α. In decompensated hearts, oleate may serve as a beneficial energy substrate versus palmitate by upregulating TG dynamics and nuclear receptor signaling.
- Received June 11, 2014.
- Revision received August 1, 2014.
- Accepted August 29, 2014.