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Dietary fat supply to failing hearts determines dynamic lipid signaling for nuclear receptor activation and oxidation of stored triglyceride.

ABSTRACT: 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 ?-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-? activation in sham-operated (SHAM) and hypertrophied (transverse aortic constriction [TAC]) rat hearts.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 ?-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-? 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-?-coactivator-1? and peroxisome proliferator-activated receptor-?-coactivator-1? 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).The findings link reduced intracellular lipid storage dynamics to impaired peroxisome proliferator-activated receptor-? signaling and contractility in diseased hearts, consistent with a rate-dependent lipolytic activation of peroxisome proliferator-activated receptor-?. In decompensated hearts, oleate may serve as a beneficial energy substrate versus palmitate by upregulating TG dynamics and nuclear receptor signaling.

SUBMITTER: Lahey R

PROVIDER: S-EPMC4229424 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Dietary fat supply to failing hearts determines dynamic lipid signaling for nuclear receptor activation and oxidation of stored triglyceride.

Lahey Ryan R Wang Xuerong X Carley Andrew N AN Lewandowski E Douglas ED

Circulation 20140929 20

<h4>Background</h4>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 ...[more]

PMID: 25266948

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Project description:AMP-activated protein kinase (AMPK) is a master metabolic switch that plays an important role in energy homeostasis at the cellular and whole body level, hence a promising drug target. AMPK is a heterotrimeric complex composed of catalytic α-subunit and regulatory β- and γ-subunits with multiple isoforms for each subunit. It has been shown that AMPK activity is increased in cardiac hypertrophy and failure but it is unknown whether changes in subunit composition of AMPK contribute to the altered AMPK activity. In this study, we determined the protein expression pattern of AMPK subunit isoforms during cardiac development as well as during cardiac hypertrophy and heart failure in mouse heart. We also compared the findings in failing mouse heart to that of the human failing hearts in order to determine whether the mouse heart is a good model of AMPK in human diseases. In mouse developmental hearts, AMPK was highly expressed in the fetal stages and fell back to the adult level after birth. In the failing mouse heart, there was a significant increase in α2, β2, and γ2 subunits both at the mRNA and protein levels. In contrary, we found significant increases in the protein level of α1, β1 and γ2c subunits in human failing hearts with no change in the mRNA level. We also compared isoform-specific AMPK activity in the mouse and human failing hearts. Consistent with the literature, in the failing mouse heart, the α2 complexes accounted for ~2/3 of total AMPK activity while the α1 complexes accounted for the remaining 30-35%. In the human hearts, however, the contribution of α1-AMPK activity was significantly higher (>40%) in the non-failing hearts, and it further increased to 50% in the failing hearts. Thus, the human hearts have a greater amount of α1-AMPK activity compared to the rodent hearts. In summary, the protein level and the isoform distribution of AMPK in the heart change significantly during normal development as well as in heart failure. These observations provide a basis for future development of therapeutic strategies for targeting AMPK.

Dataset Information

Dietary fat supply to failing hearts determines dynamic lipid signaling for nuclear receptor activation and oxidation of stored triglyceride.

Publications

Dietary fat supply to failing hearts determines dynamic lipid signaling for nuclear receptor activation and oxidation of stored triglyceride.

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