Cardiac peroxisome proliferator-activated receptor-α activation causes increased fatty acid oxidation, reducing efficiency and post-ischaemic functional loss

Hafstad, Anne Dragøy; Khalid, Ahmed M.; Hagve, Martin; Lund, Trine Meldgaard; Larsen, Terje S.; Severson, David L.; Clarke, Kieran; Berge, Rolf K.; Aasum, Ellen

doi:10.1093/cvr/cvp132

Cited by 55 publications

(61 citation statements)

References 36 publications

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“…After 30-min equilibration the unlabeled glucose, lactate, palmitate, and ketone in the buffer was switched to 13 C]3-HB) at the same concentrations as the unlabeled compounds, as described in more detail below. After 30 min of perfusion with labeled substrates, whole hearts were freeze clamped, the frozen hearts pulverized, and the heart tissue was homogenized and extracted with ice-cold 6% perchloric acid.…”

Section: Animals and Dietsmentioning

confidence: 99%

“…Proton-decoupled, NOE-enhanced 13 C NMR spectra were collected on a Bruker AVANCE 500 NMR spectrometer operating at 11.85 T using a TBI heteronuclear broadband probe. Spectra were collected at 300 K with spectral width 25 kHz and 32k data points.…”

Section: Animals and Dietsmentioning

confidence: 99%

“…Spectra were analyzed with Nuts software (AcornNMR, Livermore, CA). 13 C time domain data were processed with 1 to 2 Hz line broadening, zerofilled, Fourier transformed, and referenced to the methyl carbon peak of lactate (at 21.1 ppm). The glutamate 13 C NMR multiplet relative areas at carbons 1 through 5, and the integrated areas of the C3 and C4 resonances (corrected for relaxation effects) were measured as described previously (26,27).…”

Section: Animals and Dietsmentioning

confidence: 99%

“…Black filled circles represent carbon-13 labeling (98 to 99% enrichment), open circles natural abundance (i.e., 99% carbon-12) labeling, and gray circles may be either carbon-12 or carbon-13 as they do not contribute to the glutamate C-4 spectrum. In the 13 C NMR spectrum on the right, K represents isotopomer peaks derived from ketone (3-HB); C represents those derived from carbohydrate (glucose, lactate, and pyruvate). Note that ␤-oxidation of [1][2][3][4][5][6][7][8][9][10][11][12][13] C]palmitate results in seven unlabeled acetyl-CoA fragments and one [1-ketone buffer, high insulin led to decreased FFA oxidation and upregulated ketone oxidation (P Ͻ 0.05 for high insulin compared with low insulin with the same ketone level, perfusion condition, and diet); this effect was not seen with low ketone buffer.…”

Section: Impact Of Perfusion Buffer Composition (Insulin and Ketone Lmentioning

confidence: 99%

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Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion

Liu

Wang

Douglas

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Liu J, Wang P, Douglas SL, Tate JM, Sham S, Lloyd SG. Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion. Am J Physiol Heart Circ Physiol 311: H1-H10, 2016. First published May 6, 2016; doi:10.1152/ajpheart.00809.2015.-High-fat, low-carbohydrate Diet (HFLCD) impairs the myocardial response to ischemia-reperfusion, but the underlying mechanisms remain elusive. We sought to determine the magnitude of diet-induced alterations in intrinsic properties of the myocardium (including insulin sensitivity and substrate oxidation) and circulating substrate and insulin differences resulting from diet, leading to this impaired response. Rats were fed HFLCD (60% kcal from fat/30% protein/10% carbohydrate) or control diet (CONT) (16%/19%/65%) for 2 wk. Isolated hearts underwent global low-flow ischemia followed by reperfusion (I/R). Carbon-13 NMR spectroscopy was used to determine myocardial substrate TCA cycle entry. Myocardial insulin sensitivity was assessed as dose-response of Akt phosphorylation. There was a significant effect of HFLCD and I/R with both these factors leading to an increase in free fatty acid (FFA) oxidation and a decrease in carbohydrate or ketone oxidation. Following I/R, HFLCD led to decreased ketone and increased FFA oxidation; the recovery of left ventricular (LV) function was decreased in HFLCD and was negatively correlated with FFA oxidation and positively associated with ketone oxidation. HFLCD also resulted in reduced insulin sensitivity. Under physiologic ranges, there were no direct effects of buffer insulin and ketone levels on oxidation of any substrate and recovery of cardiac function after I/R. An insulinketone interaction exists for myocardial substrate oxidation characteristics. We conclude that the impaired recovery of function after ischemia-reperfusion with HFLCD is largely due to intrinsic diet effects on myocardial properties, rather than to diet effect on circulating insulin or substrate levels. diet; myocardial ischemia-reperfusion injury; insulin; metabolism NEW & NOTEWORTHYThe substrate oxidation and response to I/R are more dependent on diet than on physiologic range changes in circulating substrate and insulin. This was associated with altered insulin sensitivity. After I/R, there was a positive (with ketone) and negative (with FFA) correlation between recovery of function and substrate oxidation.HIGH-FAT, LOW-CARBOHYDRATE DIETS (HFLCD S ) are used by many people in an effort to lose weight. The effect of such diets on cardiovascular health has been the subject of intense investigation. Population studies evaluating the impact of HFLCD on cardiovascular clinical outcomes have provided a range of results, with some finding favorable changes in cardiovascular disease risk factors (9, 35, 37), and others showing an increased risk of adverse outcomes in both animal (29) and human studies, including in the setting of myocardial infarction (23). Consistent with this latter finding, we have p...

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Section: Animals and Dietsmentioning

confidence: 99%

Section: Animals and Dietsmentioning

confidence: 99%

Section: Animals and Dietsmentioning

confidence: 99%

Section: Impact Of Perfusion Buffer Composition (Insulin and Ketone Lmentioning

confidence: 99%

See 2 more Smart Citations

Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion

Liu

Wang

Douglas

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…Nuclear receptor PPARα is a ligand-inducible transcription factor and is highly expressed in the heart (18). In the absence of the ligand, PPARα recruits corepressors to repress transcription with its obligate heterodimeric partner, the retinoid X receptor (RXR).…”

Section: Effect Of Fenofibrate Treatment On Nrf-1-l and Nrf-1-s Gene mentioning

confidence: 99%

Improvement of myocardial lipid accumulation and prevention of PGC-1α induction by fenofibrate

Yao

Zhang

et al. 2012

Mol Med Report

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Abstract. We recently demonstrated that fenofibrate induces the activities of citrate synthase and NADH oxidase in cardiac mitochondria. To further determine the molecular mechanisms underlying fenofibrate action, 8-week-old mice were administered fenofibrate (100 mg/kg/day) for 7 and 14 days, and the expression of genes involved in cardiac mitochondrial function, such as nuclear respiratory factor 1 transcript variant 2 (NRF-1-L) and 6 (NRF-1-S), mitochondrial outer membrane protein 40 (Tom40), lipoic acid synthetase (Lias), cytochrome b, medium-chain acyl-coenzyme A dehydrogenase (MCAD) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) was determined. Expression of PGC-1α, a key regulator of the entire fatty acid oxidation system, was significantly downregulated after 14 days of fenofibrate administration. Moreover, ventricular triglycerides were also accumulated following 14 days of fenofibrate administration. Thus, fenofibrate functions to improve myocardial lipid accumulation and to prevent PGC-1α induction, which is crucial for understanding the molecular mechanisms underlying fenofibrate action on the heart.

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Dill seed extract improves abnormalities in lipid metabolism through peroxisome proliferator‐activated receptor‐α (PPAR‐α) activation in diabetic obese mice

Takahashi

Yao

Kim

et al. 2013

Molecular Nutrition Food Res

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Dill, a small annual herb, is widely used as a flavoring agent in dishes including salads. It has been demonstrated that dill extract and its essential oil show hypolipidemic effects in rats. However, the mechanism of these effects has not been elucidated yet. We found that dill seed extract (DSE) activated peroxisome proliferator-activated receptor-α (PPAR-α), an indispensable regulator for hepatic lipid metabolism, by luciferase assay. Thus, we performed DSE feeding experiments using diabetic obese model KK-Ay mice to examine the effects of DSE on PPAR-α activation in vivo. A 4-week feeding of DSE contained in a high-fat diet decreased plasma triacylglyceride and glucose levels and increased the mRNA expression levels of fatty acid oxidation-related genes in the liver. In addition, the DSE feeding as well as bezafibrate (a PPAR-α potent agonist) feeding increased oxygen consumption rate and rectal temperature. These results indicate that DSE suppresses high-fat diet-induced hyperlipidemia through hepatic PPAR-α activation.

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Cardiac peroxisome proliferator-activated receptor-α activation causes increased fatty acid oxidation, reducing efficiency and post-ischaemic functional loss

Abstract: This study for the first time observed that in vivo administration of a synthetic PPARalpha ligand elevated FA oxidation, an effect that was also associated with decreased cardiac efficiency and reduced post-ischaemic functional recovery.

Cited by 55 publications

References 36 publications

Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion

Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion

Improvement of myocardial lipid accumulation and prevention of PGC-1α induction by fenofibrate

Dill seed extract improves abnormalities in lipid metabolism through peroxisome proliferator‐activated receptor‐α (PPAR‐α) activation in diabetic obese mice

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