Julie H. Rennison

High-fat diet prevents cardiac hypertrophy and improves contractile function in the hypertensive dahl salt-sensitive rat.

1. The role that dietary lipid and plasma fatty acid concentration play in the development of cardiac hypertrophy in response to hypertension is not clear.

Prolonged exposure to high dietary lipids is not associated with lipotoxicity in heart failure.

Previous studies have reported that elevated myocardial lipids in a model of mild-to-moderate heart failure increased mitochondrial function, but did not alter left ventricular function. Whether more prolonged exposure to high dietary lipids would promote a lipotoxic phenotype in mitochondrial and myocardial contractile function has not been determined. We tested the hypothesis that prolonged exposure to high dietary lipids, following coronary artery ligation, would preserve myocardial and mitochondrial function in heart failure. Rats underwent ligation or sham surgery and were fed normal (10% kcal fat) (SHAM, HF) or high fat diet (60% kcal saturated fat) (SHAM+FAT, HF+FAT) for sixteen weeks. Although high dietary fat was accompanied by myocardial tissue triglyceride accumulation (SHAM 1.47+/-0.14; SHAM+FAT 2.32+/-0.14; HF 1.34+/-0.14; HF+FAT 2.21+/-0.20 micromol/gww), fractional shortening was increased 16% in SHAM+FAT and 28% in HF+FAT compared to SHAM and HF, respectively. Despite increased medium-chain acyl-CoA dehydrogenase (MCAD) activity in interfibrillar mitochondria (IFM) of both SHAM+FAT and HF+FAT, dietary lipids also were associated with decreased state 3 respiration using palmitoylcarnitine (SHAM 369+/-14; SHAM+FAT 307+/-23; HF 354+/-13; HF+FAT 366+/-18 nAO min(-1) mg(-1)) in SHAM+FAT compared to SHAM and HF+FAT. State 3 respiration in IFM also was decreased in SHAM+FAT relative to SHAM using succinate and DHQ. In conclusion, high dietary lipids promoted myocardial lipid accumulation, but were not accompanied by alterations in myocardial contractile function typically associated with lipotoxicity. In normal animals, high dietary fat decreased mitochondrial respiration, but also increased MCAD activity. These studies support the concept that high fat feeding can modify multiple cellular pathways that differentially affect mitochondrial function under normal and pathological conditions.

Enhanced acyl-CoA dehydrogenase activity is associated with improved mitochondrial and contractile function in heart failure

AIMS Heart failure is associated with decreased myocardial fatty acid oxidation capacity and has been likened to energy starvation. Increased fatty acid availability results in an induction of genes promoting fatty acid oxidation. The aim of the present study was to investigate possible mechanisms by which high fat feeding improved mitochondrial and contractile function in heart failure. METHODS AND RESULTS Male Wistar rats underwent coronary artery ligation (HF) or sham surgery and were immediately fed either a normal (14% kcal fat) (SHAM, HF) or high-fat diet (60% kcal saturated fat) (SHAM+FAT, HF+FAT) for 8 weeks. Mitochondrial respiration and gene expression and enzyme activities of fatty acid-regulated mitochondrial genes and proteins were assessed. Subsarcolemmal (SSM) and interfibrillar mitochondria were isolated from the left ventricle. State 3 respiration using lipid substrates octanoylcarnitine and palmitoylcarnitine increased in the SSM of HF+FAT compared with SHAM+FAT and HF, respectively (242 +/- 21, 246 +/- 21 vs. 183 +/- 8, 181 +/- 6 and 193 +/- 17, 185 +/- 16 nAO min(-1) mg(-1)). Despite decreased medium-chain acyl-CoA dehydrogenase (MCAD) mRNA in HF and HF+FAT, MCAD protein was not altered, and MCAD activity increased in HF+FAT (HF, 65.1 +/- 2.7 vs. HF+FAT, 81.5 +/- 5.4 nmoles min(-1) mg(-1)). Activities of short- and long-chain acyl-CoA dehydrogenase also were elevated and correlated to increased state 3 respiration. This was associated with an improvement in myocardial contractility as assessed by left ventricular +dP/dt max. CONCLUSION Administration of a high-fat diet increased state 3 respiration and acyl-CoA dehydrogenase activities, but did not normalize mRNA or protein levels of acyl-CoA dehydrogenases in coronary artery ligation-induced heart failure rats.

Dissociation between gene and protein expression of metabolic enzymes in a rodent model of heart failure

Studies in advanced heart failure show down‐regulation of fatty acid oxidation genes, possibly due to decreased expression of the nuclear transcription factors peroxisome proliferator activated receptor α (PPARα) and retinoid X receptor α (RXRα). We assessed mRNA and protein expression of PPARα and RXRα, and for several PPAR/RXR regulated metabolic proteins at 8 and 20 weeks following myocardial infarction induced by coronary artery ligation. Infarction resulted in heart failure, as indicated by reduced LV fractional shortening and increased end diastolic area compared to sham. There was a progressive increase in LV end systolic area, myocardial ceramide content and atrial natriuretic peptide mRNA, and a deterioration in LV fractional area of shortening from 8 to 20 weeks. Protein and mRNA expression of PPARα and RXRα were not different among groups. The mRNA for PPAR/RXR regulated genes (e.g. medium chain acyl‐CoA dehydrogenase (MCAD)) was down‐regulated at 8 and 20 weeks post‐infarction; however, neither the protein expression nor activity of MCAD was reduced compared to sham. In conclusion, reduced mRNA expression of PPAR/RXR regulated genes is not dependent on reduced PPAR/RXR protein expression.

CARNITINE PALMITOYL TRANSFERASE-I INHIBITION IS NOT ASSOCIATED WITH CARDIAC HYPERTROPHY IN RATS FED A HIGH-FAT DIET

1 Cardiac lipotoxicity is characterized by hypertrophy and contractile dysfunction and can be triggered by impaired mitochondrial fatty acid oxidation and lipid accumulation. The present study investigated the effect of dietary fatty acid intake alone and in combination with inhibition of mitochondrial fatty acid uptake with the carnitine palmitoyl transferase (CPT)‐I inhibitor oxfenicine. Long‐chain fatty acids activate peroxisome proliferator‐activated receptors (PPAR), thus mRNA levels of PPAR target genes were measured. 2 Rats were untreated or given the CPT‐I inhibitor oxfenicine (150 mg/kg per day) and were fed for 8 weeks with either: (i) standard low‐fat chow (10% of energy from fat); (ii) a long‐chain saturated fatty acid diet; (iii) a long‐chain unsaturated fatty acid diet; or (iv) a medium‐chain fatty acid diet (which bypasses CPT‐I). High‐fat diets contained 60% of energy from fat. 3 Cardiac triglyceride content was increased in the absence of oxfenicine in the saturated fat group compared with other diets. Oxfenicine treatment further increased cardiac triglyceride stores in the saturated fat group and caused a significant increase in the unsaturated fat group. Despite elevations in triglyceride stores, left ventricular mass, end diastolic volume and systolic function were unaffected. 4 The mRNA levels of PPAR‐regulated genes were increased by the high saturated and unsaturated fat diets compared with standard chow or the medium chain fatty acid chow. Oxfenicine did not further upregulate PPARα target genes within each dietary treatment group. 5 Taken together, the data suggest that consuming a high‐fat diet or inhibiting CPT‐I do not result in cardiac hypertrophy or cardiac dysfunction in normal rats.