Title: Carnitine palmitoyl transferase-I inhibition is not associated with cardiac hypertrophy in rats fed a high fat diet Authors
|Okere, Isidore - CASE WESTERN RESERVE UNIV|
|Chandler, Margaret - CASE WESTERN RESERVE UNIV|
|Mcelfresh, Tracy - CASE WESTERN RESERVE UNIV|
|Rennison, Julie - CASE WESTERN RESERVE UNIV|
|Kung, Theodore - CASE WESTERN RESERVE UNIV|
|Hoit, Brian - CASE WESTERN RESERVE UNIV|
|Ernsberger, Paul - CASE WESTERN RESERVE UNIV|
|Stanley, William - CASE WESTERN RESERVE UNIV|
Submitted to: Clinical and Experimental Pharmacology and Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: June 25, 2006
Publication Date: February 20, 2007
Citation: Okere, I.C., Chandler, M.P., McElfresh, T.A., Rennison, J.H., Kung, T.A., Hoit, B.D., Ernsberger, P., Young, M.E., Stanley, W.C. 2007. Carnitine palmitoyl transferase-I inhibition is not associated with cardiac hypertrophy in rats fed a high fat diet. Clinical and Experimental Pharmacology and Physiology. 34:113-119. Interpretive Summary: An increase in blood pressure (hypertension) causes an enlargement of the heart cells. This is called hypertrophy. Development of hypertrophy is an early event in most forms of heart disease. During hypertrophy, the heart changes its preference in the fuel that it uses for energy, from fat to carbohydrate. This has lead to the opposite question, that being whether forcing the heart to use glucose will cause hypertrophy. The present study addressed this question, by inhibiting an enzyme called carnitine palmitoyl transferase-I, which in turn increases glucose use by the heart. The results show that inhibition of carnitine palmitoyl transferase-I did not cause hypertrophy in an animal model. This results may be useful in designing future therapies for human heart disease.
Technical Abstract: 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. 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. 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. 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 PPARalpha target genes within each dietary treatment group. 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.