Abstract 19826: Cardiac DGAT1 Deficiency Decreases Triglyceride Turnover and Alters Substrate Utilization

Abstract

Triglyceride (TG) metabolism in the heart has been suggested to regulate PPARα activity and fatty acid oxidation. Reduced TG content and turnover has also been shown in rodent models of heart failure. We found that patients with heart failure displayed decreased mRNA levels of diacylglycerol:acyltransferase 1 (DGAT1), the rate limiting enzyme in TG synthesis (0.56±0.06 fold of NF, p=0.0001) and a lower myocardial TG content (3.65±0.41 vs. 8.27±1.48 mg/g tissue in NF, n=8-11, p=0.019). Therefore we hypothesized reduced TG synthesis caused metabolic remodeling in heart failure. In mice with tamoxifen-inducible cardiac specific deletion of DGAT1 (iKO) TG turnover was reduced. 13 C NMR spectroscopy in perfused hearts revealed a 30% reduction in incorporation of labeled fatty acids (FA) into TG in iKO (40 minute peak area 7.86±0.26 vs. 5.73±0.50) with no changes in total TG content. To test whether these changes affect myocardial energetics and contractile function, we simultaneously measured high energy phosphate content and contractile function using 31 P NMR in isolated perfused hearts. Contractile function and PCr/ATP ratio was unchanged in iKO hearts perfused with FA, lactate and glucose. Furthermore, there is no difference between genotypes in the expression of PPARα or its downstream target genes at baseline or after 5 weeks of high fat diet, indicating that TG turnover has minimal effect on PPARα activity. However, iKO hearts showed increased oxidation of exogenous fatty acid (67.0±4.1% vs. 48.5±5.3%) and reduced glucose oxidation (12.9±4.2% vs. 27.4±4.5%, n=5-7). These observations suggest that reduced TG synthesis diverts exogenous FA from the TG pool towards oxidative metabolism. To evaluate the dependence of iKO hearts upon exogenous FA, hearts were perfused with glucose as the only substrate. The ability to utilize TG was reduced in iKO resulting in a 50% higher TG content after 20 min perfusion, which was associated with a reduced left ventricular developed pressure (119±6 vs. 97±7 mmHg for control and iKO respectively). Taken together, we found that DGAT1 deficiency in the heart reduced TG turnover and increased reliance on the oxidation of exogenous FA, a phenotype that may contribute to the lack of metabolic flexibility in heart failure.