In the United States, the rise in obesity and diabetes has led to a concomitant increase in the incidence of heart disease. An increased incidence of cardiovascular disease is the most common complication of non-insulin dependent diabetes (NIDDM) (1). In addition to atherosclerosis, NIDDM is associated with a specific cardiomyopathy resulting in ventricular dysfunction (1). Autopsies and animal studies have identified an increase in interstitial collagen and myocardial fibrosis which causes the physiological changes observed in the heart muscle (2). Recent studies indicate that excessive deposition of triacylglycerol (TAG) in the heart leads to apoptosis and fibrosis, providing a mechanism for the loss of cardiac function (3, 4). Glycerol-3-phosphate acyltransferase (GPAT) is, perhaps, the most important site in regulating triacylglycerol synthesis because it catalyzes the initial, committed, and rate limiting step (5). Our studies indicate, surprisingly, that compared to other organs that synthesize triacylglycerol (liver and adipose), the expression of mitochondrial GPAT protein is highest in the heart although activity is very low, suggesting that GPAT may be allosterically regulated. Our experiments also show that rat heart mitochondrial GPAT activity is up-regulated following a 48 h fast. These results, together with the findings in a recent study showing up-regulation of GPAT mRNA in the hearts of diabetic obese fa/fa rats (4), suggest that heart GPAT dysregulation under conditions of high fatty acid influx, such as diabetes, obesity, and fasting, may play an important role in the accumulation of triacylglycerol. The overall aim of this proposal is to elucidate the regulation of mitochondrial GPAT and its role in myocardial triacylglycerol accumulation, apoptosis and fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01DK059931-01A1
Application #
6485152
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2002-07-01
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$89,754
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Nutrition
Type
Schools of Public Health
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Lewin, Tal M; de Jong, Hendrik; Schwerbrock, Nicole J M et al. (2008) Mice deficient in mitochondrial glycerol-3-phosphate acyltransferase-1 have diminished myocardial triacylglycerol accumulation during lipogenic diet and altered phospholipid fatty acid composition. Biochim Biophys Acta 1781:352-8
Stinnett, Lori; Lewin, Tal M; Coleman, Rosalind A (2007) Mutagenesis of rat acyl-CoA synthetase 4 indicates amino acids that contribute to fatty acid binding. Biochim Biophys Acta 1771:119-25
de Jong, Hendrik; Neal, Andrea C; Coleman, Rosalind A et al. (2007) Ontogeny of mRNA expression and activity of long-chain acyl-CoA synthetase (ACSL) isoforms in Mus musculus heart. Biochim Biophys Acta 1771:75-82
Caviglia, Jorge M; Li, Lei O; Wang, Shuli et al. (2004) Rat long chain acyl-CoA synthetase 5, but not 1, 2, 3, or 4, complements Escherichia coli fadD. J Biol Chem 279:11163-9
Lewin, Tal M; Schwerbrock, Nicole M J; Lee, Douglas P et al. (2004) Identification of a new glycerol-3-phosphate acyltransferase isoenzyme, mtGPAT2, in mitochondria. J Biol Chem 279:13488-95
Lewin, Tal M; Coleman, Rosalind A (2003) Regulation of myocardial triacylglycerol synthesis and metabolism. Biochim Biophys Acta 1634:63-75