Nutrition-related diseases such as obesity and diabetes mellitus exhibit defective acyl-CoA partitioning which affects beta-oxidation and triacylglycerol stores. Acyl CoA synthetase (ACS) catalyzes the first step in fatty acid The purpose of this study is to identify the role of the ACS5 isoform in fatty acid partitioning between pathway energy production and glycerolipid synthesis. ACS5 and ACS5 antisense mRNA will be overexpressed in primary hepatocyte cultures via recombinant adenoviral technology. Incorporation of 14-C oleate into products of beta oxidation and lipid synthesis will be measured to determine the effects of excess or reduced enzyme levels on pathways. Additionally, ACS5 will be expressed in primary hepatocytes isolated from mice lacking function mitochondrial glycerol-3-phosphate acyltransferase (GPAT), which catalyzes the initial step in glycerolipid synthesis. These experiments will determine if excess or reduced enzyme levels of ACS5 alter rates of beta-oxidation and lipid synthesis in the presence and absence of GPAT, reduce the metabolic effects of hormonal stimuli, or increase lipid synthesis when beta-oxidation is inhibited. We hypothesize that ACS5 participates in fatty acid partitioning by providing acyl-CoAs primarily for energy production by beta-oxidation.
| Mashek, Douglas G; McKenzie, Michelle A; Van Horn, Cynthia G et al. (2006) Rat long chain acyl-CoA synthetase 5 increases fatty acid uptake and partitioning to cellular triacylglycerol in McArdle-RH7777 cells. J Biol Chem 281:945-50 |
| Van Horn, Cynthia G; Caviglia, Jorge M; Li, Lei O et al. (2005) Characterization of recombinant long-chain rat acyl-CoA synthetase isoforms 3 and 6: identification of a novel variant of isoform 6. Biochemistry 44:1635-42 |
