Abstract 775: Substrate Availability Regulates Energy Metabolism via Transcriptional Mechanisms
The present study investigated the mechanisms by which enhanced substrate availability regulates cardiac metabolism and function. Chronic elevation of intracellular glucose levels were achieved by overexpressing GLUT1 in mouse hearts (TG), while chronic elevation of fatty acids (FA) availability were achieved by feeding wild-type (WT) and TG mice a high fat (HF) diet (45% energy from fat) for 20 weeks. 13C-NMR studies showed that fatty acid oxidation (FAO) failed to increase in HF-TG hearts, although it increased by 50% in HF-WT hearts (p<0.01 vs. WT). Myocardial malonyl-CoA levels were elevated by 30% in both TG and HF-TG compared to WT (p<0.05), suggesting inhibition of mCPT-1 by malonyl-CoA contributed to decreased FAO observed in TG hearts. Transcript analysis revealed increased expression of ACCα and ACCβ by 5.2 fold and 1.3 fold respectively, in TG vs. WT hearts (p<0.01 for both); these increases were sustained in HF-TG hearts but not observed in HF-WT. Glucose mediated suppression of FAO in the face of increased FA availability in HF-TG hearts was associated with impaired LV fractional shortening (p<0.01). However, induction of known PPARα target genes was greater in HF-TG hearts versus HF-WT hearts, which was associated with a greater decrease in PPARα expression in TG hearts versus WT hearts, independent of diet. In conclusion, we have shown that long-term increases in either glucose or FA supply cause upregulation of PPARα target genes with feedback inhibition of PPARα expression while the induction of ACC by increased glucose supply ultimately minimizes myocardial FAO. Although these mechanisms allow the heart to adapt to periods of increased glucose or fatty acids supply alone, they fail to accommodate simultaneous increases of both substrates (e.g. during diabetes), resulting in contractile dysfunction (i.e. glucolipotoxicity).