Transgenic studies of fatty acid oxidation gene expression in nonobese diabetic mice

Type 1 diabetes mellitus is a devastating disorder affecting both glucose a nd lipid metabolism. Using the non-obese diabetic (NOD) mouse model, we fou nd that diabetic mice had a liver-specific increase in steady state mRNA le vels for enzymes involved in oxidation of fatty acids. Increased mRNA abund ance was observed in very long-chain acyl-CoA dehydrogenase, long-chain acy l-CoA dehydrogenase (LCAD), medium-chain acyl-CoA. dehydrogenase (MCAD), ca rnitine palmitoyltransferase I (CPT-1a), and the gluconeogenic enzyme phosp hoenolpyruvate carboxykinase, whereas short-chain acyl-CoA dehydrogenase mR NA remained unchanged. In contrast, minimal elevations in LCAD and CPT-1a m RNA were observed in hearts of diabetic mice with no significant difference s found for the other enzymes, We developed NOD mice with transgenes contai ning regulatory elements of human MCAD gene controlling a reporter gene to determine if the increase in MCAD gene expression occurred via the well-cha racterized nuclear receptor response element (NRRE-1). These results demons trated that the transgene containing the NRRE-1 and adjacent 5' sequences h ad elevated liver expression in diabetic mice compared with prediabetic or normal control mice. Surprisingly, the transgene that contains NRRE-1 with adjacent 3' sequences and the transgene with the NRRE-1 deleted showed mini mal response to the fulminant diabetic condition. Collectively, these resul ts indicate that in type I diabetes there exists an excessive and liver-spe cific activation of fatty acid oxidation gene expression. Using human MCAD as a prototype gene, we have shown that this increased expression is mediat ed at the transcriptional level but does not occur via the well-characteriz ed NRRE-1 site responsible for baseline expression in normal mice.