Disruption of mitochondrial beta -oxidation of unsaturated fatty acids in the 3,2-trans-enoyl-CoA isomerase-deficient mouse.
Cellular energy metabolism is largely sustained by mitochondrial beta-oxidation of saturated and unsaturated fatty acids. To study the role of unsaturated fatty acids in cellular lipid and energy metabolism we generated a null allelic mouse, deficient in 3,2-trans-enoyl-CoA isomerase (ECI) (eci(-/-) mouse). ECI is the link in mitochondrial beta-oxidation of unsaturated and saturated fatty acids and essential for the complete degradation and for maximal energy yield. Mitochondrial beta-oxidation of unsaturated fatty acids is interrupted in eci(-/-)mice at the level of their respective 3-cis- or 3-trans-enoyl-CoA intermediates. Fasting eci(-/-) mice accumulate unsaturated fatty acyl groups in ester lipids and deposit large amounts of triglycerides in hepatocytes (steatosis). Gene expression studies revealed the induction of peroxisome proliferator-activated receptor activation in eci(-/-) mice together with peroxisomal beta- and microsomal omega-oxidation enzymes. Combined peroxisomal beta- and microsomal omega-oxidation of the 3-enoyl-CoA intermediates leads to a specific pattern of medium chain unsaturated dicarboxylic acids excreted in the urine in high concentration (dicarboxylic aciduria). The urinary dicarboxylate pattern is a reliable diagnostic marker of the ECI genetic defect. The eci(-/-) mouse might be a model of a yet undefined inborn mitochondrial beta-oxidation disorder lacking the enzyme link that channels the intermediates of unsaturated fatty acids into the beta-oxidation spiral of saturated fatty acids.
Janssen
Uwe
U
Laboratory of Molecular Neurosciences, Institute of Biochemistry, Faculty of Medicine, University of Cologne, Joseph-Stelzmannstrasse 52, D-50931 Cologne, Germany.
Stoffel
Wilhelm
W
D000483:Alleles; D000818:Animals; D015152:Blotting, Northern; D019748:Carbon-Carbon Double Bond Isomerases / Q000235:genetics* / Q000502:physiology*; D002855:Chromatography, Thin Layer; D064006:Dodecenoyl-CoA Isomerase; D005227:Fatty Acids / Q000378:metabolism*; D005822:Genetic Vectors; D022781:Hepatocytes / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D010641:Phenotype; D013997:Time Factors; D014018:Tissue Distribution; D014280:Triglycerides / Q000378:metabolism
D005227:Fatty Acids; D014280:Triglycerides; D019748:Carbon-Carbon Double Bond Isomerases; D064006:Dodecenoyl-CoA Isomerase; C576299:Eci1 protein, mouse; D010100:Oxygen