Disruption of Mitochondrial β-Oxidation of Unsaturated Fatty Acids in the 3,2-trans-Enoyl-CoA Isomerase-deficient Mouse

Abstract

Cellular energy metabolism is largely sustained by mitochondrial ␤-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 ␤-oxidation of unsaturated and saturated fatty acids and essential for the complete degradation and for maximal energy yield. Mitochondrial ␤-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 ␤-and microsomal -oxidation enzymes. Combined peroxisomal ␤-and microsomal -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 ␤-oxidation disorder lacking the enzyme link that channels the intermediates of unsaturated fatty acids into the ␤-oxidation spiral of saturated fatty acids.Long chain saturated and unsaturated (mono-and polyunsaturated) fatty acids comprising members of the -3 (␣-linolenic), -6 (linoleic), and -9 (oleic acid) families occur almost equally as acyl groups of phospholipids and triglycerides. In phospholipids they are essential in the regulation of the fluidity of biological membranes. -3 and -6 polyunsaturated fatty acids are the precursors in eicosanoid synthesis (prostaglandins, prostacyclins, thromboxanes, and leukotrienes). As constituents of triglycerides, unsaturated fatty acids are a main energy source for muscle work.Following the classical pathway of mitochondrial ␤-oxidation of unsaturated fatty acids with cis double bonds at odd-numbered C atoms, e.g. of oleic acid (18:1 9 ), linoleic acid (18:1 9,12 ), and ␣-linolenic acid (18:1 9,12,15 ), yields 3-cis-enoyl-CoA-intermediates. They are isomerized by the mitochondrial 3,2-transenoyl-CoA isomerase (ECI) 1 (EC 5.3.3.8) to their respective 2-trans-enoyl-CoA isomers, common substrates of enoyl-CoA hydratase of the ␤-oxidation cycle of saturated fatty acyl-CoA esters (1). cis double bonds at even C atoms yield 2-trans-4-cisintermediates, which are reduced and isomerized by a mitochondrial NADPH-dependent 2,4-dienoyl-CoA reductase (EC 1.3.1.34) to their respective 3-trans-intermediates (2-4). Hydration to the D(Ϫ)-3-hydroxy derivative followed by epimerization by 3-hydroxyacyl-CoA epimerase (EC 5.1.2.3) is apparently an alternative but minor pathway. Likewise, another alternative pathway has been proposed, according to which a cis-5 do...

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