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Mitochondrial 2,4-dienoyl-CoA reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis.

Miinalainen IJ, Schmitz W, Huotari A, Autio KJ, Soininen R, Ver Loren van Themaat E, Baes M, Herzig KH, Conzelmann E, Hiltunen JK - PLoS Genet. (2009)

Bottom Line: Enzyme defects in this pathway cause fatty acid oxidation disorders.Furthermore, the thermogenic response was perturbed, as demonstrated by intolerance to acute cold exposure.This study highlights the necessity of DECR and the breakdown of unsaturated fatty acids in the transition of intermediary metabolism from the fed to the fasted state.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.

ABSTRACT
The mitochondrial beta-oxidation system is one of the central metabolic pathways of energy metabolism in mammals. Enzyme defects in this pathway cause fatty acid oxidation disorders. To elucidate the role of 2,4-dienoyl-CoA reductase (DECR) as an auxiliary enzyme in the mitochondrial beta-oxidation of unsaturated fatty acids, we created a DECR-deficient mouse line. In Decr(-/-) mice, the mitochondrial beta-oxidation of unsaturated fatty acids with double bonds is expected to halt at the level of trans-2, cis/trans-4-dienoyl-CoA intermediates. In line with this expectation, fasted Decr(-/-) mice displayed increased serum acylcarnitines, especially decadienoylcarnitine, a product of the incomplete oxidation of linoleic acid (C(18:2)), urinary excretion of unsaturated dicarboxylic acids, and hepatic steatosis, wherein unsaturated fatty acids accumulate in liver triacylglycerols. Metabolically challenged Decr(-/-) mice turned on ketogenesis, but unexpectedly developed hypoglycemia. Induced expression of peroxisomal beta-oxidation and microsomal omega-oxidation enzymes reflect the increased lipid load, whereas reduced mRNA levels of PGC-1alpha and CREB, as well as enzymes in the gluconeogenetic pathway, can contribute to stress-induced hypoglycemia. Furthermore, the thermogenic response was perturbed, as demonstrated by intolerance to acute cold exposure. This study highlights the necessity of DECR and the breakdown of unsaturated fatty acids in the transition of intermediary metabolism from the fed to the fasted state.

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β-oxidation of fatty acids with double bonds at even- or odd-numbered positions in mitochondria.Degradation of fatty acids with even-numbered double bonds results in 2,4-dienoyl-CoA esters, which are oxidized as shown on the left. 2,5-dienoyl-CoA esters arising from odd-numbered double bonds can be oxidized either via an isomerase-dependent pathway (middle) or via a reductase-dependent pathway (right). AD, acyl-CoA dehydrogenase (EC 1.3.3.6, EC 1.3.99.3, EC 1.3.99.13 or EC 1.3.99.-); EH, enoyl-CoA hydratase (EC 4.1.2.17 or EC 4.2.1.74); HD, 3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35 or EC 1.1.1.211); KT, 3-ketoacyl thiolase (EC 2.3.1.16) ; ECI, Δ3,Δ2-enoyl isomerase (EC 5.3.3.8); DECI, Δ3,5,Δ2,4-dienoyl-CoA isomerase (no EC number available); DECR (shown in bold), 2,4-dienoyl-CoA reductase (EC 1.3.1.34).
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pgen-1000543-g001: β-oxidation of fatty acids with double bonds at even- or odd-numbered positions in mitochondria.Degradation of fatty acids with even-numbered double bonds results in 2,4-dienoyl-CoA esters, which are oxidized as shown on the left. 2,5-dienoyl-CoA esters arising from odd-numbered double bonds can be oxidized either via an isomerase-dependent pathway (middle) or via a reductase-dependent pathway (right). AD, acyl-CoA dehydrogenase (EC 1.3.3.6, EC 1.3.99.3, EC 1.3.99.13 or EC 1.3.99.-); EH, enoyl-CoA hydratase (EC 4.1.2.17 or EC 4.2.1.74); HD, 3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35 or EC 1.1.1.211); KT, 3-ketoacyl thiolase (EC 2.3.1.16) ; ECI, Δ3,Δ2-enoyl isomerase (EC 5.3.3.8); DECI, Δ3,5,Δ2,4-dienoyl-CoA isomerase (no EC number available); DECR (shown in bold), 2,4-dienoyl-CoA reductase (EC 1.3.1.34).

Mentions: The presence of cis double bonds in naturally occurring (poly−) unsaturated fatty acids poses problems for ß-oxidation, that require a few auxiliary enzymes (for review, see [2]). During degradation, double bonds in odd-numbered positions (e.g., oleic acid) lead to Δ3-enoyl-CoAs, which must be isomerized by an enoyl-CoA isomerase (ECI) (Figure 1, center pathway). Double bonds in even-numbered positions give rise to conjugated Δ2,Δ4-dienoyl-CoAs, which cannot be hydrated by the enoyl-CoA hydratases for thermodynamic reasons [3]. In eukaryotes, they are reduced by an NADPH-dependent 2,4-dienoyl-CoA reductase (DECR) to 3-enoyl-CoA, which is then isomerized by ECI to trans-2-enoyl-CoA, suitable for further oxidation (Figure 1, left pathway). DECR may also play a role in the degradation of fatty acids containing odd-numbered double bonds because the intermediate 2,5-dienoyl-CoA may be isomerized by ECI to 3,5-dienoyl-CoA and then converted to 2,4-dienoyl-CoA by a specific Δ3,5,Δ2,4-dienoyl-CoA isomerase (Figure 1, right pathway) [4],[5]. In mammals, both mitochondria and peroxisomes contain the full set of these auxiliary enzymes for the breakdown of unsaturated fatty acids [2].


Mitochondrial 2,4-dienoyl-CoA reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis.

Miinalainen IJ, Schmitz W, Huotari A, Autio KJ, Soininen R, Ver Loren van Themaat E, Baes M, Herzig KH, Conzelmann E, Hiltunen JK - PLoS Genet. (2009)

β-oxidation of fatty acids with double bonds at even- or odd-numbered positions in mitochondria.Degradation of fatty acids with even-numbered double bonds results in 2,4-dienoyl-CoA esters, which are oxidized as shown on the left. 2,5-dienoyl-CoA esters arising from odd-numbered double bonds can be oxidized either via an isomerase-dependent pathway (middle) or via a reductase-dependent pathway (right). AD, acyl-CoA dehydrogenase (EC 1.3.3.6, EC 1.3.99.3, EC 1.3.99.13 or EC 1.3.99.-); EH, enoyl-CoA hydratase (EC 4.1.2.17 or EC 4.2.1.74); HD, 3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35 or EC 1.1.1.211); KT, 3-ketoacyl thiolase (EC 2.3.1.16) ; ECI, Δ3,Δ2-enoyl isomerase (EC 5.3.3.8); DECI, Δ3,5,Δ2,4-dienoyl-CoA isomerase (no EC number available); DECR (shown in bold), 2,4-dienoyl-CoA reductase (EC 1.3.1.34).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2697383&req=5

pgen-1000543-g001: β-oxidation of fatty acids with double bonds at even- or odd-numbered positions in mitochondria.Degradation of fatty acids with even-numbered double bonds results in 2,4-dienoyl-CoA esters, which are oxidized as shown on the left. 2,5-dienoyl-CoA esters arising from odd-numbered double bonds can be oxidized either via an isomerase-dependent pathway (middle) or via a reductase-dependent pathway (right). AD, acyl-CoA dehydrogenase (EC 1.3.3.6, EC 1.3.99.3, EC 1.3.99.13 or EC 1.3.99.-); EH, enoyl-CoA hydratase (EC 4.1.2.17 or EC 4.2.1.74); HD, 3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35 or EC 1.1.1.211); KT, 3-ketoacyl thiolase (EC 2.3.1.16) ; ECI, Δ3,Δ2-enoyl isomerase (EC 5.3.3.8); DECI, Δ3,5,Δ2,4-dienoyl-CoA isomerase (no EC number available); DECR (shown in bold), 2,4-dienoyl-CoA reductase (EC 1.3.1.34).
Mentions: The presence of cis double bonds in naturally occurring (poly−) unsaturated fatty acids poses problems for ß-oxidation, that require a few auxiliary enzymes (for review, see [2]). During degradation, double bonds in odd-numbered positions (e.g., oleic acid) lead to Δ3-enoyl-CoAs, which must be isomerized by an enoyl-CoA isomerase (ECI) (Figure 1, center pathway). Double bonds in even-numbered positions give rise to conjugated Δ2,Δ4-dienoyl-CoAs, which cannot be hydrated by the enoyl-CoA hydratases for thermodynamic reasons [3]. In eukaryotes, they are reduced by an NADPH-dependent 2,4-dienoyl-CoA reductase (DECR) to 3-enoyl-CoA, which is then isomerized by ECI to trans-2-enoyl-CoA, suitable for further oxidation (Figure 1, left pathway). DECR may also play a role in the degradation of fatty acids containing odd-numbered double bonds because the intermediate 2,5-dienoyl-CoA may be isomerized by ECI to 3,5-dienoyl-CoA and then converted to 2,4-dienoyl-CoA by a specific Δ3,5,Δ2,4-dienoyl-CoA isomerase (Figure 1, right pathway) [4],[5]. In mammals, both mitochondria and peroxisomes contain the full set of these auxiliary enzymes for the breakdown of unsaturated fatty acids [2].

Bottom Line: Enzyme defects in this pathway cause fatty acid oxidation disorders.Furthermore, the thermogenic response was perturbed, as demonstrated by intolerance to acute cold exposure.This study highlights the necessity of DECR and the breakdown of unsaturated fatty acids in the transition of intermediary metabolism from the fed to the fasted state.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.

ABSTRACT
The mitochondrial beta-oxidation system is one of the central metabolic pathways of energy metabolism in mammals. Enzyme defects in this pathway cause fatty acid oxidation disorders. To elucidate the role of 2,4-dienoyl-CoA reductase (DECR) as an auxiliary enzyme in the mitochondrial beta-oxidation of unsaturated fatty acids, we created a DECR-deficient mouse line. In Decr(-/-) mice, the mitochondrial beta-oxidation of unsaturated fatty acids with double bonds is expected to halt at the level of trans-2, cis/trans-4-dienoyl-CoA intermediates. In line with this expectation, fasted Decr(-/-) mice displayed increased serum acylcarnitines, especially decadienoylcarnitine, a product of the incomplete oxidation of linoleic acid (C(18:2)), urinary excretion of unsaturated dicarboxylic acids, and hepatic steatosis, wherein unsaturated fatty acids accumulate in liver triacylglycerols. Metabolically challenged Decr(-/-) mice turned on ketogenesis, but unexpectedly developed hypoglycemia. Induced expression of peroxisomal beta-oxidation and microsomal omega-oxidation enzymes reflect the increased lipid load, whereas reduced mRNA levels of PGC-1alpha and CREB, as well as enzymes in the gluconeogenetic pathway, can contribute to stress-induced hypoglycemia. Furthermore, the thermogenic response was perturbed, as demonstrated by intolerance to acute cold exposure. This study highlights the necessity of DECR and the breakdown of unsaturated fatty acids in the transition of intermediary metabolism from the fed to the fasted state.

Show MeSH
Related in: MedlinePlus