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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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Related in: MedlinePlus

Serum acylcarnitine analysis under normal and fasted conditions.Serum acylcarnitines were analyzed for wild type (solid line) and Decr−/− mice (dotted line) by mass spectrometry. (A) Serum acylcarnitine profile under normal conditions, as determined from the mass spectral data. (B) To determine the serum acylcarnitine profile under fasted conditions mice were subjected to a 24 h fast prior to serum collection. The concentrations of acylcarnitine are expressed as means±SE of 5–6 mice of each genotype per group.
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pgen-1000543-g007: Serum acylcarnitine analysis under normal and fasted conditions.Serum acylcarnitines were analyzed for wild type (solid line) and Decr−/− mice (dotted line) by mass spectrometry. (A) Serum acylcarnitine profile under normal conditions, as determined from the mass spectral data. (B) To determine the serum acylcarnitine profile under fasted conditions mice were subjected to a 24 h fast prior to serum collection. The concentrations of acylcarnitine are expressed as means±SE of 5–6 mice of each genotype per group.

Mentions: To study the effect of Decr gene disruption on the acylcarnitine profile and whether disruption leads to the secretion of specific acylcarnitine species, serum acylcarnitine profiles were determined for non-fasted and fasted wild type and Decr−/− mice by mass spectrometry. Under non-fasted conditions, there were no significant differences in the levels of total serum acylcarnitines between wild type and Decr−/− mice (263±29 nM and 240±16 nM, respectively). In addition, no significant differences were detected in the levels of individual acylcarnitines from C8 to C20 (Figure 7A). Predominant acylcarnitines in the sera were C16 and C18:1 acylcarnitines. Fasting increased the total concentration of acylcarnitines by 2-fold in wild type mice (567±32 nM); however, in Decr−/− mice, a markedly higher 9-fold increase was observed (2150±230 nM). Compared with wild type mice, the levels of all analyzed acylcarnitine species were highly elevated in Decr−/− mice. The increase was most distinct for the level of decadienoylcarnitine (C10:2), the concentration of which was 44-fold higher in the sera of Decr−/− mice compared with wild type controls (Figure 7B).


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)

Serum acylcarnitine analysis under normal and fasted conditions.Serum acylcarnitines were analyzed for wild type (solid line) and Decr−/− mice (dotted line) by mass spectrometry. (A) Serum acylcarnitine profile under normal conditions, as determined from the mass spectral data. (B) To determine the serum acylcarnitine profile under fasted conditions mice were subjected to a 24 h fast prior to serum collection. The concentrations of acylcarnitine are expressed as means±SE of 5–6 mice of each genotype per group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2697383&req=5

pgen-1000543-g007: Serum acylcarnitine analysis under normal and fasted conditions.Serum acylcarnitines were analyzed for wild type (solid line) and Decr−/− mice (dotted line) by mass spectrometry. (A) Serum acylcarnitine profile under normal conditions, as determined from the mass spectral data. (B) To determine the serum acylcarnitine profile under fasted conditions mice were subjected to a 24 h fast prior to serum collection. The concentrations of acylcarnitine are expressed as means±SE of 5–6 mice of each genotype per group.
Mentions: To study the effect of Decr gene disruption on the acylcarnitine profile and whether disruption leads to the secretion of specific acylcarnitine species, serum acylcarnitine profiles were determined for non-fasted and fasted wild type and Decr−/− mice by mass spectrometry. Under non-fasted conditions, there were no significant differences in the levels of total serum acylcarnitines between wild type and Decr−/− mice (263±29 nM and 240±16 nM, respectively). In addition, no significant differences were detected in the levels of individual acylcarnitines from C8 to C20 (Figure 7A). Predominant acylcarnitines in the sera were C16 and C18:1 acylcarnitines. Fasting increased the total concentration of acylcarnitines by 2-fold in wild type mice (567±32 nM); however, in Decr−/− mice, a markedly higher 9-fold increase was observed (2150±230 nM). Compared with wild type mice, the levels of all analyzed acylcarnitine species were highly elevated in Decr−/− mice. The increase was most distinct for the level of decadienoylcarnitine (C10:2), the concentration of which was 44-fold higher in the sera of Decr−/− mice compared with wild type controls (Figure 7B).

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