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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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Effect of fasting on serum NEFA, glucose, and OH–BUT levels and liver and muscle glycogen content in wild-type and Decr−/− mice.Age-matched male wild type (open boxes/bars) and Decr−/− mice (solid boxes/bars) were fasted for 0, 24, and 48 h, after which the serum levels of non-esterified fatty acids (A) and glucose (B) were determined. Glycogen content of liver (C) and muscle (D) tissue from wild type (open bars) and Decr−/− mice (solid bars) in the fed state and after mice were fasted for 6 h and/or 15 h was analyzed using the phenol-sulfuric acid method. Serum β-hydroxybutyric acid levels were measured in the fed state and after 24 h of fasting (E). At each time point, the results are expressed as means±SE of 5–6 mice of each genotype per group. Significant differences in glucose and NEFA concentrations between wild type and Decr−/− mice are indicated by asterisks (* p<0.05, ** p<0.01).
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pgen-1000543-g005: Effect of fasting on serum NEFA, glucose, and OH–BUT levels and liver and muscle glycogen content in wild-type and Decr−/− mice.Age-matched male wild type (open boxes/bars) and Decr−/− mice (solid boxes/bars) were fasted for 0, 24, and 48 h, after which the serum levels of non-esterified fatty acids (A) and glucose (B) were determined. Glycogen content of liver (C) and muscle (D) tissue from wild type (open bars) and Decr−/− mice (solid bars) in the fed state and after mice were fasted for 6 h and/or 15 h was analyzed using the phenol-sulfuric acid method. Serum β-hydroxybutyric acid levels were measured in the fed state and after 24 h of fasting (E). At each time point, the results are expressed as means±SE of 5–6 mice of each genotype per group. Significant differences in glucose and NEFA concentrations between wild type and Decr−/− mice are indicated by asterisks (* p<0.05, ** p<0.01).

Mentions: The amounts of circulating non-esterified fatty acids (NEFA) were analyzed in the sera of Decr−/− and wild type mice. Under normal nutritional conditions, mean serum NEFA levels were comparable between wild type and Decr−/− mice (0.43±0.11 mmol/l, 0.52±0.03 mmol/l, respectively) but after fasting, the Decr−/− mice demonstrated increased serum NEFA levels, reaching 1.28±0.12 mmol/l after 48 h compared with the wild type levels of 0.68±0.16 mmol/l (p<0.001) (Figure 5A).


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)

Effect of fasting on serum NEFA, glucose, and OH–BUT levels and liver and muscle glycogen content in wild-type and Decr−/− mice.Age-matched male wild type (open boxes/bars) and Decr−/− mice (solid boxes/bars) were fasted for 0, 24, and 48 h, after which the serum levels of non-esterified fatty acids (A) and glucose (B) were determined. Glycogen content of liver (C) and muscle (D) tissue from wild type (open bars) and Decr−/− mice (solid bars) in the fed state and after mice were fasted for 6 h and/or 15 h was analyzed using the phenol-sulfuric acid method. Serum β-hydroxybutyric acid levels were measured in the fed state and after 24 h of fasting (E). At each time point, the results are expressed as means±SE of 5–6 mice of each genotype per group. Significant differences in glucose and NEFA concentrations between wild type and Decr−/− mice are indicated by asterisks (* p<0.05, ** p<0.01).
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Related In: Results  -  Collection

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

pgen-1000543-g005: Effect of fasting on serum NEFA, glucose, and OH–BUT levels and liver and muscle glycogen content in wild-type and Decr−/− mice.Age-matched male wild type (open boxes/bars) and Decr−/− mice (solid boxes/bars) were fasted for 0, 24, and 48 h, after which the serum levels of non-esterified fatty acids (A) and glucose (B) were determined. Glycogen content of liver (C) and muscle (D) tissue from wild type (open bars) and Decr−/− mice (solid bars) in the fed state and after mice were fasted for 6 h and/or 15 h was analyzed using the phenol-sulfuric acid method. Serum β-hydroxybutyric acid levels were measured in the fed state and after 24 h of fasting (E). At each time point, the results are expressed as means±SE of 5–6 mice of each genotype per group. Significant differences in glucose and NEFA concentrations between wild type and Decr−/− mice are indicated by asterisks (* p<0.05, ** p<0.01).
Mentions: The amounts of circulating non-esterified fatty acids (NEFA) were analyzed in the sera of Decr−/− and wild type mice. Under normal nutritional conditions, mean serum NEFA levels were comparable between wild type and Decr−/− mice (0.43±0.11 mmol/l, 0.52±0.03 mmol/l, respectively) but after fasting, the Decr−/− mice demonstrated increased serum NEFA levels, reaching 1.28±0.12 mmol/l after 48 h compared with the wild type levels of 0.68±0.16 mmol/l (p<0.001) (Figure 5A).

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