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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

PUFA and activation of gluconeogenesis.Simplified schematic presentation of the identified kinase cascades regulating gluconeogenesis. The activation cascade leads to phosphorylation of CREB (cAMP-responsive element binding protein), which, together with TORC2 (transducer of regulated CREB activity 2), drives the expression of coactivator PGC-1α. Transcription of the key gluconeogenic enzymes PEPCK (phosphoenoylpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase) is induced when PGC-1α associates with HNF4α (hepatic nuclear factor 4α) and FOXO1 (forkhead box transcription factor). Nuclear translocation of TORC2, which is needed for activation of the gluconeogenic program, is controlled by phosphorylation by activated AMPK (AMP–activated protein kinase) and SIK (salt-inducible kinase). Observed changes in Decr−/− mice are indicated with red arrows. Possible targets of accumulated PUFA or their derivatives are also indicated.
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pgen-1000543-g011: PUFA and activation of gluconeogenesis.Simplified schematic presentation of the identified kinase cascades regulating gluconeogenesis. The activation cascade leads to phosphorylation of CREB (cAMP-responsive element binding protein), which, together with TORC2 (transducer of regulated CREB activity 2), drives the expression of coactivator PGC-1α. Transcription of the key gluconeogenic enzymes PEPCK (phosphoenoylpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase) is induced when PGC-1α associates with HNF4α (hepatic nuclear factor 4α) and FOXO1 (forkhead box transcription factor). Nuclear translocation of TORC2, which is needed for activation of the gluconeogenic program, is controlled by phosphorylation by activated AMPK (AMP–activated protein kinase) and SIK (salt-inducible kinase). Observed changes in Decr−/− mice are indicated with red arrows. Possible targets of accumulated PUFA or their derivatives are also indicated.

Mentions: PEPCK and G6Pase are regarded, under in vivo conditions, as unidirectional enzymes that, among other factors, control the gluconeogenetic flux and show increased activity in the fasted state. The detected low PEPCK and G6Pase mRNA levels can explain, in part, the hypoglycemia observed in Decr−/− mice via contributing to the decreased flux through the gluconeogenetic pathway in the liver. Decreased mRNA levels of coactivator PGC-1α and its inducer CREB, which together drive the expression of PEPCK and G6Pase via HNF4α and FOXO1, suggest that signaling pathways leading to activation of gluconeogenesis during fasting are compromised in Decr−/− mice. However, which of the component(s) upstream of PGC-1α or CREB, especially TORC2 (transducer of regulated CREB activity 2), energy sensing kinase AMPK, and salt-inducible kinase (SIK), are affected and whether this effect is mediated by certain accumulated PUFA species will be evaluated in further studies (Figure 11). Analysis of the expression levels, activity and phosphorylation status of these factors in Decr−/− mice could elucidate the regulatory link between gluconeogenesis and the disrupted breakdown of unsaturated fatty acids.


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)

PUFA and activation of gluconeogenesis.Simplified schematic presentation of the identified kinase cascades regulating gluconeogenesis. The activation cascade leads to phosphorylation of CREB (cAMP-responsive element binding protein), which, together with TORC2 (transducer of regulated CREB activity 2), drives the expression of coactivator PGC-1α. Transcription of the key gluconeogenic enzymes PEPCK (phosphoenoylpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase) is induced when PGC-1α associates with HNF4α (hepatic nuclear factor 4α) and FOXO1 (forkhead box transcription factor). Nuclear translocation of TORC2, which is needed for activation of the gluconeogenic program, is controlled by phosphorylation by activated AMPK (AMP–activated protein kinase) and SIK (salt-inducible kinase). Observed changes in Decr−/− mice are indicated with red arrows. Possible targets of accumulated PUFA or their derivatives are also indicated.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1000543-g011: PUFA and activation of gluconeogenesis.Simplified schematic presentation of the identified kinase cascades regulating gluconeogenesis. The activation cascade leads to phosphorylation of CREB (cAMP-responsive element binding protein), which, together with TORC2 (transducer of regulated CREB activity 2), drives the expression of coactivator PGC-1α. Transcription of the key gluconeogenic enzymes PEPCK (phosphoenoylpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase) is induced when PGC-1α associates with HNF4α (hepatic nuclear factor 4α) and FOXO1 (forkhead box transcription factor). Nuclear translocation of TORC2, which is needed for activation of the gluconeogenic program, is controlled by phosphorylation by activated AMPK (AMP–activated protein kinase) and SIK (salt-inducible kinase). Observed changes in Decr−/− mice are indicated with red arrows. Possible targets of accumulated PUFA or their derivatives are also indicated.
Mentions: PEPCK and G6Pase are regarded, under in vivo conditions, as unidirectional enzymes that, among other factors, control the gluconeogenetic flux and show increased activity in the fasted state. The detected low PEPCK and G6Pase mRNA levels can explain, in part, the hypoglycemia observed in Decr−/− mice via contributing to the decreased flux through the gluconeogenetic pathway in the liver. Decreased mRNA levels of coactivator PGC-1α and its inducer CREB, which together drive the expression of PEPCK and G6Pase via HNF4α and FOXO1, suggest that signaling pathways leading to activation of gluconeogenesis during fasting are compromised in Decr−/− mice. However, which of the component(s) upstream of PGC-1α or CREB, especially TORC2 (transducer of regulated CREB activity 2), energy sensing kinase AMPK, and salt-inducible kinase (SIK), are affected and whether this effect is mediated by certain accumulated PUFA species will be evaluated in further studies (Figure 11). Analysis of the expression levels, activity and phosphorylation status of these factors in Decr−/− mice could elucidate the regulatory link between gluconeogenesis and the disrupted breakdown of unsaturated fatty acids.

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