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      Mitochondrial 2,4-dienoyl-CoA Reductase Deficiency in Mice Results in Severe Hypoglycemia with Stress Intolerance and Unimpaired Ketogenesis

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          Abstract

          The mitochondrial β-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 β-oxidation of unsaturated fatty acids, we created a DECR–deficient mouse line. In Decr −/− mice, the mitochondrial β-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 β-oxidation and microsomal ω-oxidation enzymes reflect the increased lipid load, whereas reduced mRNA levels of PGC-1α 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.

          Author Summary

          Fatty acids released from triacylglycerols or obtained from the diet serve as a main energy provider to the heart and skeletal muscle, and when carbohydrates are scarce, fatty acids provide energy for the whole organism. Inherited disorders of mitochondrial β-oxidation are among the most common inborn errors of metabolism affecting infants and children. Under normal conditions, patients are usually asymptomatic; but when challenged with metabolic stress, severe phenotypes arise. Here we describe the generation of a mouse model in which the total degradation of unsaturated fatty acids is prevented by disruption of an auxiliary enzyme of β-oxidation. Although degradation of saturated fatty acids proceeds normally, the phenotype presented here is in many ways similar to mouse models of the disrupted classical β-oxidation pathway, but with additional unique features. The null mutant mice are asymptomatic until exposed to fasting, during which they switch on ketogenesis, but simultaneously develop hypoglycemia. A number of human patients suffer from idiopathic hypoglycemia (hypoglycemia of unknown cause). Our mouse model links this disease state to a specific defect in the breakdown of polyunsaturated fatty acids. Furthermore, it shows that degradation of unsaturated fatty acids is essential for balanced fatty acid and energy metabolism, as well as adaptation to metabolic stress.

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          Most cited references 45

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          Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.

          Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor alpha (PPARalpha) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARalpha may be involved in the transcriptional response to fasting. To investigate this possibility, PPARalpha-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild-type mice. PPARalpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARalpha-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARalpha mRNA is induced during fasting in wild-type mice. The data indicate that PPARalpha plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARalpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.
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            Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis.

            PPARalpha is a nuclear receptor that regulates liver and skeletal muscle lipid metabolism as well as glucose homeostasis. Acting as a molecular sensor of endogenous fatty acids (FAs) and their derivatives, this ligand-activated transcription factor regulates the expression of genes encoding enzymes and transport proteins controlling lipid homeostasis, thereby stimulating FA oxidation and improving lipoprotein metabolism. PPARalpha also exerts pleiotropic antiinflammatory and antiproliferative effects and prevents the proatherogenic effects of cholesterol accumulation in macrophages by stimulating cholesterol efflux. Cellular and animal models of PPARalpha help explain the clinical actions of fibrates, synthetic PPARalpha agonists used to treat dyslipidemia and reduce cardiovascular disease and its complications in patients with the metabolic syndrome. Although these preclinical studies cannot predict all of the effects of PPARalpha in humans, recent findings have revealed potential adverse effects of PPARalpha action, underlining the need for further study. This Review will focus on the mechanisms of action of PPARalpha in metabolic diseases and their associated vascular pathologies.
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              Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders.

              It is now becoming evident that the liver has an important role in the control of whole body metabolism of energy nutrients. In this review, we focus on recent findings showing that AMP-activated protein kinase (AMPK) plays a major role in the control of hepatic metabolism. AMPK integrates nutritional and hormonal signals to promote energy balance by switching on catabolic pathways and switching off ATP-consuming pathways, both by short-term effects on phosphorylation of regulatory proteins and by long-term effects on gene expression. Activation of AMPK in the liver leads to the stimulation of fatty acid oxidation and inhibition of lipogenesis, glucose production and protein synthesis. Medical interest in the AMPK system has recently increased with the demonstration that AMPK could mediate some of the effects of the fat cell-derived adiponectin and the antidiabetic drugs metformin and thiazolidinediones. These findings reinforce the idea that pharmacological activation of AMPK may provide, through signalling and metabolic and gene expression effects, a new strategy for the management of metabolic hepatic disorders linked to type 2 diabetes and obesity.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                July 2009
                July 2009
                3 July 2009
                : 5
                : 7
                Affiliations
                [1 ]Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland
                [2 ]Theodor-Boveri-Institut für Biowissenschaften (Biozentrum) der Universität Würzburg, Würzburg, Germany
                [3 ]Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Kuopio, Finland
                [4 ]Department of Medical Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland
                [5 ]Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands
                [6 ]Laboratory of Cell Metabolism, Department of Pharmaceutical Sciences, Katholieke Universiteit Leuven, Leuven, Belgium
                [7 ]Department of Internal Medicine, Kuopio and Institute of Biomedicine, Division of Physiology and Biocenter of Oulu, Oulu University Medical School, Oulu, Finland
                Burnham Institute for Medical Research, United States of America
                Author notes

                Conceived and designed the experiments: IJM WS AH KJA RS EVLvT MB KHH EC JKH. Performed the experiments: IJM WS AH KJA EVLvT KHH. Analyzed the data: IJM WS AH KJA RS EVLvT MB KHH EC JKH. Contributed reagents/materials/analysis tools: RS MB JKH. Wrote the paper: IJM WS AH RS EVLvT KHH EC JKH.

                Article
                08-PLGE-RA-1281R3
                10.1371/journal.pgen.1000543
                2697383
                19578400
                Miinalainen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 17
                Categories
                Research Article
                Genetics and Genomics/Disease Models

                Genetics

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