title: Disturbed hepatic carbohydrate management during high metabolic demand in medium-chain acyl-CoA dehydrogenase (MCAD)-deficient mice.
abstract: Medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) catalyzes crucial steps in mitochondrial fatty acid oxidation, a process that is of key relevance for maintenance of energy homeostasis, especially during high metabolic demand. To gain insight into the metabolic consequences of MCAD deficiency under these conditions, we compared hepatic carbohydrate metabolism in vivo in wild-type and MCAD(-/-) mice during fasting and during a lipopolysaccharide (LPS)-induced acute phase response (APR). MCAD(-/-) mice did not become more hypoglycemic on fasting or during the APR than wild-type mice did. Nevertheless, microarray analyses revealed increased hepatic peroxisome proliferator-activated receptor gamma coactivator-1alpha (Pgc-1alpha) and decreased peroxisome proliferator-activated receptor alpha (Ppar alpha) and pyruvate dehydrogenase kinase 4 (Pdk4) expression in MCAD(-/-) mice in both conditions, suggesting altered control of hepatic glucose metabolism. Quantitative flux measurements revealed that the de novo synthesis of glucose-6-phosphate (G6P) was not affected on fasting in MCAD(-/-) mice. During the APR, however, this flux was significantly decreased (-20%) in MCAD(-/-) mice compared with wild-type mice. Remarkably, newly formed G6P was preferentially directed toward glycogen in MCAD(-/-) mice under both conditions. Together with diminished de novo synthesis of G6P, this led to a decreased hepatic glucose output during the APR in MCAD(-/-) mice; de novo synthesis of G6P and hepatic glucose output were maintained in wild-type mice under both conditions. APR-associated hypoglycemia, which was observed in wild-type mice as well as MCAD(-/-) mice, was mainly due to enhanced peripheral glucose uptake.
  
  
  CONCLUSIONS
  Our data demonstrate that MCAD deficiency in mice leads to specific changes in hepatic carbohydrate management on exposure to metabolic stress. This deficiency, however, does not lead to reduced de novo synthesis of G6P during fasting alone, which may be due to the existence of compensatory mechanisms or limited rate control of MCAD in murine mitochondrial fatty acid oxidation.
authors.affiliation: Laboratory of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. h.j.herrema@med.umcg.nl
authors.forename: Hilde
authors.initials: H
authors.lastname: Herrema
authors.forename: Terry G J
authors.initials: TG
authors.lastname: Derks
authors.forename: Theo H
authors.initials: TH
authors.lastname: van Dijk
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Bloks
authors.forename: Albert
authors.initials: A
authors.lastname: Gerding
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
authors.forename: G Peter A
authors.initials: GP
authors.lastname: Smit
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: Reijngoud
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D050260:Carbohydrate Metabolism / Q000235:genetics* / Q000502:physiology*; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D005227:Fatty Acids; D015971:Gene Expression Regulation, Enzymologic; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008107:Liver Diseases / Q000201:enzymology* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D008070:Lipopolysaccharides; D019298:Glucose-6-Phosphate; D006003:Glycogen; D042964:Acyl-CoA Dehydrogenase