Evidence for impaired gluconeogenesis in very long-chain acyl-CoA dehydrogenase-deficient mice.
Hypoketotic hypoglycaemia is a characteristic feature of fatty acid oxidation (FAO) defects. Although the underlying pathogenic mechanism is unknown, one hypothesis points to an impairment in gluconeogenesis. To study hepatic glucose production in FAO defects, we used the knockout mouse model of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency presenting with stress-induced hypoglycaemia. We analysed metabolites of hepatic glucose production under non-stressed conditions and after stress in comparison to wildtype controls. Analysis included glycogen, glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), glycerol-3-phosphate (G3P) and dihydroxyacetone-phosphate (DHAP). We also measured the activity of the key enzyme glucose-6-phosphatase. Blood and liver glucose were found to be low after stress, and liver glycogen was depleted. In addition, hepatic G6P and F6P were significantly reduced, especially during hypoglycaemia. Importantly, the activity of the enzyme converting G6P into glucose was not impaired. These data indicate a reduced rate of gluconeogenesis. The levels of DHAP and G3P were significantly lower suggesting decreased availability of glucose precursors from glycerol. This study gives biochemical evidence of impaired gluconeogenesis as one of the causes for hypoglycaemia observed in VLCAD deficiency. Whether this is due to lack of a substrate, inhibitory effects on other gluconeogenic enzymes or impaired transcription of gluconeogenic enzymes needs to be resolved in the future.
Spiekerkoetter
U
U
Department of General Pediatrics, University Children's Hospital, Moorenstrasse 5, 40225 Düsseldorf, Germany. ute.spiekerkoetter@uni-duesseldorf.de
Ruiter
J
J
Tokunaga
C
C
Wendel
U
U
Mayatepek
E
E
Wijburg
F A
FA
Strauss
A W
AW
Wanders
R J A
RJ
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D004099:Dihydroxyacetone Phosphate / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005636:Fructosephosphates / Q000378:metabolism; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000096:biosynthesis; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism; D005994:Glycerophosphates / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism* / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction
D005227:Fatty Acids; D005636:Fructosephosphates; D005994:Glycerophosphates; D019298:Glucose-6-Phosphate; D004099:Dihydroxyacetone Phosphate; C027618:fructose-6-phosphate; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D005952:Glucose-6-Phosphatase; D005947:Glucose