Subject(s)
Gene Expression Regulation, Developmental , Hydroxymethylglutaryl-CoA Synthase/genetics , Liver/embryology , Liver/growth & development , Microsomes, Liver/enzymology , Adult , Aging , Animals , Child , Child, Preschool , Embryonic and Fetal Development , Gene Expression Regulation, Enzymologic , Humans , Hydroxymethylglutaryl-CoA Synthase/metabolism , Infant , Infant, Newborn , RatsABSTRACT
There are at least two isoenzymes of 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase (EC 4.1.3.5) located in the mitochondrial matrix and the cytoplasm of hepatocytes, respectively. The mitochondrial enzyme is necessary for the synthesis of ketone bodies, which are important fuels during fasting. We report a child with a deficiency of this isoenzyme. He presented at 16 mo with hypoglycemia. There was no rise in ketone bodies during fasting or after a long chain fat load but there was a small rise after a leucine load. Measurement of beta-oxidation flux in fibroblasts was normal. Using antibodies specific for mitochondrial HMG-CoA synthase, no immunoreactive material could be detected on Western blotting. Total HMG-CoA synthase activity in liver homogenate was only slightly lower than in control samples. Presumably, as there was no mitochondrial HMG-CoA synthase enzyme protein, this activity arose from the cytoplasmic or other (e.g. peroxisomal) isoenzymes. With avoidance of fasting, our patient has had no problems since presentation and is developing normally at 4 y of age.
Subject(s)
Hydroxymethylglutaryl-CoA Synthase/deficiency , Liver/metabolism , Mitochondria, Liver/metabolism , Cells, Cultured , Child , Child, Preschool , Fibroblasts/metabolism , Humans , Hydroxymethylglutaryl-CoA Synthase/genetics , Immunoblotting , Liver/pathology , Liver/physiopathology , Male , Oxidation-ReductionABSTRACT
We examined the potential of overt carnitine palmitoyltransferase (CPT I) to control the hepatic catabolism of palmitoyl-CoA in suckling and adult rats, using a conceptually simplified model of fatty acid oxidation and ketogenesis. By applying top-down control analysis, we quantified the control exerted by CPT I over total carbon flux from palmitoyl-CoA to ketone bodies and carbon dioxide. Our results show that in both suckling and adult rat, CPT I exerts very significant control over the pathways under investigation. However, under the sets of conditions we studied, less control is exerted by CPT I over total carbon flux in mitochondria isolated from suckling rats than in those isolated from adult rats. Furthermore the flux control coefficient of CPT I changes with malonyl-CoA concentration and ATP turnover rate.
