title: A liver-specific defect of Acyl-CoA degradation produces hyperammonemia, hypoglycemia and a distinct hepatic Acyl-CoA pattern.
abstract: Most conditions detected by expanded newborn screening result from deficiency of one of the enzymes that degrade acyl-coenzyme A (CoA) esters in mitochondria. The role of acyl-CoAs in the pathophysiology of these disorders is poorly understood, in part because CoA esters are intracellular and samples are not generally available from human patients. We created a mouse model of one such condition, deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (HL), in liver (HLLKO mice). HL catalyses a reaction of ketone body synthesis and of leucine degradation. Chronic HL deficiency and acute crises each produced distinct abnormal liver acyl-CoA patterns, which would not be predictable from levels of urine organic acids and plasma acylcarnitines. In HLLKO hepatocytes, ketogenesis was undetectable. Carboxylation of [2-(14)C] pyruvate diminished following incubation of HLLKO hepatocytes with the leucine metabolite 2-ketoisocaproate (KIC). HLLKO mice also had suppression of the normal hyperglycemic response to a systemic pyruvate load, a measure of gluconeogenesis. Hyperammonemia and hypoglycemia, cardinal features of many inborn errors of acyl-CoA metabolism, occurred spontaneously in some HLLKO mice and were inducible by administering KIC. KIC loading also increased levels of several leucine-related acyl-CoAs and reduced acetyl-CoA levels. Ultrastructurally, hepatocyte mitochondria of KIC-treated HLLKO mice show marked swelling. KIC-induced hyperammonemia improved following administration of carglumate (N-carbamyl-L-glutamic acid), which substitutes for the product of an acetyl-CoA-dependent reaction essential for urea cycle function, demonstrating an acyl-CoA-related mechanism for this complication.
authors.affiliation: Centre de Recherche and Département de Pédiatrie, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gauthier
authors.forename: Jiang Wei
authors.initials: JW
authors.lastname: Wu
authors.forename: Shu Pei
authors.initials: SP
authors.lastname: Wang
authors.forename: Pierre
authors.initials: P
authors.lastname: Allard
authors.forename: Orval A
authors.initials: OA
authors.lastname: Mamer
authors.forename: Lawrence
authors.initials: L
authors.lastname: Sweetman
authors.forename: Ann B
authors.initials: AB
authors.lastname: Moser
authors.forename: Lisa
authors.initials: L
authors.lastname: Kratz
authors.forename: Fernando
authors.initials: F
authors.lastname: Alvarez
authors.forename: Yves
authors.initials: Y
authors.lastname: Robitaille
authors.forename: François
authors.initials: F
authors.lastname: Lépine
authors.forename: Grant A
authors.initials: GA
authors.lastname: Mitchell
mesh_terms: D000105:Acetyl Coenzyme A / Q000235:genetics / Q000378:metabolism*; D000214:Acyl Coenzyme A / Q000172:deficiency / Q000235:genetics; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D055786:Gene Knockout Techniques; D023061:Gene Order; D018390:Gene Targeting; D005804:Genes, Lethal; D005943:Gluconeogenesis / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D022124:Hyperammonemia / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D053609:Lethargy; D007930:Leucine / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D008954:Models, Biological; D020675:Peroxisomes; D010641:Phenotype; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D000214:Acyl Coenzyme A; D002245:Carbon Dioxide; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D007930:Leucine