A liver-specific defect of Acyl-CoA degradation produces hyperammonemia, hypoglycemia and a distinct hepatic Acyl-CoA pattern.

Nicolas Gauthier (1, 2) , Jiang Wei Wu (1) , Shu Pei Wang (1) , Pierre Allard (1) , Orval A Mamer (3) , Lawrence Sweetman (4) , Ann B Moser (5) , Lisa Kratz (5) , Fernando Alvarez (1) , Yves Robitaille (1) , François Lépine (6) , Grant A Mitchell (1, 2)

1 CHU Sainte Justine [Montréal]
2 Département de Biochimie
3 GCRC - Goodman Cancer Research Center [Montréal]
4 Institute of Metabolic Disease
5 The Hugo W Moser Research Institute, The Kennedy-Krieger Institute
6 INRS-IAF - Institut Armand Frappier

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.

Domaines: Sciences du Vivant [q-bio]; Hépatologie et Gastroentérologie

Nicolas Gauthier, Jiang Wei Wu, Shu Pei Wang, Pierre Allard, Orval A Mamer, et al.. A liver-specific defect of Acyl-CoA degradation produces hyperammonemia, hypoglycemia and a distinct hepatic Acyl-CoA pattern.. PLoS ONE, 2013, 8 (7), pp.e60581. ⟨10.1371/journal.pone.0060581⟩. ⟨pasteur-01131004⟩