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.