Impaired neonatal hepatic ketogenesis

Abstract

Why is there interest in neonatal hepatic ketogenesis?Hypoglycaemia characterizes the immediate post-partum period, as the newborn infant adapts to a transient period of starvation and then to the fast-feed cycle of milk feeds [l-31. During this fetal/neonatal transition period, the onset of P-oxidation and ketogenesis provides ketone bodies (acetoacetate and P-hydroxybutyrate, derived from endogenous fat stores accumulated pre-partum) as an alternative perinatal 'energy fuel' to maternally derived glucose, the supply of which is continuous in utem, but ceases abruptly at birth [4,5]. Subsequently, throughout suckling, hepatic ketogenesis generates (from dietary triglycerides) ketone bodies which are the main circulating oxidative fuels for the brain, heart and peripheral tissues, and carbon precursors for essential myelination of the neonatal brain [6-91. At this time, ketone bodies also have a key role as effectors that regulate: whole-body fuel selection/ utilization, neonatal glucose homoeostasis and, Abbreviations used: FFA, free fatty acids; CPT, carnitine palmitoyltransferase; (m)HMG-CoA, (mitochondrial) 3-hydroxy-3-methylglutaryl-CoA; MCA, metabolic control analysis; TPN, total parenteral nutrition; IUGR, intra-uterine growth-retardation; ROS, reactive oxygen species; EM, electron microscopy; CJstep, *CLImk, flux control coefficient describing control exerted by step or block of reactions over flux J.

Fuel Metabolism in Starvation

“…Next, the fact that nature delayed the synthesis of adequate lactose for the first day or so suggests βOHB might be of help in any newborn, particularly if small for gestational age. It has already been used in children with congenital disorders in fat oxidation or ketone production with some dramatic success (54,75). As mentioned above, its use in drug-resistant childhood epilepsy to displace the ketogenic diet awaits the availability of orally absorbable esters.…”

“…Levels of β-hydroxybutyrate in starving subjects of different ages(5,13,30,54,59,66). Not shown is the accelerated ketosis in fasting pregnant or lactating women or in any subject with marked renal glucosuria requiring increased gluconeogenesis, e.g., when the renal threshold is surpassed, as in type 1 diabetes (40), or with genetic renal glucosuria or chemical inhibition of tubular reabsorption of glucose (phlorizin administration).…”