Development and regulation of ketogenesis in hepatocytes isolated from newborn rats

Abstract

The development of fatty acid metabolism was studied in isolated hepatocytes from newborn rats. Ketone-body production from oleate is increased 6-fold between 0 and 16 h after birth. This increase is related to an enhanced beta-oxidation rather than to a channeling of acetyl-CoA from the tricarboxylic acid cycle to ketone-body synthesis. The increase in oleate oxidation is not related to a decreased esterification rate, as the latter is already low at birth and does not decrease further. At birth, lipogenic rate is 2-3-fold lower than in fed adult rats and it decreases to undetectable values in 16 h-old rats. A 90% inhibition of lipogenesis in hepatocytes of newborn rats (0 h) by glucagon and 5-(tetradecyloxy)-2-furoic acid does not lead to an increased oxidation of non-esterified fatty acids. This suggests that the inverse relationship between lipogenesis and ketogenesis in the starved newborn rat is not responsible for the switch-on of fatty acid oxidation at birth. Moreover, ketogenesis from octanoate, a medium-chain fatty acid the oxidation of which is independent of carnitine acyltransferase, follows the same developmental pattern at birth as that from oleate.

Mitochondrial glycerol-3-phosphate acyltransferase-1 directs the metabolic fate of exogenous fatty acids in hepatocytes

“…14 C]CO2 that we measured per total [ 14 C]oleate oxidized was similar to that in other studies that used closed flasks (3,16). Briefly, CO2 was driven from 1 ml of medium by adding 200 l of 70% perchloric acid and trapped on a suspended filter wick (Kontes) saturated with NaOH.…”

Control of hepatic mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase during the foetal/neonatal transition, suckling and weaning in the rat

“…The feasibility of this hypothesis was investigated in hepatocytes isolated from starved newborn rats 0, 6 or 16 h after birth [39]. The authors of the study concluded that, in contrast to the adult liver in which it is well established that ketogenesis is mainly regulated at the carnitine palmitoyltransferase I step [9, 101, the switch-on of ketogenesis at birth seems to involve another or several metabolic-control sites.…”

Fatty acid oxidation and ketogenesis during development

“…Several lines of evidence indicate that this hypothesis may not be valid : (1) liver carnitine concentration increases 2 h after birth whereas maximal ketonemia is reached only at 12 h after birth (Ferré et al, 1978), (2) 16-hour old starved rats fed with triglyceride emulsLon alone or supplemented with carnitine reach the same degree of hyperketonemia (Ferre etal., 1978), and (3) ketogenesis from oleate is 6-fold higher at 16 h after birth than at delivery in hepatocytes isolated from newborn rats and incubated with carnitine (1 mM) (Ferre et al, 1983).…”

“…In newborn rats, octanoate oxidation is considered to be independent from the step catalysed by CAT I (Ferre et al, 1983). Ketone body production from octanoate increases 6-fold between 0 and 16 h after birth in hepatocytes from starved newborn rats (Ferré et al, 1983), indicating alterations in metabolic regulation at sites including octanoyi-CoA formation, /3-oxidation and the HMGCoA pathway.…”

“…Using f1-!4C]-oleate, it has been shown that the increase in ketone body production that occurs between birth and 16 h after delivery does not result from a fall in fatty acid esterification but is related to increased fatty acid oxidation (Ferre et al, 1983 (Cook, Otto and Cornell, 1980 ;Ontko and Johns, 1980 ;Bremer, 1981 ;Saggerson and Carpenter, 1981 ; Stephens and Harris, 1984). The rate of lipogenesis from I H 2 0 is 60 % lower in hepatocytes from newborn rats than in those from fed adult rats, and it decreases to undetectable values in 16-hour old starved newborns (fig.…”