Hepatic Ketogenesis Research Articles

Sex-specific regionality of liver metabolism during starvation; with special reference to the heterogeneity of the lobular periphery.

Staining procedures for glucose-6-phosphatase and 3-hydroxybutyrate dehydrogenase activity and for glycogen were used to investigate adaptive changes in the regionality of hepatic gluconeogenesis and ketogenesis in fasting male and female rats. A reciprocal distribution of gluconeogenic and ketogenic capacities was found in both sexes, but male and female animals were different with respect to: a) the time necessary for full induction of glucose-6-phosphatase activity (24 h in females, 48 h in males); b) the overall activity of 3-hydroxybutyrate dehydrogenase; and c) glycogen content. The activity of the latter enzyme and the glycogen content did increase with time of starvation, but at all times, were higher in males, than in females. Results, thus, indicate that the extent to which ketone bodies replace glucose as major fuel for the brain is larger in males than in females. This may explain the delayed induction of glucose-6-phosphatase activity and the higher glycogen content in the male during starvation. Distributions of enzyme activities and of glycogen, furthermore, revealed the heterogeneity of the lobular periphery, i.e. functional differences among sinusoids dependent upon whether they originate from the portal tract or the vascular septum, and thus confirm the lobular concept proposed by Matsumoto et al. (1979).

Inhibition by acetyl-CoA of hepatic carnitine acyltransferase and fatty acid oxidation.

At micromolar concentrations, acetyl-CoA inhibited hepatic carnitine acyltransferase activity and mitochondrial fatty acid oxidation. The inhibitory effects were not nearly as potent on a molar basis as those of malonyl-CoA; nevertheless, the cytosolic concentrations of acetyl-CoA, as yet unknown, may be sufficient (greater than 30 microM) to curtail appreciably the mitochondrial transfer of long-chain acyl-CoA units and fatty acid oxidation. Hence acetyl-CoA may also partially regulate hepatic ketogenesis.

Mechanism of adrenergic stimulation of hepatic ketogenesis

The effects of alpha- and beta-adrenergic stimulation on ketogenesis were examined in freshly isolated rat hepatocytes in order to determine which alpha- or beta-adrenergic stimulation is involved in the enhancement of ketogenesis. In the presence of 0.3 mmol/L (U- 14C)-palmitate, epinephrine, norepinephrine, and phenylephrine at 500 ng/mL increasd ketogenesis by 25% (16.0 ± 0.17 v 12.8 ± 0.13 nmol/mL protein per hour), 20% (15.3 ± 0.28) and 20% (15.4 ± 0.36), respectively. However, isoproterenol even at 1 μg/mL did not stimulate ketogenesis. Phentolamine (5 μg/mL) almost completely abolished the effect of epinephrine on ketogenesis (13.7 ± 0.30 v 16.0 ± 0.17) but propranolol did not inhibit the stimulation by epinephrine (15.6 ± 0.38 v 16.0 ± 0.17). Trifluoperazine (10 μmll/L), presumably an inhibitor of calcium-dependent protein kinase, abolished the effect of epinephrine (13.6 ± 0.22 v 16.0 ± 0.17). These results indicate that catecholamines increase ketogenesis predominantly through the alpha-adrenergic system independent of cyclic AMP, and calcium-dependent protein kinase is thought to be involved in the activation of ketogenesis. On the other hand, glucagon stimulated ketogenesis with an increase of cyclic AMP, which was not inhibited by alpha- and beta-adrenergic antagonists. Alpha-adrenergic stimulation increased hepatic glycogenolysis much more at much lower concentrations when compared with ketogenesis. Stimulation of ketogenesis by catecholamines seemed to be less sensitive and responsive compared with hepatic glycogenolysis.

The control of fatty acid metabolism in liver cells from fed and starved sheep.

Isolated liver cells prepared from starved sheep converted palmitate into ketone bodies at twice the rate seen with cells from fed animals. Carnitine stimulated palmitate oxidation only in liver cells from fed sheep, and completely abolished the difference between fed and starved animals in palmitate oxidation. The rates of palmitate oxidation to CO2 and of octanoate oxidation to ketone bodies and CO2 were not affected by starvation or carnitine. Neither starvation nor carnitine altered the ratio of 3-hydroxybutyrate to acetoacetate or the rate of esterification of [1-14C]palmitate. Propionate, lactate, pyruvate and fructose inhibited ketogenesis from palmitate in cells from fed sheep. Starvation or the addition of carnitine decreased the antiketogenic effectiveness of gluconeogenic precursors. Propionate was the most potent inhibitor of ketogenesis, 0.8 mM producing 50% inhibition. Propionate, lactate, fructose and glycerol increased palmitate esterification under all conditions examined. Lactate, pyruvate and fructose stimulated oxidation of palmitate and octanoate to CO2. Starvation and the addition of gluconeogenic precursors stimulated apparent palmitate utilization by cells. Propionate, lactate and pyruvate decreased cellular long-chain acylcarnitine concentrations. Propionate decreased cell contents of CoA and acyl-CoA. It is suggested that propionate may control hepatic ketogenesis by acting at some point in the beta-oxidation sequence. The results are discussed in relation to the differences in the regulation of hepatic fatty acid metabolism between sheep and rats.

A 6-hour nocturnal interruption of a continuous subcutaneous insulin infusion: 2. Marked attenuation of the metabolic deterioration by somatostatin.

We investigated the respective roles of insulin deprivation and counter-regulatory hormones in the metabolic deterioration after a nocturnal interruption of continuous subcutaneous insulin infusion in Type 1 (insulin-dependent) diabetic patients without residual insulin secretion. Changes in blood glucose, plasma non-esterified fatty acids, 3-hydroxybutyrate, glucagon, growth hormone, cortisol and free insulin in seven patients whose pumps were deliberately stopped between 23.00 h and 05.00 h were compared in two randomized tests carried out either during an intravenous somatostatin infusion at a constant rate of 250 μg/h from 22.00 h until 07.00 h (somatostatin test) or during a saline infusion (control test). Arrest of the pumps resulted in a rapid (already significant after 1 h) and progressive (nadir after 5–6 h) decrease in plasma free insulin concentrations with no statistically significant differences between the two tests. Somatostatin remarkably depressed basal levels of growth hormone and the late significant increase in glucagon (+39±14 pg/ml at 05.00 h, 2p< 0.05) observed during the control test. In contrast, cortisol secretion was not inhibited. The sharp linear increase in blood glucose observed from 01.00 to 05.00 h (38±4 μmol·l-1· min-1) in the control test was fully suppressed with a paradoxical tendency to hypoglycaemia until 03.00 h and a less steep rise from 03.00 to 05.00 h (18±5 μmol·l-1·min-1, 2p<0.05) during the somatostatin test. Initial plasma non-esterified fatty acids levels were slightly higher on somatostatin but did not show any statistically significant rise despite arrest of the pump, contrasting with the increase from 491±27 to 741±96 μmol/l (2p<0.05) in the control test. Consequently, plasma non-esterified fatty acids levels from 01.00 to 05.00 h were not significantly different between the two tests. The abrupt rise in 3-hydroxybutyrate from 00.00 to 05.00 h (3.0±0.5 μmol·l-1·min-1) in the control test was not altered by somatostatin until 03.00 h. In contrast, during the last 2 h after arrest of the pump, somatostatin inhibited any further rise in 3-hydroxybutyrate levels. In conclusion, somatostatin significantly reduces metabolic deterioration during a 6-h nocturnal interruption of a continuous subcutaneous insulin infusion. Somatostatin-induced glucagon suppression seems to be involved in reducing hyperglycaemia as well as, together with the somatostatin-induced growth hormone suppression, in the limitation of hepatic ketogenesis in hours 5 and 6 after cessation of insulin supply. In contrast, the early rise in 3-hydroxybutyrateplasma levels is unaffected by somatostatin and thus appears entirely due to the fall in free insulin circulating concentrations.

Development of Hepatic Fatty Acid Oxidation and Ketogenesis in the Newborn Guinea Pig

Summary: The capacity for ketone synthesis by the liver is low for at least 8 h after delivery in newborn human infants. The present studies define developmental changes in hepatic ketogenesis in the newborn guinea pig with particular emphasis on whether there is a delay in development after birth and the site of developmental change. Studies in fresh liver homogenates indicated that the capacity to synthesize ketones from the oxidation of long-chain fatty acid (1 mM oleate plus 0.5 mM L-carnitine) was very low in term-fetal (5.4 ± 0.4) and newborn pups less than 12 h old (7.7 ± 1) compared to pups 24 or more h old (24–26) and adult guinea pigs (17.8 ± 0.3 μM/h/g). In contrast to the newborn rat, no developmental changes were observed in the carnitine content of tissues (liver, heart, skeletal muscle) or plasma in newborn guinea pigs. The developmental limitation in ketogenesis in the newborn guinea pig was not due to low activity of the enzymes of the hydroxymethylglutaryl-CoA pathway. More rapid rates of ketone production were found with 0.5 mM palmityl-carnitine in term-fetal (13.4 ± 1.7) and newborn pups less than 12 hours old (17.8–21 μM/h/g), suggesting that part of the limitation in ketone synthesis in the newborn guinea pig resides at the step of fattyacyl carnitine formation on the outer aspect of the inner mitochondrial membrane. The activity of this carnitine palmityl transferase (CPT1) was low in term fetal liver (1.0 ± 0.03 μM/h/g), remained low for 5–10 h after delivery, and then rose to 13 ± 0.7 μM/h/g at 24–48 h of age. Evidence for at least two additional sites of developmental change in fatty acid oxidation was found in studies of ketogenesis from short-(butyrate)- and medium-(octanoate)-chain fatty acids. (1) In term-fetuses, ketone production from butyrate (17.8 ± 1.5 μM/h/g) was only half that found after 24–36 h of age (36 ± 3.8 μM/h/g), suggesting a limitation in the intramitochondrial beta-oxidation capacity. (2) In adult guinea pigs and in pups 8–10 days old, ketone synthesis from octanoate was 40–45 μM/h/g compared to 4.1 ± .8 μM/h/g in term-fetuses. At 24–36 h old, carnitine-stimulated ketone production from octanoate from 2.4 ± 2.1 to 37 ± 0.9 μM/h/g. This third site of developmental change in hepatic ketogenesis may involve the intramitochondrial activating step for medium-chain fatty acids.

The calorigenic nature of hepatic ketogenesis: an explanation for the stimulation of respiration induced by fatty acid substrates.

The rates of O2 consumption during fatty acid oxidation to acetyl‐CoA and to CO2 were determined for isolated liver cells from starved rats on the basis of measured rates of respiration and ketogenesis. About 60% of the endogenous O2 uptake was associated with acetyl‐CoA formation. The remainder was assumed to represent total combustion of fatty acid to CO2 and H2O through the Krebs cycle. In the absence of added fatty acid, 1.90 μmol · min‐1· g‐1 of acetyl‐CoA was generated, of which 1.40 μmol · min‐1· g−1 gave rise to ketone bodies. O2 consumption was stimulated about 30% by the addition of 2 mM palmitate or 4 mM hexanoate. This increase was entirely due to stimulation of O2 consumption related to oxidation of fatty acid to acetyl‐CoA. The extra acetyl‐CoA produced was channelled into ketone body formation.The gluconeogenic substrate lactate, which increases hepatic demand for ATP, stimulated O2 consumption almost 40%, but in this case the increase was due to an enhancement of Krebs cycle activity, and acetyl‐CoA generation was depressed 25%. In the absence of added fatty acid, 83% of the total acetyl‐CoA produced by cells incubated with lactate was oxidized in the Krebs cycle. Addition of fatty acid caused a further stimulation of O2 uptake which reflected a promotion of acetyl‐CoA production with an associated increase in ketone body formation.The uncoupling agent, 2,4‐dinitrophenol, stimulated total O2 consumption of cells incubated without exogenous substrate or with added fatty acid. In each circumstance this stimulation of O2 uptake was related entirely to enhancement of Krebs cycle activity and depression of ketogeneis. The large increment in O2 consumption induced by the combination of lactate and 2,4‐dinitrophenol in the presence of added fatty acid was likewise attributable solely to a marked stimulation of Krebs cycle flux. Added ethanol caused only a small inhibition of total acetyl‐CoA production and had little effect on respiration, but considerably depressed Krebs cycle activity. This depression was relieved by 2,4‐dinitrophenol.Oligomycin and antimycin had markedly different effects on fatty acid catabolism although both inhibitors depressed O2 consumption to the same extent. Oligomycin caused only a small diminution of rates of acetyl‐CoA formation but induced a strong depression of cellular ATP concentrations and of acetyl‐CoA oxidation to CO2. In contrast antimycin had no effect on acetyl‐CoA oxidation and brought about only a small decline in cellular ATP levels, but considerably depressed formation of acetyl‐CoA.These results are interpreted as indicating that addition of fatty acid to liver cells induces various energy‐dependent processes, including ATP synthesis, reversed electron transfer and metabolite translocation, all of which contribute to the observed stimulation of O2 uptake. It is inferred that oxidation of acetyl‐CoA to CO2 is preferentially coupled to ATP synthesis whereas oxidation of fatty acid to acetyl‐CoA is obligatorily associated with reversed electron transfer. Thus, ketogenesis is not constrained by the hepatic phosphorylation potential and provides a mechanism for the rapid disposal of fatty acids, independent of the ATP demands of the liver.

Ketogenesis in mitochondria isolated from liver biopsies of normal and starved dogs: Comparison with rat-liver mitochondria

1. 1. Fatty acid oxidation and ketogenesis were studied in isolated dog-liver mitochondria in order to investigate whether the absence of hyperketonemia in fasting dogs results from a low capacity of hepatic ketogenesis. Isolated rat-liver mitochondria were used as reference. 2. 2. The results indicate that: 2.1. (a) Dog-liver mitochondria oxidize long-chain fatty acids and produce ketone bodies at about equal rates as rat-liver mitochondria. No differences were detected in the regulation of ketogenesis. 2.2. (b) Rates of oxidation of medium-chain fatty acids are significantly lower in dog-liver mitochondria than in rat-liver mitochondria. 2.3. (c) Fasting does not influence the capacity of liver mitochondria for fatty acid oxidation but their ketogenic capacity is slightly enhanced in both species. 2.4. 3. The regulation of the energy metabolism in the fasting dog is discussed and compared with that in other mammalian species.

The effects of ketone bodies, bicarbonate, and calcium on hepatic mitochondrial ketogenesis

The effect of various factors on hepatic mitochondrial ketogenesis was investigated in the rat. A comparison of three different incubation media revealed that bicarbonate ion inhibited the rate of ketone body production and decreased the ratio of 3-hydroxybutyrate/acetoacetate. The addition of 0.8 m m calcium caused significant inhibition of ketogenesis from both octanoate (40–50%) and palmitate (25–30%) and no change in the ratio of 3-hydroxybutyrate/acetoacetate. In the presence of components of the malate/aspartate shuttle, the inhibition by calcium was 80% or more with both substrates. Experimental alteration of the respiratory state of the mitochondria from state 3 to state 4 was associated with an enhanced rate of ketogenesis. The addition of ketone bodies themselves had marked effects on the rate of ketone body production. Increasing amounts of exogenously added acetoacetate were accompanied by increasing rates of total ketone body production reflecting enhanced 3-hydroxybutyrate synthesis. In the presence of added 3-hydroxybutyrate, there was striking inhibition of ketogenesis. Rotenone, which prevents oxidation of NADH 2 via the electron transport chain, almost completely inhibited ketone body synthesis. This inhibition was partially overcome by the addition of acetoacetate which regenerates NAD + from NADH 2 during conversion to 3-hydroxybutyrate. These observations provide evidence for additional sites of metabolic control over hepatic ketogenesis.

Starvation-Induced Ketone Body Production in the Conscious Unrestrained Miniature Pig

The effect of short-term starvation (up to 5 days) on hepatic ketone body production was investigated in the conscious unrestrained miniature pig in vivo. Starvation induced an increase in arterial free fatty acid concentration (0.2– 0.7mm) with a concomitant elevation in hepatic free fatty acid extraction [-1.4–5.7 µmol/kg · minute), r = 0.53, P < 0.005]. Ketone body production (sum of acetoacetate + β-hydroxybutyrate) increased from 1.5 to 5.8 µmol/(kg · minute) in parallel (r = 0.71, P < 0.0005). During starvation arterial insulin levels decreased, glucagon increased, cortisol remained unchanged and a “low T3 state” was observed. These data differ in some aspects from those reported for humans and dogs. Thus a species-specific variation in the fuel economy of the pig's body is proposed.starvation miniature pig hepatic ketogenesis hepatic free fatty acid extraction

Metabolic effects of acetate in perfused rat liver studies on ketogenesis, glucose output, lactate uptake and lipogenesis

1. Livers from fed male rats were perfused in situ in a non-recirculating system with whole rat blood containing acetate at six concentrations, from 0.04 to 1.5 μmol/ml, to cover the physiological range encountered in the hapatic portal venous blood in vivo. 2. Below a concentration of 0.25 μmol/ml there was net production of acetate by the liver, while above it there was ner uptake with a fractional extraction of 40%. 3.No relationship was observed between blood [acetate] and hepatic ketogenesis, the ration [3-hydroxybutyrate]/[acetoacetate] or glucose output, either at low fatty acid concentration s or during oleate infusion. 4. Following the increase in serum fatty acid concentration, induced by oleate infusion, there were suquential incresase in ketogenesis and the ratio of [3-hydroxybutyrate]/[acetoacetate] while glucose output rose and lactate uptake fell significantly after in redox state. 5. There was a highly significant negative correlation between blood [acetate] and hepatic lactate uptake during oleate infusion. At the highest acetate concentration of 1.5 μmol/ml there was a small net hepatic lactate output. After oleate infusion ceased, lactate uptake increased, but the negative correlation between blood [acetate] and hepatic lactate uptake persisted. 6. Livers were also perfused with iether [1- 14C]acetate or [U- 14C]lactate at a concentration of acetate of either 0.3 or 1.3 μmol/ml of blood. With [1- 14C]acetate, most of the radioactivity was recovered as fatty acids at the lower concentration of blood acetate. At the higher blood [acetate] a considerably smaller proportion of the radioactivity was recovered in lipids. With [U- 14C]lactate the reverse pattern obtained i.e., recovery was greater at the high concentration of acetate and fell at the low concentration. Fatty acid biosynthesis, measured with 3H 2O, was stimulated from 2.4 to 6.6 μmol of fatty acid/g of liver per h by high blood [acetate] although the contribution of (acetate+lactate) to synthesis remained constant at 33–38% of the total. 7. These results emphasize the important role of the liver in regulating blood acetate concentrations and indicate that it can be major hepatic substrate. Acetate taken up by the liver appeared to compete directly with lactate, for lipogenesis and metabolism and acetate uptake was inhibited by raised bloodd [lactate].

Effect of Postnatal Undernutrition on Ketone Metabolism and Its Relation to Metabolic Changes in Brain and Liver of Rats

The effects of undernutrition on ketone metabolism and its relation to brain growth in developing rats were studied. In the first series of experiments, under-nutrition was induced by increasing the litter size from 4 to 16 pups. Body weight of pups was inversely related to litter size. Increasing the litter size lowered brain weight by 6–16% and liver weight by 20–46%. The ratio of brain weight:body weight was greater by 16 to 39% in the larger litters. Increasing the litter size did not alter concentration of brain lipid, liver glycogen or plasma ketone bodies. In the second series of experiments, undernutrition was induced by restricting maternal dietary intake to 40% of that of the control dam. This undernutrition caused a more pronounced growth retardation than that resulting from increasing litter size. At 14 days of age, the mean body weight of the undernourished group was 44% lower than the control value. The dietary restriction lowered brain weight by 19%, liver weight by 38%, liver glycogen by 47%, brain lipid by 11%, plasma ketone bodies by 30%, glucose by 37% and the rate of hepatic ketogenesis by 28%. The results suggest that brain-growth retardation is related to low brain lipids and impaired ketone metabolism.postnatal undernutrition brain retardation brain lipids ketone bodies ketogenesis dietary restriction

Palmitate metabolism and norepinephrine sensitivity in brown adipose, liver, and white adipose tissues of Zucker rats.

AbstractInterscapular brown adipose tissue (BAT) in vitro utilization of palmitate (0.5 mM) and glucose (5.0 mM) were examined at 0, 0.1, 1.0, and 10.0 μg norepinephrine-bitartrate (NE)/ml. With increasing NE concentrations, in vitro palmitate oxidation was stimulated and glucose oxidation was inhibited in BAT of nonobese rats. This characterization of BAT metabolism provided the constraints for our analysis of fatty acid utilization and norepinephrine sensitivity at submaximal response concentrations in BAT of lean and obese Zucker rats. Liver and inguinal white adipose were used for tissue comparisons. In comparison to its lean littermates, it was demonstrated that the obese rat: (i) had heavier interscapular BAT pads, (ii) oxidized a similar amount of palmitate to CO2 per 100 mg of BAT, (iii) oxidized more palmitate in response to NE stimulation of BAT, and (iiii) had slower rates of hepatic ketogenesis and palmitate oxidation. Altered palmitate oxidation or NE sensitivity in BAT was not contributing t...

Primary Ketosis in the High-Producing Dairy Cow: Clinical and Subclinical Disorders, Treatment, Prevention, and Outlook

Bovine ketosis typically occurs in early lactation. Clinical signs include diminished appetite, decreased milk production, loss of weight, hypoglycemia, and hyperketonemia. Susceptibility to ketosis is probably due to the combination of appetite limitation and a high degree of precedence given to the demand of the mammary gland for nutrients, in particular glucose. The precipitating cause is likely to be development of a marked imbalance between glucose supply and glucose requirement. This imbalance then leads to decreased carbohydrate status, decreased insulin secretion, increased fat mobilization, and increased hepatic ketogenesis. Hepatic ketogenesis may be augmented by the diminished carbohydrate status. The role of hormones other than insulin in the etiology of ketosis, although probably important, has not yet been elucidated satisfactorily. Treatment of ketosis involves increasing glucose supply relative to glucose demand. Incidence of clinical ketosis can be minimized by correct nutrition and management as outlined in recommended guidelines. Besides decreasing milk yield, clinical ketosis may affect productivity adversely in other ways, for example, by impairing fertility. Subclinical ketosis is important because it may remain undetected and yet have effects on productivity which parallel those elicited by clinical ketosis. Future research should be directed toward understanding mechanisms conferring priority on milk production and regulating appetite.

The effect of acetate on the regulation of the branched chain α-keto acid and the pyruvate dehydrogenase complexes in the perfused rat liver

The regulatory consequences of acetate infusion on the pyruvate and the branched chain α-keto acid dehydrogenase reactions in the isolated, perfused rat liver were investigated. Metabolic flux through these two decarboxylation reactions was monitored by measuring the rate of 14CO 2 production from infused 1- 14C-labeled substrates. When acetate was presented to the liver as the sole substrate the rate of ketogenesis which resulted was maximal at concentrations of acetate in excess of 10 m m. The increase in hepatic ketogenesis during acetate infusion was not accompanied by an alteration of the mitochondrial oxidation-reduction state as measured by the ratio of β-hydroxybutyrate/ acetoacetate in the effluent perfusate. While acetate infusion did not affect the rate of α-keto[1- 14C]isocaproate decarboxylation, the rate of α-keto[1- 14C]isovalerate decarboxylation was stimulated appreciably upon acetate addition. No change was observed in the amount of extractable branched chain α-keto acid dehydrogenase during acetate infusion. The rate of [1- 14C]pyruvate decarboxylation was stimulated in the presence of acetate at low (<1 m m) but not at high (>1 m m) perfusate pyruvate concentrations. The stimulation of the metabolic flux through the pyruvate dehydrogenase reaction upon acetate infusion was accompanied by an increase in the activation state of the pyruvate dehydrogenase complex from 25.7 to 35.6% in the active form. In a liver perfused in the presence of the pyruvate dehydrogenase kinase inhibitor, dichloroacetate, at a low concentration of pyruvate (0.05 m m) the infusion of acetate did not affect the rate of pyruvate decarboxylation. As the rate of mitochondrial acetoacetate efflux is increased during acetate infusion the stimulation of pyruvate and α-ketoisovalerate decarboxylation is attributed to an accelerated rate of exchange of mitochondrial acetoacetate for cytosolic pyruvate or α-ketoisovalerate on the monocarboxylate transporter.

Importance of experimental conditions in evaluating the malonyl-CoA sensitivity of liver carnitine acyltransferase. Studies with fed and starved rats.

The experiments reconfirm the powerful inhibitory effect of malonyl-CoA on carnitine acyltransferase I and fatty acid oxidation in rat liver mitochondria (Ki 1.5 microM). Sensitivity decreased with starvation (Ki after 18 h starvation 3.0 microM, and after 42 h 5.0 microM). Observations by Cook, Otto & Cornell [Biochem. J. (1980) 192, 955--958] and Ontko & Johns [Biochem. J. (1980) 192, 959--962] have cast doubt on the physiological role of malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. The high Ki values obtained in the cited studies are shown to be due to incubation conditions that cause substrate depletion, destruction of malonyl-CoA or generation of excessively high concentrations of unbound acyl-CoA (which offsets the competitive inhibition of malonyl-CoA towards carnitine acyltransferase I). The present results are entirely consistent with the postulated role of malonyl-CoA as the primary regulatory of fatty acid synthesis and oxidation in rat liver.

Lipid metabolism during starvation: hepatic energy balance and ketogenesis.

The purpose of this paper is to integrate lipid catabolism, ketogenesis and acid-base balance during starvation. The calculations made in this presentation may be approximate, but the values give useful information. Emphasis is directed toward hydrogen (hydronium and hydride) transfer during the hyperketonaemic state of starvation, and a special role is assigned to /%hydroxybutyrate as a regulator of hepatic ketogenesis, and therefore a regulator of lipid catabolism. In order to compare the values in this paper with those in the literature, the results are expressed per 1.73m2 body surface area.

Hepatic, gut, and renal substrate flux rates in patients with hepatic cirrhosis.

The roles of liver, kidney, and gut in maintaining fuel homeostasis were studied in 28 patients with severe hepatic cirrhosis, 25 of whom had alcohol-induced cirrhosis. Hepatic, portal, and renal blood flow rates were measured and combined with substrate concentration differences across liver, gut, and kidney to calculate the net flux of free fatty acids, ketone bodies, triglycerides, and glucose with selected glucose precursors, including glycerol, lactate, pyruvate, and amino acids. Data from the catheterization studies were related to hepatic histology, glycogen content, and activities of gluconeogenic enzymes and compared with data obtained from control patients. The effects of food deprivation on net flux of fuels across the liver, gut, and kidney were assessed after overnight and after 3d of fasting. Activities of gluconeogenic enzymes were normal, but hepatic glycogen content was diminished in cirrhotic livers, probably as a consequence of extensive hepatic fibrosis. Extrahepatic splanchnic tissues (gut) had only a small influence on total splanchnic flux rates of carbohydrates, lipids and, amino acids. In cirrhotic patients, there was no mean renal glucose contribution to the bloodstream after an overnight or after a 3-d fast. After an overnight fast hepatic glucose production in patients with cirrhosis was diminished as a result of low-rate glycogenolysis. Hepatic gluconeogenesis and ketogenesis were increased. This pattern of hepatic metabolism mimics that seen in "normal" patients after more advanced stages of starvation. After 3 d of starvation, patients with hepatic cirrhosis have hepatic gluconeogenic and ketogenic profiles comparable to those of normal patients undergoing starvation of similar duration. Nevertheless, the total number of caloric equivalents derived from ketone bodies plus glucose corrected for recycled lactate and pyruvate added to the bloodstream by the cirrhotic livers that could be terminally oxidized by peripheral tissues was less than the contributions made by the normal livers, both after and overnight and after a 3-d fast.

Hepatic insulin and glucagon receptors in pregnancy: their role in the enhanced catabolism during fasting.

The response to dietary deprivation in late pregnancy, as compared to the non-pregnant condition, is more rapid and profound in terms of mobilization of fuels frm peripheral tissues as well as hepatic ketogenesis and gluconeogenesis ("accelerated starvation"). We examined the potential role of hepatic insulin and glucagon receptors in mediating these changes by comparing 48-h fasted 18-day pregnant and age-matched nongravid rats. Molar ratios for insulin:glucagon in peripheral and portal blood were significantly higher in the pregnant rats. Insulin binding to purified liver plasma membrane receptors, when appropriately corrected for differences in insulin degradation by the membrane system, was marginally diminished in the pregnant animals. Glucagon binding and adenylate cyclase activation by glucagon was indistinguishable in the two groups of animals. On the basis of portal vein hormone concentrations and the values for receptor binding, liver insulinization relative to glucagonization appears to be unchanged or slightly increased in the fasted pregnant rat compared to the fasted nongravid rat. Thus, it seems unlikely that much of the "accelerated starvation" response in late pregnancy can be ascribed to diminished insulin and/or increased glucagon availability at the hepatocellular level. Instead, it is hypothesized that postreceptor events play the major role in sustaining the intrahepatic realignments of established fasting in late pregnancy.

Hepatic gluconeogenesis and ketogenesis in hyperthyroidism

Metabolically, hyperthyroidism is characterized by an increase in total energy expenditure and an augmented pulmonary oxygen uptake (1). There is also an increase in adipose tissue lipolysis (2,3) and net protein catabolism (4,5). This augmented mobilization of peripheral substrate depots is similar to that seen in fasting. In the fasted state, the liver plays an important metabolic role in converting the flux of amino acids and fatty acids into glucose and ketone bodies, respectively, thus supplying substrates that can be used by the central nervous system (6). The present study was undertaken to evaluate the effects of hyperthyroidism on splanchnic gluconeogenesis and ketogenesis.