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PubMed2004

The role of insulin, glucagon, dexamethasone, and leptin in the regulation of ketogenesis and glycogen storage in primary cultures of porcine hepatocytes prepared from 60 kg pigs.

A study was conducted to elucidate hormonal control of ketogenesis and glycogen deposition in primary cultures of porcine hepatocytes. Hepatocytes were isolated from pigs (54-68 kg) by collagenase perfusion and seeded into collagen-coated T-25 flasks. Monolayers were established in medium containing fetal bovine serum for 1 day and switched to a serum-free medium for the remainder of the culture period. Hepatocytes were maintained in DMEM/M199 containing 1% DMSO, dexamethasone (10(-6) or 10(-7) M), linoleic acid (3.4 x 10(-5) M), and carnitine (10(-3) M) for 3 days. On the first day of serum-free culture, insulin was added at 1 or 100 ng/ml and glucagon was added at 0, 1, or 100 ng/ml. Recombinant human leptin (200 ng/ml) was added during the final 24 h; medium and all cells were harvested on the third day. Concentrations of acetoacetate and beta-hydroxybutyrate (ketone bodies) in media and glycogen deposition in the cellular compartment were determined. Ketogenesis was highly stimulated by glucagon (1 and 100 ng/ml) and inhibited by insulin. In contrast, glycogen deposition was stimulated by insulin and attenuated by glucagon; high insulin was also associated with a reduction in the ketone body ratio (acetoacetate:beta-hydroxybutyrate). High levels of dexamethasone stimulated ketogenesis, but inhibited glycogen deposition at low insulin. Culture of cells with leptin for 24 h, over the range of insulin, glucagon, and dexamethasone concentrations had no effect on either glycogen deposition or ketogenesis. These data suggest that while adult porcine hepatocytes are indeed sensitive to hormonal manipulation, leptin has no direct influence on hepatic energy metabolism in swine.

Animals↗

PubMed2005

Synthesis, characterization and antimicrobial activity of some substituted 1,2,3-triazoles.

Two substituted 1,2,3-triazoles 4 and 6 have been synthesized by the 1,3-dipolar cycloaddition reaction of 4-azido-8-(trifluoromethyl)quinoline 2 with ethyl acetoacetate and acetylacetone, respectively. The reaction of 2 with ethyl acetoacetate afforded 1-[8-(trifluoromethyl)quinolin-4-yl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid 3 and with acetylacetone afforded 1-{1-[8-(trifluoromethyl)quinolin-4-yl]-5-methyl-1H-1,2,3-triazol-4-yl}ethanone 5. Compound 3 is converted into its corresponding acid hydrazide and then condensed with different aromatic aldehydes to yield Schiff's base, N-[1-arylmethylene]-1-[8-(trifluoromethyl)quinolin-4-yl]-5-methyl-1H-1,2,3-triazole-4-carbohydrazides 4. Compound 5 is condensed with aromatic aldehydes to obtain [1-aryl-4-{1-[8-(trifluoromethyl)quinolin-4-yl]-5-methyl-1H-1,2,3-triazol-4-yl}prop-2-en-1-ones 6. The newly prepared 1,2,3-triazole derivatives 4 and 6 have been characterized by IR, NMR and mass spectral data. These compounds were screened for their antimicrobial activity.

Anti-Bacterial Agents↗

PubMed2004

Brain uptake and metabolism of ketone bodies in animal models.

As a consequence of the high fat content of maternal milk, the brain metabolism of the suckling rat represents a model of naturally occurring ketosis. During the period of lactation, the rate of uptake and metabolism of the two ketone bodies, beta-hydroxybutyrate and acetoacetate is high. The ketone bodies enter the brain via monocarboxylate transporters whose expression and activity is much higher in the brain of the suckling than the mature rat. beta-Hydroxybutyrate and acetoacetate taken up by the brain are efficiently used as substrates for energy metabolism, and for amino acid and lipid biosynthesis, two pathways that are important for this period of active brain growth. Ketone bodies can represent about 30-70% of the total energy metabolism balance of the immature rat brain. The active metabolism of ketone bodies in the immature brain is related to the high activity of the enzymes of ketone body metabolism. Thus, the use of ketone bodies by the immature rodent brain serves to spare glucose for metabolic pathways that cannot be fulfilled by ketones such as the pentose phosphate pathway mainly. The latter pathway leads to the biosynthesis of ribose mandatory for DNA synthesis and NADPH which is not formed during ketone body metabolism and is a key cofactor in lipid biosynthesis. Finally, ketone bodies by serving mainly biosynthetic purposes spare glucose for the emergence of various functions such as audition, vision as well as more integrated and adapted behaviors whose appearance during brain maturation seems to critically relate upon active glucose supply and specific regional increased use.

Amino Acids↗

PubMed2002

Effects of streptozotocin-induced diabetes on acetoacetyl-CoA synthetase activity in rats.

In order to investigate the physiological role of acetoacetyl-CoA synthetase (acetoacetate-CoA ligase, EC 6.2.1.16), a cytosolic acetoacetate-activating enzyme, effects of streptozotocin (STZ)-induced diabetes on the enzyme activity was investigated in rats. At 72 hr of the STZ administration (80 mg/kg body weight, injected intravenously), hepatic enzyme specific activity decreased to 23% of its initial activity. However, the enzyme activities in non-hepatic tissues were not significantly affected by the STZ treatment. Feeding of rats with both 4% cholestyramine and 0.4% pravastatin for 3 days remarkably increased the hepatic acetoacetyl-CoA synthetase activity and decreased the plasma ketone bodies level in the diabetic rats. These results suggest that acetoacetyl-CoA synthetase has important roles in the regulation of ketone body utilization in rat liver and that these hypocholesterolemic agents have the ability to remedy the impaired utilization of ketone bodies under the diabetic condition.

Animals↗

PubMed1986

Enhanced lipid utilization in infants receiving oral L-carnitine during long-term parenteral nutrition.

Fourteen infants requiring long-term total parenteral nutrition but able to tolerate small quantities of enteral feedings were randomized into carnitine treatment and placebo control groups. All infants had received nutritional support devoid of carnitine. Plasma carnitine levels and observed plasma lipid indices were not different before supplementation. Under standardized, steady-state conditions, 0.5 g/kg fat emulsion (intralipid) was administered intravenously over 2 hours both before and after infants received 7 days of continuous nasogastric or gastric tube L-carnitine (50 mumol/kg/day) or placebo. Plasma triglyceride, free fatty acid, acetoacetate, beta-hydroxybutyrate, and carnitine concentrations were observed at 0 (start of lipid infusion), 2, and 4 hours for pre- and post-treatment periods, and in addition at 6 and 8 hours after carnitine supplementation. Infants receiving carnitine had significantly greater beta-hydroxybutyrate plasma concentrations (P less than 0.05) and carnitine (P less than 0.001) at 0, 2, 4, 6, and 8 hours, and greater plasma acetoacetate concentrations (P less than 0.05) at 2, 4, 6, and 8 hours, compared with controls. Twenty-four-hour urinary carnitine excretion was very low for both groups before supplementation; after supplementation, excretion was higher (P less than 0.05) in the carnitine group. No significant differences were found between groups for plasma triglyceride or free fatty acid concentrations at any observation period. This study demonstrated enhanced fatty acid oxidation, as evidenced by increased ketogenesis, with L-carnitine supplementation in infants receiving long-term total parenteral nutrition.

3-Hydroxybutyric Acid↗

PubMed2003

Preliminary characterization of beta-decarboxylase activities in Staphylococcus carnosus 833, a strain used in sausage fermentation.

In sausage, Staphylococcus carnosus increases the levels of methyl ketones which could arise from incomplete beta-oxidation of fatty acids followed by a decarboxylation. The objective of this work was to characterize the beta-decarboxylase activities in cell-free extract. By using different substrates, at least two kinds of beta-decarboxylase activities were shown: an acetoacetate-like and an oxaloacetate-like. The first one leads to the production of ketones from ethylbutyryl acetate or acetoacetic acid. The activity was optimal at pH 6.0, stimulated by pyridoxal phosphate but ethylenediamine tetraacetic acid (EDTA), NaCl, iodoacetate and curing additives were inhibitory. The second decarboxylase activity leads to the production of pyruvic acid from oxaloacetic acid. This activity was optimal at pH 5.0 and stimulated by divalent ions and biotin.

Biotin↗

PubMed1999

Crystal structure and mechanism of a carbon-carbon bond hydrolase.

BACKGROUND: Fumarylacetoacetate hydrolase (FAH) catalyzes the final step of tyrosine and phenylalanine catabolism, the hydrolytic cleavage of a carbon-carbon bond in fumarylacetoacetate, to yield fumarate and acetoacetate. FAH has no known sequence homologs and functions by an unknown mechanism. Carbon-carbon hydrolysis reactions are essential for the human metabolism of aromatic amino acids. FAH deficiency causes the fatal metabolic disease hereditary tyrosinemia type I. Carbon-carbon bond hydrolysis is also important in the microbial metabolism of aromatic compounds as part of the global carbon cycle. RESULTS: The FAH crystal structure has been determined by rapid, automated analysis of multiwavelength anomalous diffraction data. The FAH polypeptide folds into a 120-residue N-terminal domain and a 300-residue C-terminal domain. The C-terminal domain defines an unusual beta-strand topology and a novel 'mixed beta-sandwich roll' structure. The structure of FAH complexed with its physiological products was also determined. This structure reveals fumarate binding near the entrance to the active site and acetoacetate binding to an octahedrally coordinated calcium ion located in close proximity to a Glu-His dyad. CONCLUSIONS: FAH represents the first structure of a hydrolase that acts specifically on carbon-carbon bonds. FAH also defines a new class of metalloenzymes characterized by a unique alpha/beta fold. A mechanism involving a Glu-His-water catalytic triad is suggested based on structural observations, sequence conservation and mutational analysis. The histidine imidazole group is proposed to function as a general base. The Ca(2+) is proposed to function in binding substrate, activating the nucleophile and stabilizing a carbanion leaving group. An oxyanion hole formed from sidechains is proposed to stabilize a tetrahedral alkoxide transition state. The proton transferred to the carbanion leaving group is proposed to originate from a lysine sidechain. The results also reveal the molecular basis for mutations causing the hereditary tyrosinemia type 1.

Amino Acids↗

PubMedDate not supplied

Effects of transjugular intrahepatic portosystemic shunts on hepatic metabolic function determined with serial monitoring of arterial ketone bodies.

PURPOSE: To investigate the effects of transjugular intrahepatic portosystemic shunt (TIPS) on hepatic metabolic function by measuring serial arterial ketone body ratio (acetoacetate/-hydroxybutyrate; AKBR). MATERIAL AND METHODS: The arterial blood of 30 TIPS patients was assayed before TIPS, 30 minutes after TIPS, and 24 hours after TIPS for acetoacetate, beta-hydroxybutyrate, and glucose. The authors compared the AKBR values to clinical outcome stratified by Child class, emergent versus elective TIPS, and before-TIPS AKBR value < or = 0.5 versus before-TIPS AKBR value > 0.5. RESULTS: A significant change was noted between the AKBR values obtained before TIPS and values 30 minutes after TIPS (0.76 +/- 0.09 vs 0.61 +/- 0.05, P < .05) and between 30 minutes and 24 hours after TIPS (0.81 +/- 0.10, P < .001), but not between the value obtained before TIPS and that obtained 24 hours after TIPS. The 30-day mortality rate in emergency TIPS patients was 50% compared to 7% in the elective TIPS patients (P < .01). The pre-TIPS AKBR values were significantly suppressed in the emergency TIPS patients compared to the elective TIPS patients (0.56 +/- 0.04 vs 0.99 +/- 0.17, P < .005). The 30-day mortality rate in patients with a pre-TIPS AKBR value < or = 0.5 was 75%, which was significantly higher than the 14% rate in patients with a pre-TIPS AKBR value > 0.5 (P < .01). CONCLUSION: A low pre-TIPS AKBR may be predictive of poor outcome after TIPS. Furthermore, AKBR may be of value in determining the timing for performing an elective TIPS.

Adolescent↗

PubMed2003

Simultaneous measurement of plasma concentrations and 13C-enrichment of short-chain fatty acids, lactic acid and ketone bodies by gas chromatography coupled to mass spectrometry.

A new method has been developed for the simultaneous measurement, in a reduced plasma sample, of concentration and 13C-isotopic enrichment of acetic, propionic, butyric, lactic, acetoacetic and beta-hydroxybutyric acids by gas chromatography coupled to mass spectrometry. After plasma deproteinisation, a diethylic extraction and a N-tert.-butyldimethylsilyl-N-methyltrifluoroacetamide derivatisation were performed. Both diethyl extraction and derivatisation procedures were optimised using the central composite designs methodology. The optimised method provides good linearity, intra-day and within-day repeatability. Except for beta-hydroxybutyric (49 microM) and acetoacetic acid (5 microM), detection limits were ranging between 0.2 and 0.7 microM allowing uses of this method for colonic metabolism studies.

Animals↗

PubMed1995

Role of binding energy with coenzyme A in catalysis by 3-oxoacid coenzyme A transferase.

Succinyl-CoA:3-oxoacid coenzyme A transferase (EC 2.8.3.5), which catalyzes the reversible conversion of succinyl-CoA and acetoacetate into acetoacetyl-CoA and succinate through a covalent enzyme thiol ester intermediate, E-CoA, utilizes binding energy from noncovalent interactions with CoA to bring about an increase in kcat/KM of approximately 10(10)-fold. The approximately 40-fold stronger binding of desulfo-CoA (KI = 2.7 +/- 0.7 mM) compared to desulfopantetheine (KI = 110 +/- 15 mM), both of which inhibit competitively with respect to acetoacetyl-CoA, shows that binding to the nucleotide domain of CoA at the active site provides ca. -2.2 kcal/mol of binding energy to stabilize noncovalent complexes with the enzyme. This is much smaller than the ca. -8.9 kcal/mol that the nucleotide domain contributes to the stabilization of the transition state and the ca. -7.2 kcal/mol that it contributes to stabilizing the E-CoA intermediate [Fierke, C. A., & Jencks, W. P. (1986) J. Biol. Chem. 261, 7603-7606]. This shows that most of the approximately 10(6)-fold increase in kcat/KM that is brought about by binding to this domain is in kcat, which is increased by a factor of about 10(5). Binding to the central pantoic acid domain of CoA is stronger in the transition state than in the Michaelis complex by ca. -3.4 kcal/mol; this corresponds to an additional increase in kcat of approximately 350-fold. Covalent enzyme thiol esters analogous to E-CoA but containing the short-chain CoA analogues N-acetylaletheine (NAA) and N-acetylcysteamine (NAC) are more stable than the enzyme thiol ester containing pantetheine (E-Pant) by approximately 3.5 and approximately 4.8 kcal/mol, respectively. Thus, interactions between the pantoic acid domain of CoA and the active site destabilize E-CoA by approximately 4.8 kcal/mol, approximately 1.3 kcal/mol of which arises from interaction with the amide group of the pantoic acid domain and approximately 3.5 kcal/mol of which arises from interaction with other portions of the pantoic acid domain. E-Pant is more reactive toward acetoacetate and succinate by a factor of approximately 10(7) than E-NAA and E-NAC. This shows that the destabilization caused by these interactions in E-CoA is relieved in the transition state, in which binding to the pantoic acid moiety is strongly favorable with delta delta G approximately -5.2 kcal/mol.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2002

Structural basis for CO2 fixation by a novel member of the disulfide oxidoreductase family of enzymes, 2-ketopropyl-coenzyme M oxidoreductase/carboxylase.

The NADPH:2-ketopropyl-coenzyme M oxidoreductase/carboxylase (2-KPCC) is the terminal enzyme in a metabolic pathway that results in the conversion of propylene to the central metabolite acetoacetate in Xanthobacter autotrophicus Py2. This enzyme is an FAD-containing enzyme that is a member of the NADPH:disulfide oxidoreductase (DSOR) family of enzymes that include glutathione reductase, dihydrolipoamide dehydrogenase, trypanothione reductase, thioredoxin reductase, and mercuric reductase. In contrast to the prototypical reactions catalyzed by members of the DSOR family, the NADPH:2-ketopropyl-coenzyme M oxidoreductase/carboxylase catalyzes the reductive cleavage of the thioether linkage of 2-ketopropyl-coenzyme M, and the subsequent carboxylation of the ketopropyl cleavage product, yielding the products acetoacetate and free coenzyme M. The structure of 2-KPCC reveals a unique active site in comparison to those of other members of the DSOR family of enzymes and demonstrates how the enzyme architecture has been adapted for the more sophisticated biochemical reaction. In addition, comparison of the structures in the native state and in the presence of bound substrate indicates the binding of the substrate 2-ketopropyl-coenzyme M induces a conformational change resulting in the collapse of the substrate access channel. The encapsulation of the substrate in this manner is reminiscent of the conformational changes observed in the well-characterized CO2-fixing enzyme ribulose 1,5-bisphosphate carboxylase/oxidase (Rubisco).

Acetone↗

PubMed2004

Evaluation of 3-hydroxy-3-methylglutaryl-coenzyme A lyase arginine-41 as a catalytic residue: use of acetyldithio-coenzyme A to monitor product enolization.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase catalyzes the divalent cation-dependent cleavage of HMG-CoA to produce acetyl-CoA and acetoacetate. Arginine-41 is an invariant residue in HMG-CoA lyases. Mutation of this residue (R41Q) correlates with human HMG-CoA lyase deficiency. To evaluate the functional importance of arginine-41, R41Q and R41M recombinant mutant human HMG-CoA lyase proteins have been constructed, expressed, and purified. These mutant proteins retain structural integrity based on Mn(2+) binding and affinity labeling stoichiometry. R41Q exhibits a 10(5)-fold decrease in V(max); R41M activity is >or=10-fold lower than the activity of R41Q. Acetyldithio-CoA, an analogue of the reaction product, acetyl-CoA, has been employed to test the function of arginine-41, as well as other residues (e.g., aspartate-42 and histidine-233) implicated in catalysis. Acetyldithio-CoA supports enzyme-catalyzed exchange of the methyl protons of the acetyl group with solvent; exchange is dependent on the presence of Mg(2+) and acetoacetate. In comparison with wild-type human enzyme, D42A and H233A mutant enzymes exhibit 4-fold and 10-fold decreases, respectively, in the proton exchange rate. In contrast, R41Q and R41M mutants do not catalyze any substantial enzyme-dependent proton exchange. These results suggest a role for arginine-41 in deprotonation or enolization of acetyldithio-CoA and implicate this residue in the HMG-CoA cleavage reaction chemistry that leads to acetyl-CoA product formation. Assignment of arginine-41 as an active site residue is also supported by a homology model for HMG-CoA lyase based on the structure of 4-hydroxy-2-ketovalerate aldolase. This model suggests the proximity of arginine-41 to other amino acids (aspartate-42, glutamate-72, histidine-235) implicated as active site residues based on their function as ligands to the activator cation.

Acetyl Coenzyme A↗

PubMed2004

A modular and concise total synthesis of (+/-)-daurichromenic acid and analogues.

A modular and concise total synthesis of (+/-)-daurichromenic acid has been accomplished in four steps from ethyl acetoacetate, ethyl crotonate, and trans,trans-farnesal. A series of analogues of this natural product, which has potent anti-HIV activity, were also prepared from ethyl or methyl acetoacetate and a series of readily available alpha,beta-unsaturated esters and aldehydes.

Anti-HIV Agents↗

PubMed2004

Solvent-free reactions of C60 with active methylene compounds, either with or without carbon tetrabromide, in the presence of bases under high-speed vibration milling conditions.

Solvent-free reactions of C(60) with active methylene compounds, either with or without carbon tetrabromide (CBr(4)), in the presence of a base under high-speed vibration milling (HSVM) conditions were investigated. The reaction of C(60) with diethyl bromomalonate was conducted under HSVM conditions in the presence of piperidine, triethylamine or Na(2)CO(3) to afford cyclopropane derivative. In the presence of CBr(4), methanofullerenes, and could be obtained by the direct reaction of C(60) with diethyl malonate, dimethyl malonate, ethyl acetoacetate and ethyl cyanoacetate, respectively, with the aid of 1,8-diazabicyclo[5,4,0]undec-7-ene, piperidine, triethylamine or Na(2)CO(3). More interestingly, 1,4-bisadducts and were produced by the reaction of C(60) with diethyl malonate and dimethyl malonate in the presence of piperidine, triethylamine or Na(2)CO(3) under HSVM conditions. On the other hand, dihydrofuran-fused C(60) derivatives, and were obtained from the reaction of C(60) with ethyl acetoacetate, 2,4-pentanedione and 5,5-dimethyl-1,3-cyclohexanedione with the aid of a base. Under the same conditions, less activated aryl methyl ketones such as 2-acetylpyridine, 2-acetylpyrazine and acetophenone provided monocarbonylated methanofullerene derivatives, and. Except for the Bingel reactions, all other reactions under the HSVM conditions are considered to proceed according to a single-electron-transfer mechanism.

Journal Article↗

PubMed1966

The effect of hexokinase and tricarboxylic acid-cycle intermediates on fatty acid oxidation and formation of ketone bodies by rat-liver mitochondria.

1. The oxidation of butyrate, hexanoate and octanoate by rat-liver mitochondria suspended in a tris-potassium chloride medium in the presence of malate and serum albumin has been investigated. 2. The oxidation of butyrate to acetoacetate was markedly decreased by the addition of a system competitive for ATP (hexokinase-glucose). 3. Serum albumin or tricarboxylic acid-cycle intermediates prevented the inhibition by hexokinase and in their presence a greater proportion of the oxygen consumption was contributed by the tricarboxylic acid cycle. The results suggest that the energy supply for fatty acid activation is either compartmentalized in a spatial or kinetic sense or there exists a special activating mechanism not involving ATP. 4. Malate and other tricarboxylic acid-cycle intermediates caused substantial reduction (to beta-hydroxybutyrate) of the acetoacetate formed during the oxidation of butyrate, hexanoate and octanoate.

Animals↗

PubMed1978

Pyruvate and ketone-body transport across the mitochondrial membrane. Exchange properties, pH-dependence and mechanism of the carrier.

The effects of exchangeable ions and pH on the efflux of pyruvate from preloaded mitochondria are reported. Efflux obeys first-order kinetics, and the stimulation of efflux by exchangeable ions such as acetoacetate and lactate obeys Michaelis--Menten kinetics. The apparent Km value +/- S.E. for acetoacetate was 0.56 +/- 0.14 mM (n = 5) and that for lactate 12.3 +/- 2.3 mM (n = 6). The Vmax. values +/- S.E. at 0 degrees C were 16.2 +/- 2.0 and 21.9 +/- 2.7 nmol/min per mg of protein. The exchange of a variety of other substituted monocarboxylates was also studied. Efflux was also stimulated by increasing the external pH. The data gave a pK for the transport process of 8.35 and a Vmax. of 3.31 +/- 0.14 nmol/min per mg. The similarity of the Vmax. values for various exchangeable ions but the difference of this from the Vmax. in the absence of exchangeable ions may indicate that transport of pyruvate occurs with H+ and not in exchange for an OH- ion. The inhibition of transport by alpha-cyano-4-hydroxycinnamate took several seconds to reach completion at 0 degrees C. It is proposed that inhibition occurs by binding to the substrate site and subsequent reaction with an -SH group on the inside of the membrane. The inhibitor can be displaced by substrates that can also enter the mitochondria independently of the carrier and so compete with the inhibitor for the substrate-binding site on the inside of the membrane. A mechanism for transport is proposed that invokes a transition state of pyruvate involving addition of an -SH group to the 2-carbon of pyruvate. Evidence is presented that suggests that ketone bodies may cross the mitochondrial membrane either on the carrier or by free diffusion. The physiological involvement of the carrier in ketone-body metabolism is discussed. The role of ketone bodies and pH in the physiological regulation of pyruvate transport is considered.

Animals↗

PubMed1980

Impaired sensitivity to insulin of rat livers perfused with blood of diminished haematocrit.

1. In livers from fed rats perfused with homologous whole blood of a haematocrit value of 37%, insulin decreased the perfusate concentrations of glucose and amino acids, production of ketone bodies (3-hydroxybutyrate + acetoacetate) and increased bile flow. 2. Perfusion with blood diluted with buffer to a haematocrit value of 17% decreased hepatic O2 consumption by 40-50%. Perfusate concentrations of glucose and lactate, the rate of ketogenesis and the ratios [lactate]/[pyruvate] and [3-hydroxybutyrate]/[acetoacetate] were all increased. 3. In livers perfused with blood of diminished haematocrit, effects of insulin on perfusate glucose an amino acids, ketogenesis and bile flow were abolished.

Amino Acids↗

PubMed1981

Regulation of hepatic fatty acid metabolism. The activities of mitochondrial and microsomal acyl-CoA:sn-glycerol 3-phosphate O-acyltransferase and the concentrations of malonyl-CoA, non-esterified and esterified carnitine, glycerol 3-phosphate, ketone bodies and long-chain acyl-CoA esters in livers of fed or starved pregnant, lactating and weaned rats.

1. The concentrations of malonyl-CoA, glycerol 3-phosphate, non-esterified carnitine, acid-soluble and acid-insoluble acylcarnitines, acetoacetate, 3-hydroxybutyrate and acid-insoluble acyl-CoA were measured in rapidly-frozen liver samples from fed or starved (24h) virgin, pregnant (19-20 days), lactating (2, 10-12 and 18-20 days) and weaned (for 24h, on 10th day of lactation) rats. The activities of total and N-ethylmaleimide-sensitive and -insensitive glycerophosphate acyltransferase (acyl-CoA:sn-glycerol 3-phosphate O-acyltransferase; EC 2.3.1.15) were also measured. 2. The concentration of malonyl-CoA was significantly higher in liver of fed pregnant, mid- and late-lactating rats than in liver of fed virgin rats. After starvation for 24h hepatic malonyl-CoA concentrations were higher in mid-lactating rats and lower in pregnant and weaned rats than in virgin animals. 3. After starvation for 24h the hepatic concentrations of glycerol 3-phosphate, ketone bodies, acid-soluble acylcarnitines and the value for the [3-hydroxybutyrate]/[acetoacetate] ratio were all highest in pregnant rats, intermediate in virgin, 2-day lactating and weaned animals and lowest in mid- and late-lactating rats. The concentrations of acid-insoluble acylcarnitines also increased most in pregnant rats, after starvation. The concentration of acid-insoluble acyl-CoA increased equally after starvation in virgin and pregnant animals but did not increase significantly in all other animals studied. 4. The total concentration of carnitine was similar in livers of fed virgin, pregnant and 2-day lactating animals but fell markedly by the 10th day of lactation and remained low in late-lactating animals. The concentration of non-esterified carnitine followed the same pattern. After starvation for 24h the hepatic concentration of non-esterified carnitine decreased significantly in virgin, pregnant and 2-day lactating animals, but remained unchanged in mid- and late-lactating or weaned animals. 5. The activities of N-ethylmaleimide-sensitive and -insensitive glycerophosphate acyltransferase both increased significantly in livers of mid-lactating animals. After starvation for 24h the activity of the N-ethylmaleimide-insensitive O-acyltransferase decreased in livers of virgin, pregnant and mid-lactating animals, whereas the activity of the N-ethylmaleimide-sensitive O-acyltransferase was unchanged in virgin animals but decreased markedly in livers of pregnant and lactating rats. 6. The results are discussed in relation to the importance of different metabolic parameters in the regulation of long-chain acyl-CoA metabolism in the liver.

Acyl Coenzyme A↗