Acyl-CoA oxidase of rat liver: a new enzyme for fatty acid oxidation.
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Acyl-CoA oxidase from Candida tropicalis.
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Acyl Coenzyme A↗
Properties of fatty acyl-CoA oxidase from rat liver, a peroxisomal flavoprotein.
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Acyl Coenzyme A↗
Detection of peroxisomal fatty acyl-coenzyme A oxidase activity.
It has been postulated that the peroxisomal fatty acid-oxidizing system [Lazarow & de Duve (1976) Proc. Natl. Acad. Sci. U.S.A. 73, 2043--2046; Lazarow (1978) J. Biol. Chem. 253, 1522--1528] resembles that of mitochondria, except for the first oxidative reaction. In this step, O2 would be directly reduced to H2O2 by an oxidase. Two specific procedures developed to detect the activity of the characteristic enzyme fatty acyl-CoA oxidase are presented, namely polarographic detection of palmitoyl-CoA-dependent cyanide-insensitive O2 consumption and palmitoyl-CoA-dependent H2O2 generation coupled to the peroxidation of methanol in an antimycin A-insensitive reaction. Fatty acyl-CoA oxidase activity is stimulated by FAD, which supports the flavoprotein nature postulated for this enzyme. Its activity increases 7-fold per g wet wt. of liver in rats treated with nafenopin, a hypolipidaemic drug. Subcellular fractionation of livers from normal and nafenopin-treated animals provides evidence for its peroxisomal localization. The stoicheiometry for palmitoyl-CoA-dependent O2 consumption, H2O2 generation and NAD+ reduction is 1 : 1 : 1. This suggests that fatty acyl-CoA oxidase is the rate-limiting enzyme of the peroxisomal fatty acid-oxidizing system.
Acyl Coenzyme A↗
Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors.
Peroxisomes are cytoplasmic organelles which are important in mammals in modulation of lipid homeostasis, including the metabolism of long-chain fatty acids and conversion of cholesterol to bile salts (reviewed in refs 1 and 2). Amphipathic carboxylates such as clofibric acid have been used in man as hypolipidaemic agents and in rodents they stimulate the proliferation of peroxisomes. These agents, termed peroxisome proliferators, and all-trans retinoic acid activate genes involved in peroxisomal-mediated beta-oxidation of fatty acids. Here we show that the receptor activated by peroxisome proliferators and the retinoid X receptor-alpha (ref. 6) form a heterodimer that activates acyl-CoA oxidase gene expression in response to either clofibric acid or the retinoid X receptor-alpha ligand, 9-cis retinoic acid, an all-trans retinoic acid metabolite; simultaneous exposure to both activators results in a synergistic induction of gene expression. These data demonstrate the coupling of the peroxisome proliferator and retinoid signalling pathways and provide evidence for a physiological role for 9-cis retinoic acid in modulating lipid metabolism.
Acyl-CoA Oxidase↗
Induction of peroxisomal beta-oxidation genes by retinoic acid in cultured rat hepatocytes.
Retinoic acid is reported here to induce peroxisomal beta-oxidation activities in cultured rat hepatocytes, with a concomitant increase in respective peroxisomal mRNAs. The concentrations of retinoic acid required for inducing liver peroxisomal acyl-CoA oxidase were similar to those required for inducing liver transglutaminase. A putative 5'-flanking response element for retinoic acid may be found within the enhancer region involved in the induction of peroxisomal genes by xenobiotic amphipathic carboxylates.
Acetyl-CoA C-Acetyltransferase↗
Induction of peroxisomal beta-oxidation enzymes by dehydroepiandrosterone and its sulfate in primary cultures of rat hepatocytes.
Treatment of cultured rat-hepatocytes with 50 microM dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) for up to 5 days resulted in a progressive increase in peroxisomal beta-oxidation and carnitine acetyltransferase activity. After 5 days, the increases in activity were 2.6- and 4.8-fold for peroxisomal beta-oxidation and 11.7- and 17.1-fold for carnitine acetyltransferase over the initial activity, in DHEA- and DHEAS-treated cells, respectively. The stimulation of the activity of these enzymes by the respective agents was dose-related; it was maximum with 50 to 100 microM DHEA and 50 to 250 microM DHEAS, although DHEAS was more effective for stimulation than DHEA. Western blot analyses revealed the induction of acyl-CoA oxidase, enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme and carnitine acetyltransferase in the treated cells. Moreover, induction of fatty acid omega-hydroxylase proteins (P-450IVAS) was also revealed. These results indicate that DHEA and DHEAS act directly on hepatocytes. The induction of hepatic peroxisomal beta-oxidation enzymes and several other enzymes in rats administered with DHEA could be accounted for, at least in part, by the direct action of DHEA and its sulfate-conjugate (DHEAS) on liver cells.
Animals↗
[Study on mechanism of Wendan Decoction in intervening in nonalcoholic fatty liver disease based on proteomics and network pharmacology].
This study systematically explored the molecular mechanism of Wendan Decoction(WDD) in treating nonalcoholic fatty liver disease(NAFLD) by integrating network pharmacology, proteomics, and experimental validation. A mouse NAFLD model was established using a high-fat diet, and the mice were randomly divided into a blank control group, a model group, a positive drug group(simvastatin, 3.03 mg·kg~(-1)), and low-(3.035 g·kg~(-1)), medium-(6.07 g·kg~(-1)), and high-dose(12.14 g·kg~(-1)) WDD groups, with intervention lasting for 6 weeks. After the intervention, the serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), triglycerides(TG), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), and high-density lipoprotein cholesterol(HDL-C) were measured using an automatic biochemical analyzer. The serum levels of interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) were detected by ELISA. Liver histopathology was observed via hematoxylin-eosin(HE) staining and oil red O staining. Network pharmacology was used to predict potential targets and pathways, and proteomics was applied to identify differentially expressed proteins and related pathways. RT-qPCR and Western blot were performed to detect mRNA and protein expression of relevant genes. Animal experiments demonstrated that WDD dose-dependently ameliorated hepatic steatosis, inflammation, and lipid deposition, significantly reducing serum levels of ALT, AST, TG, TC, LDL-C, and pro-inflammatory cytokines(IL-1β, IL-6, and TNF-α), while significantly increasing serum HDL-C levels. Network pharmacology screening identified naringenin, baicalein, and other key active components, which were involved in pathways such as the peroxisome proliferator-activated receptor(PPAR), lipid, and atherosclerosis pathways. Proteomics further revealed differentially expressed pathways including the PPAR and advanced glycation end product-receptor(AGE-RAGE) signaling pathways. Integrated analysis highlighted the PPAR signaling pathway as the core mechanism. Molecular biology validation showed that WDD significantly regulated the mRNA expression of sterol regulatory element-binding protein-1c(SREBP-1c), fatty acid synthase(FASN), carnitine palmitoyl transferase 1A(CPT1A), acyl-CoA oxidase 1(ACOX1), and PPARα, as well as protein expression of PPARα, CPT1A, and PPARγ in mouse liver tissue. These results suggested that WDD might exert a multi-component, multi-target, and multi-pathway synergistic effect to improve lipid metabolism disorders and inflammatory responses with the PPAR signaling pathway as the central hub, thereby alleviating NAFLD progression.
Animals↗
The peroxisome proliferator-activated receptor mediates the induction of CYP4A6, a cytochrome P450 fatty acid omega-hydroxylase, by clofibric acid.
Gene transfer experiments indicate that induction by the peroxisome proliferators, clofibric acid and WY-14,643, of luciferase expression driven by the promoter and 5'-flanking sequences of the rabbit cytochrome P450 4A6 gene (CYP4A6) is dependent on cotransfection of expression plasmids for the peroxisome proliferator-activated receptor, PPAR. Activation by PPAR is observed in the absence of the inducers. However, a mutant, PPAR-G (Glu282----Gly) activated luciferase expression only in the presence of peroxisome proliferators. Deletion analysis has localized a response element to a 34-base pair segment located 677 base pairs upstream of the CYP4A6 transcription start site that is similar to an element that regulates the response of the rat fatty acyl-CoA oxidase gene to peroxisome proliferators and that binds PPAR.
Animals↗
Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors.
Three novel members of the Xenopus nuclear hormone receptor superfamily have been cloned. They are related to each other and similar to the group of receptors that includes those for thyroid hormones, retinoids, and vitamin D3. Their transcriptional activity is regulated by agents causing peroxisome proliferation and carcinogenesis in rodent liver. All three Xenopus receptors activate the promoter of the acyl coenzyme A oxidase gene, which encodes the key enzyme of peroxisomal fatty acid beta-oxidation, via a cognate response element that has been identified. Therefore, peroxisome proliferators may exert their hypolipidemic effects through these receptors, which stimulate the peroxisomal degradation of fatty acids. Finally, the multiplicity of these receptors suggests the existence of hitherto unknown cellular signaling pathways for xenobiotics and putative endogenous ligands.
Acyl-CoA Oxidase↗
The molecular mechanism of peroxisome proliferator action: a model for species differences and mechanistic risk assessment.
An increasing number of chemicals that produce tumours in rodent bioassays belong to the non-genotoxic class of carcinogens. There are no suitable tests for these carcinogens and our understanding of their mechanism of action is poor. Importantly, assessment of their potential hazard to man is usually difficult without extensive research. Peroxisome proliferators (PP) are a diverse group of rodent non-genotoxic carcinogens that include hypolipidemic drugs, plasticizers and herbicides. We have reported previously the cloning of a member of the nuclear hormone receptor superfamily and, through the use of chimeric receptors, discovered that it could be activated by PPs. The receptor is therefore termed the PP activated receptor (PPAR). The most widely used marker of PP action is the peroxisomal beta-oxidation enzyme acyl CoA oxidase (ACO). Interestingly, it has been speculated that the hydrogen peroxide produced as a result of ACO activity could lead to DNA damage and tumorigenesis. We have now demonstrated that PPAR recognizes a specific PP response element (PPRE) located in the ACO gene promoter and that the response is dependent upon the presence of receptor and the addition of the PP Wy-14,643. These data therefore support a model in which the mechanism of PP action is mediated by PPAR in a manner similar to that of steroid hormone action. Learning more about the function of PPAR offers a unique opportunity to understand the mechanism of action of some non-genotoxic carcinogens. Furthermore, this knowledge when combined with comparison of receptor expression between rodents and man will be important in providing a framework for a new threshold model of risk assessment based upon receptor-mediated carcinogenesis.
Acyl-CoA Oxidase↗
Perfluorooctanoic acid has persistent effects on peroxisome proliferation and related parameters in mouse liver.
Male C57Bl/6 mice were treated for 5 days with 0.05% perfluorooctanoic acid (PFOA) in their diet. This treatment resulted in a potent induction of peroxisomal fatty acid beta-oxidation in the liver. In order to investigate recovery from treatment with PFOA, mice were given normal laboratory chow for up to 20 days after termination of PFOA administration. It was established that the activities of peroxisomal lauoryl-CoA oxidase and palmitoyl-CoA oxidation were still elevated 2-3 weeks after termination of treatment. The catalase activity recovered in the cytosolic fraction was also still significantly elevated after 20 days with normal laboratory chow. Furthermore, the protein content of the mitochondrial fraction was increased by PFOA and had not returned to control level at the end of the recovery period. Perfluorooctanoic acid also caused a persistent effect in omega hydroxylation of lauric acid (cytochrome P-452). The activities of cytosolic DT-diaphorase and glutathione transferase were also enhanced by PFOA. However, these two enzymes recovered relatively rapidly from the treatment (2-20 days). This study reveals two different patterns of recovery from PFOA treatment, one involving parameters that recovered completely, or almost completely, from PFOA treatment after 20 days and another involving parameters that were still elevated at the end of the recovery period.
Acyl-CoA Oxidase↗
Studies on the delta 5-desaturation in ergosterol biosynthesis in yeast.
Studies were carried out on the delta 5-desaturation reaction in ergosterol biosynthesis with a particulate fraction of cell-free extract of yeast. A reduced pyridine nucleotide coenzyme and molecular oxygen were required for the reaction. It was shown that the enzyme activity is located in a fraction corresponding to microsomes. The reaction was inhibited by KCN, but not by CO. Menadione and potassium ferricyanide inhibited the NADPH- and NADH-dependent reactions, respectively, and cytochrome c inhibited both of them. These results suggested an involvement in delta 5-desaturation of a mixed function oxidase system resembling that for the fatty acyl-CoA desaturation reaction.
Ascorbic Acid↗
The intracellular localization of long-chain acyl-CoA synthetase in brown adipose tissue.
1. The acyl-CoA synthetase activity in brown adipose tissue of cold-exposed guinea pig has been studied by measuring the rate of palmitoylcarnitine formation in the presence of excess carnitine palmitoyltransferase. 2. The rate of palmitoylcarnitine formation in the mitochondria was found to be 161 plus or minus 64 nmol.mg-minus-1. min-minus-1 (n=9). 3. In the absence of added palmitate and bovine serum albumin a total of 35 plus or minus 1 nmol endogenous fatty acids.mg-minus-1 were activated with three different mitochondrial preparations. 4. Three different experimental approaches have been used to study the subcellular localization of the enzyme: (a) conventional differential centrifugation (De Duve, C., Pressman, B.C., Gianetto, R., Wattiaux, R. and Appelmans, F. (1955) Biochem. J. 60, 604-617) (B) the determination of the sediterm of different marker enzymes (Slinde, E. and Flatmark. T. (1973) Anal. Biochem. 56, 324-340) and (c) the determination of the stoichiometry between the activities of these enzymes sedimented at higher centrifugal effects. 5. Throughout all fractionation procedures, the long-chain acyl-CoA synthetase follows strictly the amine oxidase generally considered to be exclusively located on the mitochondrial outer membrane.
Adipose Tissue, Brown↗
Enhancement of fatty acyl-CoA oxidizing activity in rat liver peroxisomes by di-(i-ethylhexyl)phthalate.
The effect of di-(2-ethylhexyl)phthalate (DEHP) administration on cyanide-insensitive palmitoyl-CoA oxidizing activity in liver was studied. Two weeks of DEHP treatment increased the activity by one order of magnitude in male Wistar rats. A similar effect was also observed in male and female Sprague-Dawley rats and mice, but not in guinea pigs. When the liver was fractionated by differential centrifugation, the activity was concentrated in the light mitochondrial fraction. On the subfractionation of this fraction by sucrose density gradient centrifugation, the activity was distributed in a pattern similar to that of urate oxidase, but not resembling that of glutamate dehydrogenase. These data suggest that a fatty acyl-CoA oxidizing enzyme system which is located in peroxisomes is induced by the administration of DEHP.
Acyl Coenzyme A↗
Cytochrome c oxidase deficiency and long-chain acyl coenzyme A dehydrogenase deficiency with Leigh's subacute necrotizing encephalomyelopathy.
A female infant was seen at the age of 2 months because of hypotonia, delayed motor development, and lactic acidosis, and she died at age 13 months due to respiratory failure. In a muscle specimen taken at 11 months and in a liver specimen obtained 1.5 hours postmortem, we found decreased activities of cytochrome c oxidase and long-chain acyl coenzyme A dehydrogenase. Neuropathological changes were typical for Leigh's subacute necrotizing encephalomyelopathy. To our knowledge, this is the first report of a combined defect of complex IV of the respiratory chain and of the long-chain specific acyl coenzyme A dehydrogenase of beta-oxidation in muscle and liver.
Acyl-CoA Dehydrogenase↗
Comparison of the intermediary metabolism of fatty acids in denervated and dystrophic murine skeletal muscle.
Certain aspects of lipid metabolism have been examined in denervated muscle from normal mice and in dystrophic muscle from mice of the Bar Harbor strain 129. A number of parameters show no change or similar changes. For example, the utilization of palmitate-[1-14C] and palmitylcarnitine by mitochondria from denervated and dystrophic hind leg skeletal muscle showed parallel decreased in the oxidation of palmitate (30-42%) and palmitylcarnite (37-66%). A comparable study with acetylcarnitine showed a striking difference with no change evident in mitochondria from denervated muscle and 80-85% decrease in dystrophic muscle. The study of succinate dehydrogenase and the enzymes of beta-oxidation in the above mitochondrial preparation showed similar findings except for acyl CoA dehydrogenase activity (an enzyme with a regulatory role in beta-oxidation) which was significantly diminished (29%) in denervated muscle, whereas no change was observed in dystrophic muscle. The findings show a close parallel in a number of parameters but distinct differences were observed in denervated as compared with dystrophic muscle. It is unlikely that the muscular disorder in murine muscular dystrophy can be explained solely on the basis of denervation or the loss of a neural trophic factor.
Acyl-CoA Dehydrogenases↗
Glucocorticoid induction of pulmonary maturation in the rabbit fetus. The effect of maternal injection of betamethasone on the activity of enzymes in fetal lung.
1. Maternal administration of betamethasone (0.2 mg/kg) on day 25 or 26 of gestation produced a significant decrease in the lung/body weight ratio of the rabbit fetuses within 24 h. 2. The incorporation of [14C]choline but not [14C]ethanolamine into the lipids of fetal lung slices was significantly increased, indicating that there was a specific effect on phosphatidylcholine synthesis. 3. The activities of a number of marker enzymes for subcellular organelles were elevated, especially in the lungs of fetuses delivered on day 26. The increases in monoamine oxidase (mitochondrial outer membrane), beta-glycerophosphatase and aqueously dispersed phosphatidic acid-dependent phosphatidic acid phosphohydrolase (lysosomal) activities were significant. 4. Although the activity of cholinephosphotransferase was not affected by glucocorticoid treatment, the activities of glycerol-3-phosphate phosphatidyltransferase and the activities of two enzymes in the auxiliary pathways for the production of disaturated phosphatidylcholine (lysophosphatidylcholine:lysophosphatidylcholine transacylase and lysophosphatidylcholine:acyl-CoA acyl-transferase) were significantly increased. 5. Membrane-bound phosphatidic acid-dependent phosphatidic acid phosphohydrolase activity was elevated to a lesser extent than the aqueously dispersed phosphatidate-dependent activity and this increase was not significant. 6. The incorporation of E135S]methionine into protein by slices of fetal lung was significantly reduced after maternal treatment with betamethosone. 7. These results are consistent with the general view that glucocorticoids can induce pulmonary maturation and surfactant production in the rabbit fetus but indicate that some of the former hypotheses regarding the mechanism by which lipid synthesis is accelerated must be reevaluated.
Animals↗