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J K Reddy - One of the best experts on this subject based on the ideXlab platform.
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peroxisomal Beta Oxidation and steatohepatitis
Seminars in Liver Disease, 2001Co-Authors: M S Rao, J K ReddyAbstract:Abstract Fatty acid Beta-Oxidation occurs in both mitochondria and peroxisomes. Mitochondria catalyze the Beta-Oxidation of the bulk of short-, medium-, and long-chain fatty acids derived from diet, and this pathway constitutes the major process by which fatty acids are oxidized to generate energy. Peroxisomes are involved, preferentially, in the Beta-Oxidation chain shortening of very long chain fatty acids (VLCFAs) and in the process produce H2O2. Long-chain fatty acids and VLCFAs are also metabolized by the cytochrome P450 CYP4A omega-Oxidation system to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal Beta-Oxidation, and this process also leads to the production of superoxide and H2O2. The genes encoding peroxisomal, microsomal, and certain mitochondrial fatty acid metabolizing enzymes in liver are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha). Deficiencies of the enzymes of peroxisomal Beta-Oxidation have been recognized as important causes of disease. Evidence from mice deficient in PPAR alpha (PPAR alpha-/-), deficient in peroxisomal fatty acyl-CoA oxidase (AOX-/-), the first enzyme of the classical Beta-Oxidation system, and deficient in both PPAR alpha and AOX (PPAR alpha-/-AOX-/-) points to the critical importance of PPAR alpha-inducible peroxisomal and microsomal Oxidation systems that metabolize LCFAs and VLCFAs in the pathogenesis of nonalcoholic microvesicular hepatic steatosis and steatohepatitis. These and other mouse models should provide greater understanding of the molecular mechanism responsible for hepatic steatosis and steatohepatitis. Deficiency of AOX disrupts the Oxidation of VLCFAs, DCAs, and other substrates leading to extensive microvesicular steatosis and steatohepatitis. Loss of this enzyme also causes sustained hyperactivation of PPAR alpha, leading to transcriptional up-regulation of PPAR alpha-regulated genes, indicating that unmetabolized substrates of AOX function as ligands of PPAR alpha. Beta-Oxidation is the major process by which fatty acids are oxidized to generate energy, especially when glucose availability is low during periods of starvation. Mice deficient in PPAR alpha and those nullizygous for both PPAR alpha and AOX show a minimal steatotic phenotype under fed conditions but manifest an exaggerated steatotic response to fasting, indicating that defects in PPAR alpha-inducible fatty acid Oxidation determine the severity of fatty liver phenotype to conditions reflecting energy-related stress.
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peroxisomal and mitochondrial fatty acid Beta Oxidation in mice nullizygous for both peroxisome proliferator activated receptor alpha and peroxisomal fatty acyl coa oxidase genotype correlation with fatty liver phenotype
Journal of Biological Chemistry, 1999Co-Authors: Takashi Hashimoto, Frank J Gonzalez, Tomoyuki Fujita, Nobuteru Usuda, W A Cook, Jeffrey M Peters, Anjana V Yeldandi, Sambasiva M Rao, J K ReddyAbstract:Fatty acid Beta-Oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also metabolized by the cytochrome P450 CYP4A omega-Oxidation enzymes to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal Beta-Oxidation. Synthetic peroxisome proliferators interact with peroxisome proliferator activated receptor alpha (PPARalpha) to transcriptionally activate genes that participate in peroxisomal, microsomal, and mitochondrial fatty acid Oxidation. Mice lacking PPARalpha (PPARalpha-/-) fail to respond to the inductive effects of peroxisome proliferators, whereas those lacking fatty acyl-CoA oxidase (AOX-/-), the first enzyme of the peroxisomal Beta-Oxidation system, exhibit extensive microvesicular steatohepatitis, leading to hepatocellular regeneration and massive peroxisome proliferation, implying sustained activation of PPARalpha by natural ligands. We now report that mice nullizygous for both PPARalpha and AOX (PPARalpha-/- AOX-/-) failed to exhibit spontaneous peroxisome proliferation and induction of PPARalpha-regulated genes by biological ligands unmetabolized in the absence of AOX. In AOX-/- mice, the hyperactivity of PPARalpha enhances the severity of steatosis by inducing CYP4A family proteins that generate DCAs and since they are not metabolized in the absence of peroxisomal Beta-Oxidation, they damage mitochondria leading to steatosis. Blunting of microvesicular steatosis, which is restricted to few liver cells in periportal regions in PPARalpha-/- AOX-/- mice, suggests a role for PPARalpha-induced genes, especially members of CYP4A family, in determining the severity of steatosis in livers with defective peroxisomal Beta-Oxidation. In age-matched PPARalpha-/- mice, a decrease in constitutive mitochondrial Beta-Oxidation with intact constitutive peroxisomal Beta-Oxidation system contributes to large droplet fatty change that is restricted to centrilobular hepatocytes. These data define a critical role for both PPARalpha and AOX in hepatic lipid metabolism and in the pathogenesis of specific fatty liver phenotype.
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thyroid hormone t3 inhibits ciprofibrate induced transcription of genes encoding Beta Oxidation enzymes cross talk between peroxisome proliferator and t3 signaling pathways
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Ruiyin Chu, M S Rao, Laird D Madison, Yao Lin, P Kopp, J L Jameson, J K ReddyAbstract:Abstract Peroxisome proliferators cause rapid and coordinated transcriptional activation of genes encoding peroxisomal Beta-Oxidation system enzymes by activating peroxisome proliferator-activated receptor (PPAR) isoform(s). Since the thyroid hormone (T3; 3,3',5-triiodothyronine) receptor (TR), another member of the nuclear hormone receptor superfamily, regulates a subset of fatty acid metabolism genes shared with PPAR, we examined the possibility of interplay between peroxisome proliferator and T3 signaling pathways. T3 inhibited ciprofibrate-induced luciferase activity as well as the endogenous peroxisomal Beta-Oxidation enzymes in transgenic mice carrying a 3.2-kb 5'-flanking region of the rat peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase gene fused to the coding region of luciferase. Transfection assays in hepatoma H4-II-E-C3 and CV-1 cells indicated that this inhibition is mediated by TR in a ligand-dependent fashion. Gel shift assays revealed that modulation of PPAR action by TR occurs through titration of limiting amounts of retinoid X receptor (RXR) required for PPAR activation. Increasing amounts of RXR partially reversed the inhibition in a reciprocal manner; PPAR also inhibited TR activation. Results with heterodimerization-deficient TR and PPAR mutants further confirmed that interaction between PPAR and TR signaling systems is indirect. These results suggest that a convergence of the peroxisome proliferator and T3 signaling pathways occurs through their common interaction with the heterodimeric partner RXR.
Ronald J A Wanders - One of the best experts on this subject based on the ideXlab platform.
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metabolic interplay between peroxisomes and other subcellular organelles including mitochondria and the endoplasmic reticulum
Frontiers in Cell and Developmental Biology, 2015Co-Authors: Ronald J A Wanders, Hans R. Waterham, Sacha FerdinandusseAbstract:Peroxisomes are unique subcellular organelles which play an indispensable role in several key metabolic pathways which include: (1.) etherphospholipid biosynthesis; (2.) fatty acid Beta-Oxidation; (3.) bile acid synthesis; (4.) docosahexaenoic acid (DHA) synthesis; (5.) fatty acid alpha-Oxidation; (6.) glyoxylate metabolism; (7.) amino acid degradation, and (8.) ROS/RNS metabolism. The importance of peroxisomes for human health and development is exemplified by the existence of a large number of inborn errors of peroxisome metabolism in which one of these functions is impaired. Although the clinical signs and symptoms of affected patients differ depending upon the enzyme which is deficient and the extent of the deficiency, the disorders involved are usually (very) severe diseases with neurological dysfunction and early death in many of them. With respect to the role of peroxisomes in metabolism it is clear that peroxisomes are dependent on the functional interplay with other subcellular organelles to sustain their role in metabolism. Indeed, whereas mitochondria can oxidize fatty acids all the way to CO2 and H2O, peroxisomes are only able to chain-shorten fatty acids and the end products of peroxisomal Beta-Oxidation need to be shuttled to mitochondria for full Oxidation to CO2 and H2O. Furthermore, NADH is generated during Beta-Oxidation in peroxisomes and Beta-Oxidation can only continue if peroxisomes are equipped with a mechanism to re-oxidize NADH back to NAD+, which is now known to be mediated by specific NAD(H)-redox shuttles. In this paper we describe the current state of knowledge about the functional interplay between peroxisomes and other subcellular compartments notably the mitochondria and endoplasmic reticulum for each of the metabolic pathways in which peroxisomes are involved.
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The enzymology of mitochondrial fatty acid Beta-Oxidation and its application to follow-up analysis of positive neonatal screening results
Journal of Inherited Metabolic Disease, 2010Co-Authors: Ronald J A Wanders, Jos P N Ruiter, Lodewijk Ijlst, Hans R. Waterham, Sander M. HoutenAbstract:Oxidation of fatty acids in mitochondria is a key physiological process in higher eukaryotes including humans. The importance of the mitochondrial Beta-Oxidation system in humans is exemplified by the existence of a group of genetic diseases in man caused by an impairment in the mitochondrial Oxidation of fatty acids. Identification of patients with a defect in mitochondrial Beta-Oxidation has long remained notoriously difficult, but the introduction of tandem-mass spectrometry in laboratories for genetic metabolic diseases has revolutionalized the field by allowing the rapid and sensitive analysis of acylcarnitines. Equally important is that much progress has been made with respect to the development of specific enzyme assays to identify the enzyme defect in patients subsequently followed by genetic analysis. In this review, we will describe the current state of knowledge in the field of fatty acid Oxidation enzymology and its application to the follow-up analysis of positive neonatal screening results.
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complete Beta Oxidation of valproate cleavage of 3 oxovalproyl coa by a mitochondrial 3 oxoacyl coa thiolase
Biochemical Journal, 2002Co-Authors: Margarida F B Silva, Jos P N Ruiter, Henk Overmars, Albert H Bootsma, Albert H Van Gennip, Cornelis Jakobs, M Duran, Isabel Tavares De Almeida, Ronald J A WandersAbstract:The Beta-Oxidation of valproic acid (VPA; 2-n-propylpentanoic acid) was investigated in vitro in intact rat liver mitochondria incubated with (3)H-labelled VPA. The metabolism of [4,5-(3)H(2)]VPA and [2-(3)H]VPA was studied by analysing the different acyl-CoA intermediates formed by reverse-phase HPLC with radiochemical detection. Valproyl-CoA, Delta(2(E))-valproyl-CoA,3-hydroxyvalproyl-CoA and 3-oxovalproyl-CoA (labelled and non-labelled) were determined using continuous on-line radiochemical and UV detection. The formation of these intermediates was investigated using the two tritiated precursors in respiratory states 3 and 4. Valproyl-CoA was present at highest concentrations under both conditions. Two distinct labelled peaks were found, which were identified as (3)H(2)O and [4,5-(3)H(2)]3-oxo-VPA. The formation of (3)H(2)O strongly suggested that VPA underwent complete Beta-Oxidation and that [4,5-(3)H(2)]3-oxo-VPA was formed by hydrolysis of the corresponding thioester. The hypothesis that 3-oxovalproyl-CoA undergoes thiolytic cleavage was investigated further. For this purpose a mito chondrial lysate was incubated with synthetic 3-oxovalproyl-CoA, carnitine and carnitine acetyltransferase for subsequent monitoring of the formation of propionylcarnitine and pentanoylcarnitine using electrospray ionization tandem MS. The detection of these compounds demonstrated unequivocally that the intermediate 3-oxovalproyl-CoA is a substrate of a mitochondrial thiolase, producing propionyl-CoA and pentanoyl-CoA, thus demonstrating the complete Beta-Oxidation of VPA in the mitochondrion. Our data should lead to a re-evaluation of the generally accepted concept that the biotransformation of VPA by mitochondrial Beta-Oxidation is incomplete
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subcellular localization and physiological role of alpha methylacyl coa racemase
Journal of Lipid Research, 2000Co-Authors: Sacha Ferdinandusse, Lodewijk Ijlst, Hans R. Waterham, Simone Denis, Georges Dacremont, Ronald J A WandersAbstract:alpha-Methylacyl-CoA racemase plays an important role in the Beta-Oxidation of branched-chain fatty acids and fatty acid derivatives because it catalyzes the conversion of several (2R)-methyl-branched-chain fatty acyl-CoAs to their (S)-stereoisomers. Only stereoisomers with the 2-methyl group in the (S)-configuration can be degraded via Beta-Oxidation. Patients with a deficiency of alpha-methylacyl-CoA racemase accumulate in their plasma pristanic acid and the bile acid intermediates di- and trihydroxycholestanoic acid, which are all substrates of the peroxisomal Beta-Oxidation system. Subcellular fractionation experiments, however, revealed that both in humans and rats alpha-methylacyl-CoA racemase is bimodally distributed to both the peroxisome and the mitochondrion. Our findings show that the peroxisomal and mitochondrial enzymes are produced from the same gene and that, as a consequence, the bimodal distribution pattern must be the result of differential targeting of the same gene product. In addition, we investigated the physiological role of the enzyme in the mitochondrion. Both in vitro studies with purified heterologously expressed protein and in vivo studies in fibroblasts of patients with an alpha-methylacyl-CoA racemase deficiency revealed that the mitochondrial enzyme plays a crucial role in the mitochondrial Beta-Oxidation of the breakdown products of pristanic acid byconverting (2R,6)-dimethylheptanoyl-CoA to its (S)-stereoisomer.
Takashi Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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peroxisomal and mitochondrial fatty acid Beta Oxidation in mice nullizygous for both peroxisome proliferator activated receptor alpha and peroxisomal fatty acyl coa oxidase genotype correlation with fatty liver phenotype
Journal of Biological Chemistry, 1999Co-Authors: Takashi Hashimoto, Frank J Gonzalez, Tomoyuki Fujita, Nobuteru Usuda, W A Cook, Jeffrey M Peters, Anjana V Yeldandi, Sambasiva M Rao, J K ReddyAbstract:Fatty acid Beta-Oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also metabolized by the cytochrome P450 CYP4A omega-Oxidation enzymes to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal Beta-Oxidation. Synthetic peroxisome proliferators interact with peroxisome proliferator activated receptor alpha (PPARalpha) to transcriptionally activate genes that participate in peroxisomal, microsomal, and mitochondrial fatty acid Oxidation. Mice lacking PPARalpha (PPARalpha-/-) fail to respond to the inductive effects of peroxisome proliferators, whereas those lacking fatty acyl-CoA oxidase (AOX-/-), the first enzyme of the peroxisomal Beta-Oxidation system, exhibit extensive microvesicular steatohepatitis, leading to hepatocellular regeneration and massive peroxisome proliferation, implying sustained activation of PPARalpha by natural ligands. We now report that mice nullizygous for both PPARalpha and AOX (PPARalpha-/- AOX-/-) failed to exhibit spontaneous peroxisome proliferation and induction of PPARalpha-regulated genes by biological ligands unmetabolized in the absence of AOX. In AOX-/- mice, the hyperactivity of PPARalpha enhances the severity of steatosis by inducing CYP4A family proteins that generate DCAs and since they are not metabolized in the absence of peroxisomal Beta-Oxidation, they damage mitochondria leading to steatosis. Blunting of microvesicular steatosis, which is restricted to few liver cells in periportal regions in PPARalpha-/- AOX-/- mice, suggests a role for PPARalpha-induced genes, especially members of CYP4A family, in determining the severity of steatosis in livers with defective peroxisomal Beta-Oxidation. In age-matched PPARalpha-/- mice, a decrease in constitutive mitochondrial Beta-Oxidation with intact constitutive peroxisomal Beta-Oxidation system contributes to large droplet fatty change that is restricted to centrilobular hepatocytes. These data define a critical role for both PPARalpha and AOX in hepatic lipid metabolism and in the pathogenesis of specific fatty liver phenotype.
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rat very long chain acyl coa dehydrogenase a novel mitochondrial acyl coa dehydrogenase gene product is a rate limiting enzyme in long chain fatty acid Beta Oxidation system cdna and deduced amino acid sequence and distinct specificities of the cdna
Journal of Biological Chemistry, 1994Co-Authors: T Aoyama, Ichiro Ueno, T Kamijo, Takashi HashimotoAbstract:Abstract cDNA encoding the precursor of rat very-long-chain acyl-CoA dehydrogenase (VLCAD) was cloned and sequenced. The longest cDNA insert had 2117 bases. This cDNA encodes the entire protein of 655 amino acids, including a 40-amino acid leader peptide and a 615-amino acid mature polypeptide. The identity of the VLCAD clone was confirmed by matching the amino acid sequence predicted from the cDNA to the NH2 terminus and seven internal proteolytic peptide sequences from purified rat liver VLCAD. The calculated molecular masses of the precursor protein, the mature protein, and the leader peptide are 70,961, 66,508, and 4,470 daltons, respectively. At the amino acid level, the significant homology to the other acyl-CoA dehydrogenases was found at the range from the 94th to the 473rd amino acid residue of the amino-terminal side. The catalytic residue and the residue lying near the dimethylbenzene side (si-side) of the flavin ring were speculated to be Glu-462 and Trp-249, respectively. The VLCAD cDNA was expressed in four kinds of hepatoma cells using a vaccinia virus expression system and was shown to encode the catalytically active enzyme. The cDNA expression in both rat hepatoma H4IIEC3 and McA-RH7777 enhanced about 3-fold mitochondrial Beta-Oxidation activity of long-chain fatty acids such as palmitic acid and stearic acid; hence, VLCAD is probably a rate-limiting enzyme in the long-chain fatty acid Beta-Oxidation system in these cell lines.
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novel fatty acid Beta Oxidation enzymes in rat liver mitochondria i purification and properties of very long chain acyl coenzyme a dehydrogenase
Journal of Biological Chemistry, 1992Co-Authors: K Izai, Yasushi Uchida, Tadao Orii, Shigeki Yamamoto, Takashi HashimotoAbstract:Abstract Freeze-thawed rat liver mitochondria were extensively washed with potassium phosphate, pH 7.5, and the residue was extracted with 10 mM potassium phosphate, pH 7.5, 1% (w/v) sodium cholate, 0.5 M KCl. The four Beta-Oxidation enzyme activities of the washes and the last extract were assayed with substrates of various carbon chain lengths. Our data suggest that the last extract contains a novel acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase. A novel acyl-CoA dehydrogenase was purified. The molecular masses of the native enzyme and the subunit were estimated to be 150 and 71 kDa, respectively. One mole of enzyme contained 2 mole of FAD. These properties and immunochemical properties of the enzyme differed from those of three other acyl-CoA dehydrogenases: short-, medium-, and long-chain acyl-CoA dehydrogenases. Carbon chain length specificity of the enzyme differed from that of other acyl-CoA dehydrogenases. The enzyme was active toward CoA esters of long- and very-long-chain fatty acids, but not toward those of medium- and short-chain fatty acids. The specific enzyme activity was greater than 10 times that of long-chain acyl-CoA dehydrogenase when palmitoyl-CoA was used as substrate. We propose the name "very-long-chain acyl-CoA dehydrogenase" for this enzyme.
R. J. A. Wanders - One of the best experts on this subject based on the ideXlab platform.
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differential effect of valproate and its delta2 and delta4 unsaturated metabolites on the Beta Oxidation rate of long chain and medium chain fatty acids
Chemico-Biological Interactions, 2001Co-Authors: M F B Silva, Jos P N Ruiter, M Duran, Lodewijk Ijlst, C Jakobs, I T De Almeida, R. J. A. WandersAbstract:Overall fatty acid Oxidation rates were investigated in rat hepatocytes using [9,10-3H]-palmitic, [9,10-3H]-oleic, [9,10-3H]-myristic and [2,3-3H]-phenylpropionic acids. The effect of both valproate (VPA) (0-10 mM) and two of its unsaturated metabolites, Delta2(E)-VPA and Delta4-VPA (0-10 mM), on the overall 3H2O production rate was studied. The results give evidence of a general inhibitory effect of VPA on the Beta-Oxidation rate of all the tested substrates. Similar effects were observed with both VPA metabolites but these effects appeared to be dependent on the chain length of the substrate. When the effect on the Oxidation of the medium-chain fatty acid 3-phenylpropionate (PPA) was studied, Delta2(E)-VPA at 0.5 mM caused a 94% inhibition of the overall Beta-Oxidation rate. However, with long-chain substrates, 0.5 mM Delta(4)-VPA was a more potent inhibitor (20-30% of control activity) than 0.5 mM Delta(2E)-VPA (60-80% of control activity). Our results suggest that VPA and/or its metabolites inhibit fatty acyl-CoA metabolism within the mitochondrion by two different mechanisms. The first mechanism involves CoASH sequestration, which affects the Oxidation rate of all fatty acids with different chain length. The second mechanism is more specific in nature and involves selective inhibition of particular enzymes implicated in fatty acid Beta-Oxidation.
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lipid metabolism in peroxisomes enzymology functions and dysfunctions of the fatty acid alpha and Beta Oxidation systems in humans
Biochemical Society Transactions, 2000Co-Authors: R. J. A. Wanders, E G Van Grunsven, Gerbert A JansenAbstract:Peroxisomes are subcellular organelles present in virtually all eukaryotic cells catalysing a number of indispensable functions in cellular metabolism. The importance of peroxisomes in man is stressed by the existence of an expanding group of genetic diseases in which there is an impairment in one or more peroxisomal functions. One of the major functions of peroxisomes concerns their role in lipid metabolism, which includes: (i) fatty acid BetaOxidation; (ii) ether phospholipid synthesis; (iii) fatty acid alpha-Oxidation; and (iv) isoprenoid biosynthesis. In this paper, we review the current state of knowledge concerning the peroxisomal fatty acid alpha- and Beta-Oxidation systems with particular emphasis on the enzymes involved and the various disorders of fatty acid Oxidation in peroxisomes. We also pay attention to the fact that some of the metabolites that accumulate as the result of a defect in peroxisomal alpha- and/or Beta-Oxidation are activators of members of the family of nuclear receptors, including peroxisome-proliferator-activated receptor alpha.
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peroxisomal Beta Oxidation of polyunsaturated fatty acids in saccharomyces cerevisiae isocitrate dehydrogenase provides nadph for reduction of double bonds at even positions
The EMBO Journal, 1998Co-Authors: C W T Van Roermund, Ewald H Hettema, A J Kal, M Van Den Berg, H F Tabak, R. J. A. WandersAbstract:The Beta-Oxidation of saturated fatty acids in Saccharomyces cerevisiae is confined exclusively to the peroxisomal compartment of the cell. Processing of mono- and polyunsaturated fatty acids with the double bond at an even position requires, in addition to the basic Beta-Oxidation machinery, the contribution of the NADPH-dependent enzyme 2,4-dienoyl-CoA reductase. Here we show by biochemical cell fractionation studies that this enzyme is a typical constituent of peroxisomes. As a consequence, the Beta-Oxidation of mono- and polyunsaturated fatty acids with double bonds at even positions requires stoichiometric amounts of intraperoxisomal NADPH. We suggest that NADP-dependent isocitrate dehydrogenase isoenzymes function in an NADP redox shuttle across the peroxisomal membrane to keep intraperoxisomal NADP reduced. This is based on the finding of a third NADP-dependent isocitrate dehydrogenase isoenzyme, Idp3p, next to the already known mitochondrial and cytosolic isoenzymes, which turned out to be present in the peroxisomal matrix. Our proposal is strongly supported by the observation that peroxisomal Idp3p is essential for growth on the unsaturated fatty acids arachidonic, linoleic and petroselinic acid, which require 2, 4-dienoyl-CoA reductase activity. On the other hand, growth on oleate which does not require 2,4-dienoyl-CoA reductase, and NADPH is completely normal in Deltaidp3 cells.
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pristanic acid and phytanic acid in plasma from patients with peroxisomal disorders stable isotope dilution analysis with electron capture negative ion mass fragmentography
Journal of Lipid Research, 1992Co-Authors: H Ten J Brink, R. J. A. Wanders, F Stellaard, C M M Van Den Heuvel, R M Kok, D S M Schor, C JakobsAbstract:A sensitive and selective stable isotope dilution method was developed for the accurate quantitation of pristanic acid and phytanic acid using electron capture negative ion mass fragmentography on pentafluorobenzyl derivatives. This technique allows detection of 1 pg of each compound and was applied to plasma from healthy controls and patients suffering from various peroxisomal disorders. The age-dependency of phytanic and pristanic acid levels in plasma from healthy controls was demonstrated. The involvement of peroxisomes in the Beta-Oxidation of pristanic acid was concluded from its accumulation in plasma from patients with peroxisomal deficiencies. Pristanic acid/phytanic acid ratios were markedly increased in bifunctional protein and/or 3-oxoacyl-CoA thiolase deficiency, indicating their role in the (differential) diagnosis of disorders of peroxisomal Beta-Oxidation.
Keisuke Tachibana - One of the best experts on this subject based on the ideXlab platform.
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activation of peroxisome proliferator activated receptor δ induces fatty acid β Oxidation in skeletal muscle and attenuates metabolic syndrome
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Toshiya Tanaka, Joji Yamamoto, Satoshi Iwasaki, Hiroshi Asaba, Hiroki Hamura, Yukio Ikeda, Mitsuhiro Watanabe, Kenta Magoori, Ryoichi X Ioka, Keisuke TachibanaAbstract:In this study, we defined the role of peroxisome proliferator-activated receptor Beta/delta (PPARdelta) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPARdelta subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPARdelta controls fatty acid Oxidation by regulating genes involved in fatty acid transport, Beta-Oxidation, and mitochondrial respiration. Similar PPARdelta-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid Beta-Oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid Beta-Oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob/ob mice. These data suggest that PPARdelta is pivotal to control the program for fatty acid Oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.