DOCSLIB.ORG

Genetic Disorders of Mitochondrial and Peroxisomal Fatty Acid Oxidation and Peroxisome Proliferator-Activated Receptors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genetic Disorders of Mitochondrial and Peroxisomal Fatty Acid Oxidation and Peroxisome Proliferator-Activated Receptors Genetic Expression and Nutrition, edited by Claude Bachmann and Berthold Koletzko. Nestle Nutrition Workshop Series, Pediatric Program, Vol. 50. Nestec Ltd., Vevey/Lippincott Williams & Wilkins, Philadelphia, © 2003. Genetic Disorders of Mitochondrial and Peroxisomal Fatty Acid Oxidation and Peroxisome Proliferator-Activated Receptors Ronald J. A. Wanders Department of Pediatrics, Academic Medical Center; Department of Clinical Chemistry, University of Amsterdam, Amsterdam, The Netherlands Fatty acids are an important source of energy in humans, especially during fasting. Most tissues are able to degrade fatty acids to carbon dioxide and water, but in addi- tion, some organs—notably the liver—have the capacity to convert the acetyl-CoA units produced during |3 oxidation into the ketone bodies acetoacetate and 3-hydrox- ybutyrate. These are important fuels for certain organs, especially the brain. Fatty acids are the main source of energy in the heart. Indeed, under normal conditions 60% to 70% of the energy requirements of the heart are provided by fatty acid oxi- dation, and even more under certain conditions such as fasting and diabetes. In principle, fatty acids can be degraded by several mechanisms, including a, (3, and &) oxidation. However, most fatty acids are degraded by |3 oxidation, which can occur in the mitochondria or in the peroxisomes. It is generally agreed that the mito- chondria form the major site of fatty acid (3 oxidation, catalyzing the oxidation of all major dietary fatty acids. In recent years, tremendous progress has been made in the identification of patients affected by a genetic deficiency in either the mitochondrial or the peroxisomal (3 oxidation system, and defects in virtually all the steps involved have now been identified. Thanks to these efforts, reliable laboratory methods have now become available to identify patients with these conditions. Much remains to be learned, however, about the pathophysiologic mechanisms behind these disorders. In this respect, the role of peroxisome proliferator-activated receptors (PPARs) is in- triguing, especially since the metabolites accumulating as a result of a block in mito- chondrial or peroxisomal (3 oxidation are PPAR activators. In this chapter, I will describe our current state of knowledge about mitochondrial and peroxisomal fatty acid oxidation, with particular emphasis on the various inher- ited diseases and the role of PPARs. FATTY ACID OXIDATION Fatty acids may undergo a, 0, or a> oxidation. 85 86 MITOCHONDRIAL AND FATTY ACID OXIDATION Alpha-Oxidation a-oxidation is required for fatty acids with a methyl group at the 3-position, as 3- methyl branched chain fatty acids cannot undergo direct (3 oxidation. The mechanism of fatty acid a oxidation has remained mysterious ever since its discovery in the early 1960s, when the accumulation of the 3-methyl branched chain fatty acid phytanic acid (3,7,11,14-tetramethylhexadecanoic acid) was identified in patients suffering from a rare genetic disease known as Refsum disease. Patients with Refsum disease show various abnormalities including retinitis pigmentosa, cerebellar ataxia, periph- eral neuropathy, anosmia, and cardiac abnormalities (1). The finding of markedly raised phytanic acid concentrations has led to detailed studies of phytanic acid oxi- dation. These studies showed that phytanic acid undergoes oxidative decarboxyla- tion, with pristanic acid (2,4,6,10-tetramethylpentadecanoic acid) and CO2 as the end products, and that patients with Refsum disease cannot convert phytanic acid to pris- tanic acid and CO2. Despite intense efforts, the mechanism of phytanic acid a oxi- dation remained unclear until very recently. However, work from our laboratory and others has now established the sequence of events (Fig. 1 A), and most of the enzymes involved have been characterized, purified, and studied at the molecular level (2). This led to the identification of the enzyme defect in Refsum disease—at the level of phytanoyl-CoA hydroxylase (3)—and later to the resolution of the molecular basis of Refsum disease (4). Interestingly, phytanic acid has been found to be a powerful lig- and for some nuclear receptors, including PPARa (5-8), as discussed below. Omega-Oxidation ft Oxidation is a relatively minor pathway, like a oxidation. The initial step occurs in the smooth endoplasmic reticulum by to hydroxylases belonging to the CYP4A sub- family, with a oo-hydroxy fatty acid as the product. The CYP4A family of cytochrome P450 enzymes, which are constitutively expressed in liver and kidney, catalyze both the to and the (00-1) hydroxylation of long-chain fatty acids (9). The major w-hydroxy- lase expressed in human liver and kidney is CYP4A11, which is functionally similar to the rat CYP4A1. The co-hydroxy fatty acids produced by the initial hydroxylation re- action then undergo two dehydrogenations to generate the corresponding co-keto fatty acids and w-carboxy fatty acids. These reactions are catalyzed by alcohol and aldehyde dehydrogenases in the cytosol. Subsequently, the dicarboxylic acids are activated to their CoA esters by an acyl-CoA synthetase present in the endoplasmic reticulum (10). The long-chain dicarboxylyl-CoA esters produced then appear to undergo several B ox- idation cycles in the peroxisome to produce medium-chain dicarboxylyl-CoA esters that undergo final oxidation to CO2 and H2O in the mitochondrion (Fig. IB). Beta-Oxidation 3 Oxidation is the main mechanism whereby fatty acids are broken down, and in- volves a sequence of four reactions including dehydrogenation, hydration, dehydro- genation again, and thiolytic cleavage (Fig. 2). Both mitochondria and peroxisomes Phytanic acid CoASH, ATP phytanoyl-CoA synthetase[ AMP, PP,- phytanoyl-CoA 2-ketoglutarate, O2 I phytanayl-CoA hydroxylase ( 2 succirtate, CO2 2-OH-phytanoyl-CoA H2O I 2-OH-phytanoyl-CoA lyase formate + CoASH -< formyl-CoA pristanal NAD(P)* phstanal dehydrogenase | NAD(P)H' pristanic acid CoASH, ATP I phstanoyl-CoA synthetasel 5 AMP, PP, pristanoyl-CoA B-oxidation Long-chain fatty acid NADPH, O2 omega-hydroxylase ( 1 NADP, H2O omega -OH-LCFA NAD alcohol dehydrogenase NADH omega -keto-LCFA NAD aldehyde dehydrogenase NADH omega -carboxy-LCFA CoASH, ATP acyl-CoA synthetase AMP, PP, Long-chain dicarboxylyl-CoA I B-oxidation in peroxisomes FIG. 1. Schematic representa- tion of the fatty acid a oxidation system (A) and the u> oxidation B medium-chain dicarboxylyl-CoA system (B). 88 MITOCHONDRIAL AND FATTY ACID OXIDATION MITOCHONDRIAL (J-OXIDATION PEROXISOMAL B-OXIDATION ATP 4. Fatty acyl-CoA Fatty acyl-CoA ' FAD jAcyhCoA dehydrogenases]] Acyl-CoA oxidases Enoyl-CoA 3-OH-acyl-CoA 3-OH-acyl-CoA NAD -^.^JL JL _ NAD -]3-hydroxy acyl-CoA dehydrogenases^ NADH ^~ ^ ^ ^NADH 3-keto-acyl-CoA 3-keto-acyl-CoA 3-keto acyt-CoA thlolases (n-2) acyl-CoA (n-2) acyl-CoA FIG. 2. The mitochondrial and peroxisomal 3 oxidation of fatty acids. The first step in the (5 oxi- dation of fatty acids in mitochondria is catalyzed by acyl-CoA dehydrogenases but in peroxi- somes by acyl-CoA oxidases. Both acyl-CoA dehydrogenases and acyl-CoA oxidases are flavo- proteins which use different mechanisms for the reoxidation of enzyme-bound FADH2. In case of mitochondrial acyl-CoA dehydrogenases, enzyme-bound E-FADH2 is reoxidized by electron transfer flavoprotein (ETF) followed by reoxidation of reduced ETF by ETF-dehydrogenase, so that the electrons ultimately enter the respiratory chain at the level of ubiquinone. In case of acyl- CoA oxidases, enzyme-bound FADH2 is directly reoxidized by molecular oxygen to produce H2O2. Steps 2, 3, and 4 are catalyzed by enoyl-CoA hydratases, 3-hydroxyacyl-CoA dehydro- genases, and 3-ketothiolases, which catalyze identical reactions. RC, respiratory chain. use the same mechanism for p oxidation of fatty acids, although the two systems dif- fer in many respects as summarized below. Oxidation of Fatty Acids to CO2 and H2O in Mitochondria Versus Peroxisomes Peroxisomes lack a citric acid cycle and thus cannot degrade the acetyl-CoA units produced during fatty acid oxidation to CO2 and H2O. Available evidence indicates that the acetyl-CoA units produced in peroxisomes are transferred to mitochondria in the form of acetylcarnitine (11,12). M1T0CH0NDRIAL AND FATTY ACID OXIDATION 89 Peroxisomal 3 Oxidation Versus Mitochondrial (3 Oxidation In mitochondria the first step in the 3 oxidation of fatty acids is catalyzed by various acyl-CoA dehydrogenases, all FAD-linked, which donate their electrons to the respi- ratory chain, thus generating adenosine triphosphate (ATP). In peroxisomes, how- ever, the acyl-CoA oxidases—which are also FAD linked—donate their electrons di- rectly to molecular oxygen to produce H2O2 which is subsequently decomposed to H2O and O2. Consequently, one cycle of 3 oxidation in peroxisomes is at most half as efficient as 3 oxidation in mitochondria in terms of ATP production. Role ofCarnitine in Peroxisomal and Mitochondrial 3 Oxidation Camitine plays an indispensable role in both mitochondrial and peroxisomal 3 oxida- tion, but at different levels. In the mitochondria, camitine is involved in the transfer of long-chain fatty acids across the mitochondrial inner membrane by the concerted ac- tion of camitine palmitoyltransferase 1 (CPT1), mitochondrial camitine/acylcarnitine translocase (CACT), and camitine palmitoyltransferase 2 (CPT2) (13). In peroxi- somes, however, camitine plays no role in fatty acid uptake but does play an indis- pensable role in the transfer of chain-shortened fatty acids from peroxisomes
Load more

Recommended publications
  • Abstract DRAYTON, JOSEPHINE BENTLEY
    Abstract DRAYTON, JOSEPHINE BENTLEY. Methylated Medium- and Long-Chain Fatty Acids as Novel Sources of Anaplerotic Carbon for Exercising Mice. (Under the direction of Dr. Jack Odle and Dr. Lin Xi.) We hypothesized that methylated fatty acids (e.g. 2-methylpentanoic acid (2MeP), phytanic acid or pristanic acid) would provide a novel source of anaplerotic carbon and thereby enhance fatty acid oxidation, especially under stressed conditions when tricarboxylic acid (TCA) cycle intermediates are depleted. The optimal dose of 2MeP, hexanoic acid (C6) and pristanic acid for increasing in vitro [1-14C]-oleic acid oxidation in liver or skeletal muscle homogenates from fasted mice was determined using incremental doses of 0, 0.25, 0.5, 0.75, or 1.0 mM. The 0.25 mM amount maximally stimulated liver tissue oxidation of 14 14 14 [1- C]-oleate to CO2 and [ C]-acid soluble products (ASP; P < 0.05). Similar incubations of 0.25 mM 2MeP, C6, palmitate, phytanic acid, or pristanic acid or 0.1 mM malate or propionyl-CoA were conducted with liver or skeletal muscle homogenates from exercised or sedentary mice. In vitro oxidation of [1-14C]-oleic acid in liver homogenates with 2MeP 14 14 increased mitochondrial CO2 accumulation (P <0.05), but no change in [ C]-ASP accumulation as compared to C6 (P > 0.05). Phytanic acid treatment increased [14C]-ASP accumulation in liver tissue as compared to palmitate (P < 0.05). Exercise increased [14C] accumulations (P < 0.05). Results were consistent with our hypothesis that methyl-branched fatty acids (2-MeP, phytanic and pristanic acids) provide a novel source of anaplerotic carbon and thereby stimulate in vitro fatty acid oxidation in liver and skeletal muscle tissues.
    [Show full text]
  • Substrate Specificity of Rat Liver Mitochondrial Carnitine Palmitoyl Transferase I: Evidence Against S-Oxidation of Phytanic Acid in Rat Liver Mitochondria
    FEBS 15107 FEBS Letters 359 (1995) 179 183 Substrate specificity of rat liver mitochondrial carnitine palmitoyl transferase I: evidence against s-oxidation of phytanic acid in rat liver mitochondria Harmeet Singh*, Alfred Poulos Department of Chemical Pathology, Women's and Children's Hospital 72 King William Road, North Adelaide, SA 5006, Australia Received 23 December 1994 demonstrated that CPTI activity is reversibly inhibited by Abstract The two branched chain fatty acids pristanic acid malonyl-CoA. Recently, it has been shown that malonyl-CoA (2,6,10,14-tetramethylpentadecanoic acid) and phytanic acid inhibits peroxisomal, microsomal and plasma membrane car- (3,7,11,15-tetramethylhexadecanoic acid) were converted to co- nitine acyl transferases [8,10,13]. Therefore, in order to under- enzyme A thioesters by rat liver mitochondrial outer membranes. However, these branched chain fatty acids could not be converted stand the role of CPTI in fatty acid oxidation, CPTI must be to pristanoyl and phytanoyl carnitines, respectively, by mitochon- separated from other carnitine acyl transferases. In view of the drial outer membranes. As expected, the unbranched long chain difficulties in isolating CPTI in the active state, we decided to fatty acids, stearic acid and palmitic acid, were rapidly converted investigate CPTI activity in highly purified mitochondrial outer to stearoyl and palmitoyl carnitines, respectively, by mitochon- membranes from rat liver. We present evidence that branched drial outer membranes. These observations indicate that the chain fatty acids with ~- or fl-methyl groups are poor substrates branched chain fatty acids could not be transported into mito- for CPTI, suggesting that these branched chain fatty acids chondria.
    [Show full text]
  • Ataxia with Loss of Purkinje Cells in a Mouse Model for Refsum Disease
    Ataxia with loss of Purkinje cells in a mouse model for Refsum disease Sacha Ferdinandussea,1,2, Anna W. M. Zomerb,1, Jasper C. Komena, Christina E. van den Brinkb, Melissa Thanosa, Frank P. T. Hamersc, Ronald J. A. Wandersa,d, Paul T. van der Saagb, Bwee Tien Poll-Thed, and Pedro Britesa Academic Medical Center, Departments of aClinical Chemistry (Laboratory of Genetic Metabolic Diseases) and dPediatrics, Emma’s Children Hospital, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; bHubrecht Institute, Royal Netherlands Academy of Arts and Sciences 3584 CT Utrecht, The Netherlands; and cRehabilitation Hospital ‘‘De Hoogstraat’’ Rudolf Magnus Institute of Neuroscience, 3584 CG Utrecht, The Netherlands Edited by P. Borst, The Netherlands Cancer Institute, Amsterdam, The Netherlands, and approved October 3, 2008 (received for review June 23, 2008) Refsum disease is caused by a deficiency of phytanoyl-CoA hy- Clinically, Refsum disease is characterized by cerebellar droxylase (PHYH), the first enzyme of the peroxisomal ␣-oxidation ataxia, polyneuropathy, and progressive retinitis pigmentosa, system, resulting in the accumulation of the branched-chain fatty culminating in blindness, (1, 3). The age of onset of the symptoms acid phytanic acid. The main clinical symptoms are polyneuropathy, can vary from early childhood to the third or fourth decade of cerebellar ataxia, and retinitis pigmentosa. To study the patho- life. No treatment is available for patients with Refsum disease, genesis of Refsum disease, we generated and characterized a Phyh but they benefit from a low phytanic acid diet. Phytanic acid is knockout mouse. We studied the pathological effects of phytanic derived from dietary sources only, specifically from the chloro- acid accumulation in Phyh؊/؊ mice fed a diet supplemented with phyll component phytol.
    [Show full text]
  • The Role of Alpha Oxidation in Lipid Metabolism, 2017
    THE ROLE OF ALPHA OXIDATION IN LIPID METABOLISM Benjamin John Jenkins Darwin College Medical Research Council – Human Nutrition Research Department of Biochemistry University of Cambridge This dissertation is submitted for the degree of Doctor of Philosophy July 2018 DECLARATION This dissertation is the result of my own work and includes nothing, which is the outcome of work done in collaboration except as declared in the preface and specified in the text. It is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. In accordance with the University of Cambridge guidelines, this thesis does not exceed 60,000 words. Signed: ______________________________________________________________ Date: _______________________________________________________________ Benjamin John Jenkins BSc. MSc. Darwin College, Silver Street, Cambridge, CB3 9EU by i 2014 Word Template Template Friedman Friedman & Morgan Morgan & ii The Role of Alpha Oxidation in Lipid Metabolism, 2017 ABSTRACT Recent findings have shown an inverse association between the circulating levels of pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) with the risk of pathological development in type 2 diabetes, cardio vascular disease and neurological disorders. From previously published research, it has been said that both these odd chain fatty acids are biomarkers of their dietary intake and are significantly correlated to dietary ruminant fat intake.
    [Show full text]
  • Oxidation of Pristanic Acid in Fibroblasts and Its Application to the Diagnosis of Peroxisomal ␤-Oxidation Defects
    Oxidation of Pristanic Acid in Fibroblasts and Its Application to the Diagnosis of Peroxisomal ␤-Oxidation Defects Barbara C. Paton,* Peter C. Sharp,* Denis I. Crane,‡ and Alf Poulos* *Department of Chemical Pathology, Women’s and Children’s Hospital, North Adelaide, South Australia 5006; and ‡Faculty of Science and Technology, Griffith University, Nathan, Queensland 4111, Australia Abstract phology of peroxisomes in their tissues is accompanied by a series of biochemical abnormalities. Subsequent complemen- Pristanic acid oxidation measurements proved a reliable tation analyses have indicated that the three clinical pheno- tool for assessing complementation in fused heterokaryons types can arise from defects in a single gene (1, 2). In addition, from patients with peroxisomal biogenesis defects. We, in spite of all of these patients sharing the same series of bio- therefore, used this method to determine the complementa- chemical abnormalities, it is now clear that the peroxisomal tion groups of patients with isolated defects in peroxisomal biogenesis disorders, as a group, can result from defects in any ␤-oxidation. The rate of oxidation of pristanic acid was re- of at least 10 genes (2, 3). Recent evidence suggests that three duced in affected cell lines from all of the families with in- of these complementation groups have defects in the import of herited defects in peroxisomal ␤-oxidation, thus excluding peroxisomal matrix proteins via both of the known targeting the possibility of a defective acyl CoA oxidase. Complemen- mechanisms (peroxisomal targeting signals [PTS]1 1 and 2), tation analyses indicated that all of the patients belonged to but that for one of the complementation groups the defect is the same complementation group, which corresponded to restricted to proteins targeted via PTS1 (4).
    [Show full text]
  • LIPID METABOLISM-3 Regulation of Fatty Acid Oxidation
    LIPID METABOLISM-3 Regulation of Fatty Acid Oxidation 1. Carnitine shuttle by which fatty acyl groups are carried from cytosolic fatty acyl–CoA into the mitochondrial matrix is rate limiting for fatty acid oxidation and is an important point of regulation. 2. Malonyl-CoA, the first intermediate in the cytosolic biosynthesis of long-chain fatty acids from acetyl-CoA increases in concentration whenever the body is well supplied with carbohydrate; excess glucose that cannot be oxidized or stored as glycogen is converted in the cytosol into fatty acids for storage as triacylglycerol. The inhibition of CAT I by malonyl-CoA ensures that the oxidation of fatty acids is inhibited whenever the liver is actively making triacylglycerols from excess glucose. Two of the enzymes of β-oxidation are also regulated by metabolites that signal energy sufficiency. 3. When the [NADH]/[NAD+] ratio is high, β- hydroxyacyl-CoA dehydrogenase is inhibited; 4. When acetyl-CoA concentration is high, thiolase is inhibited. 5. During periods of vigorous muscle contraction or during fasting, the fall in [ATP] and the rise in [AMP] activate the AMP-activated protein kinase (AMPK). AMPK phosphorylates several target enzymes, including acetyl-CoA carboxylase (ACC), which catalyzes malonyl-CoA synthesis. Phosphorylation and inhibition of ACC lowers the concentration of malonyl-CoA, relieving the inhibition of acyl–carnitine transport into mitochondria and allowing oxidation to replenish the supply of ATP. MITOCHONDRIA PEROXISOME Respiratory chain Respiratory chain Out of organel To citric acid cycle Out of organel Comparison of mitochondrial and peroxisomal beta-oxidation • Another important difference between mitochondrial and peroxisomal oxidation in mammals is in the specificity for fatty acyl– CoAs; the peroxisomal system is much more active on very-long-chain fatty acids such as hexacosanoic acid (26:0) and on branched chain fatty acids such as phytanic acid and pristanic acid.
    [Show full text]
  • Fatty Acid Oxidation
    FATTY ACID OXIDATION 1 FATTY ACIDS A fatty acid contains a long hydrocarbon chain and a terminal carboxylate group. The hydrocarbon chain may be saturated (with no double bond) or may be unsaturated (containing double bond). Fatty acids can be obtained from- Diet Adipolysis De novo synthesis 2 FUNCTIONS OF FATTY ACIDS Fatty acids have four major physiological roles. 1)Fatty acids are building blocks of phospholipids and glycolipids. 2)Many proteins are modified by the covalent attachment of fatty acids, which target them to membrane locations 3)Fatty acids are fuel molecules. They are stored as triacylglycerols. Fatty acids mobilized from triacylglycerols are oxidized to meet the energy needs of a cell or organism. 4)Fatty acid derivatives serve as hormones and intracellular messengers e.g. steroids, sex hormones and prostaglandins. 3 TRIGLYCERIDES Triglycerides are a highly concentrated stores of energy because they are reduced and anhydrous. The yield from the complete oxidation of fatty acids is about 9 kcal g-1 (38 kJ g-1) Triacylglycerols are nonpolar, and are stored in a nearly anhydrous form, whereas much more polar proteins and carbohydrates are more highly 4 TRIGLYCERIDES V/S GLYCOGEN A gram of nearly anhydrous fat stores more than six times as much energy as a gram of hydrated glycogen, which is likely the reason that triacylglycerols rather than glycogen were selected in evolution as the major energy reservoir. The glycogen and glucose stores provide enough energy to sustain biological function for about 24 hours, whereas the Triacylglycerol stores allow survival for several weeks. 5 PROVISION OF DIETARY FATTY ACIDS Most lipids are ingested in the form of triacylglycerols, that must be degraded to fatty acids for absorption across the intestinal epithelium.
    [Show full text]
  • Thermal Alteration of Organic Matter in Recent Marine Sediments
    THERMAL ALTERATION OF ORGANIC MATTER IN RECENT MARINE SEDIMENTS II. ISOPRENOIDS 1 R. Ikan 2 , M.J. Baedecker an I.R. Kaplan Department of Geophysics and Planetary Physics University of California Los Angeles, California 90024 (NASA-CR-139195) THERHAL ALTERATION OF N74- 30839' ORGANIC HATTER IN RECENT BARINE SEDIHENTS. 2: ISOPRENOIDS (California Univ.) 45 p r'- CSCL 08J Unclas - G3/13 46340 Reproduced by NATIONAL TECHNICAL INFORMATION SERVICE US Department of Commerce Springfield, VA. 22151 Publication No. 1244: Institute of Geophysics & Planetary Physics University of California, Los Angeles, California 90024 Permanent address: Department of Organic Chemistry, Natural Products Laboratory, Hebrew University Jerusa lern, Israel ABSTRACT A series of isoprenoid compounds were isolated from a heat-treated marine sediment (from Tanner Basin) which were not present in the original sediment. Among the compounds identified were: phytol, dihydrophytol, C,,-isoprenoid ketone, phytanic and pristanic acids, C19 - and Co0 -monoolefines, and the alkanes pristane and phytane. The significance and possible routes leading to these compounds is discussed. 2. INTRODUCTION Ever since Bendoraitis et al. (1962) first isolated pristane (2,6,10,14-tetramethylpentadecane) from crude oil in concentrations equal to 0.5% of the total, there has been considerable discussion on the origin of the -isoprenoid hydrocarbons 'in sediments and in petroleum. The two major isoprenoid hydrocarbons normally detected are pristane and phytane (2,6, 10, 14-tetramethylhexadecane), although Cl8 , C16 and CI5 alkanes are also common in oil shales and crude oil, and in some environments, these become the dominant branched hydrocarbons (Arpino et al. 1972). Bendoraitis et al. (1962) believed that the starting compound was chlorophyll from which the phytyl side chain is cleaved and subsequently oxidized to an acid and finally decarboxylated to the C 19 alkane.
    [Show full text]
  • Phytanic Acid, but Not Pristanic Acid, Mediates the Positive Effects of Phytol Derivatives on Brown Adipocyte Differentiation
    FEBS 25988 FEBS Letters 517 (2002) 83^86 View metadata, citation and similar papers at core.ac.uk brought to you by CORE Phytanic acid, but not pristanic acid, mediates the positiveprovided e¡ects by Elsevier of - Publisher Connector phytol derivatives on brown adipocyte di¡erentiation Agatha Schluter, Marta Giralt, Roser Iglesias, Francesc Villarroyaà Departament de Bioqu|¤mica i Biologia Molecular, Universitat de Barcelona, Avinguda Diagonal 645, E-08028 Barcelona, Spain Received 11 February 2002; accepted 12 March 2002 First published online 25 March 2002 Edited by Jacques Hanoune L-oxidation in a transport pathway that involves peroxisomal Abstract The phytol derivatives phytanic acid and pristanic acid may activate nuclear hormone receptors and influence gene carnitine octanoyl transferase (COT) [3]. expression and cell differentiation. Phytanic acid induces brown Phytanic acid can bind and activate at least two types of adipocyte differentiation. It was determined that brown fat and nuclear hormone receptors, retinoid X receptors (RXR) [4,5] brown adipocytes are sites of high gene expression of phytanoyl- and peroxisome proliferator-activated receptor (PPAR)K [6], CoA hydroxylase, the enzyme required for initiation of with a⁄nities lower than other ligands but in the range of the peroxisomal K-oxidation of phytanic acid. However, the effects physiological levels of this fatty acid in blood. Pristanic acid of phytanic acid were not mediated by its K-oxidation product can also activate PPARK [7]. We have recently reported that pristanic acid, which did not promote brown adipocyte differ- phytanic acid, when added to cell culture medium, is an acti- entiation or stimulate transcription of the uncoupling protein-1 vator of brown adipocyte di¡erentiation and transcription of gene.
    [Show full text]
  • Integrated Physiology and Systems Biology of Ppara
    Review Integrated physiology and systems biology of PPARa Sander Kersten* ABSTRACT The Peroxisome Proliferator Activated Receptor alpha (PPARa) is a transcription factor that plays a major role in metabolic regulation. This review addresses the functional role of PPARa in intermediary metabolism and provides a detailed overview of metabolic genes targeted by PPARa, with a focus on liver. A distinction is made between the impact of PPARa on metabolism upon physiological, pharmacological, and nutritional activation. Low and high throughput gene expression analyses have allowed the creation of a comprehensive map illustrating the role of PPARa as master regulator of lipid metabolism via regulation of numerous genes. The map puts PPARa at the center of a regulatory hub impacting fatty acid uptake, fatty acid activation, intracellular fatty acid binding, mitochondrial and peroxisomal fatty acid oxidation, ketogenesis, triglyceride turnover, lipid droplet biology, gluconeogenesis, and bile synthesis/secretion. In addition, PPARa governs the expression of several secreted proteins that exert local and endocrine functions. Ó 2014 The Author. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/). Keywords PPARa; Liver; Transcriptional networks; Lipid metabolism; Expression profiling; Metabolic homeostasis; Systems biology 1. INTRODUCTION deacetylase and histone acetyltransferase activity, respectively, necessary for the assembly of the transcription initiation complex [10]. PPARa was the first member to be cloned of a small subfamily of Readers are referred to another review for more detailed information nuclear receptors called Peroxisome Proliferators Activated Receptors on co-activators in PPAR-dependent gene regulation [11].
    [Show full text]
  • Fatty Acid Oxidation- Notes
    Fatty acid oxidation- Notes See how fatty acids are broken down and used to generate ATP . Fatty acids provide highly efficient energy storage, delivering more energy per gram than carbohydrates like glucose. In tissues with high energy requirement, such as heart, up to 50– 70% of energy, in the form of ATP production, comes from fatty acid (FA) beta-oxidation. During fatty acid β-oxidation long chain acyl-CoA molecules – the main components of FAs – are broken to acetyl-CoA molecules. Fatty acid transport into mitochondria Fatty acids are activated for degradation by conjugation with coenzyme A (CoA) in the cytosol. The long-chain fatty-acyl-CoA is then modified by carnitine palmitoyltransferase 1 (CPT1) to acylcarnitine and transported across the inner mitochondrial membrane by carnitine translocase (CAT). CPT2 then coverts the long chain acylcarnitine back to long- chain acyl-CoA before beta-oxidation. Breakdown of fats yields fatty acids and glycerol. Glycerol can be readily converted to DHAP for oxidation in glycolysis or synthesis into glucose in gluconeogenesis. Fatty acids are broken down in two carbon units of acetyl-CoA. To be oxidized, they must be transported through the cytoplasm attached to coenzyme A and moved into mitochondria. The latter step requires removal of the CoA and attachment of the fatty acid to a molecule of carnitine. The carnitine complex is transported across the inner membrane of the mitochondrion after which the fatty acid is reattached to coenzyme A in the mitochondrial matrix. Dr Anjali Saxena Page 1 Figure- Movement of Acyl-CoAs into the Mitochondrial Matrix The process of fatty acid oxidation, called beta oxidation, is fairly simple.
    [Show full text]
  • Oxidation of Pristanic Acid in Fibroblasts and Its Application to the Diagnosis of Peroxisomal Beta-Oxidation Defects
    Oxidation of pristanic acid in fibroblasts and its application to the diagnosis of peroxisomal beta-oxidation defects. B C Paton, … , D I Crane, A Poulos J Clin Invest. 1996;97(3):681-688. https://doi.org/10.1172/JCI118465. Research Article Pristanic acid oxidation measurements proved a reliable tool for assessing complementation in fused heterokaryons from patients with peroxisomal biogenesis defects. We, therefore, used this method to determine the complementation groups of patients with isolated defects in peroxisomal beta-oxidation. The rate of oxidation of pristanic acid was reduced in affected cell lines from all of the families with inherited defects in peroxisomal beta-oxidation, thus excluding the possibility of a defective acyl CoA oxidase. Complementation analyses indicated that all of the patients belonged to the same complementation group, which corresponded to cell lines with bifunctional protein defects. Phytanic acid oxidation was reduced in fibroblasts from some, but not all, of the patients. Plasma samples were still available from six of the patients. The ratio of pristanic acid to phytanic acid was elevated in all of these samples, as were the levels of saturated very long chain fatty acids (VLCFA). However, the levels of bile acid intermediates, polyenoic VLCFA, and docosahexaenoic acid were abnormal in only some of the samples. Pristanic acid oxidation measurements were helpful in a prenatal assessment for one of the families where previous experience had shown that cellular VLCFA levels were not consistently elevated in affected individuals. Find the latest version: https://jci.me/118465/pdf Oxidation of Pristanic Acid in Fibroblasts and Its Application to the Diagnosis of Peroxisomal ␤-Oxidation Defects Barbara C.
    [Show full text]