Peroxisome Proliferator-induced Long Chain Acyl-CoA Thioesterases Comprise a Highly Conserved Novel Multi-gene Family Involved in Lipid Metabolism

Hunt, Mary C.; Nousiainen, Sari; Huttunen, Merja; Orii, Kenji E.; Svensson, Thomas; Alexson, Stefan E.H.

doi:10.1074/jbc.274.48.34317

Cited by 98 publications

(117 citation statements)

References 45 publications

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“…53 Previous studies have also described upregulation of some but not all of the genes of lipid metabolism shown in Table 1 and Figure 3, including triglyceride lipolysis, 5,6 FA transport 54,55 and b-oxidation. 11,12,[56][57][58] In agreement with previous studies, 58 we did not find significant changes in the lipogenic genes in response to fenofibrate treatment. The upregulation of both Scd-1, which has been observed previously, 59 and Elovl3 suggest that fibrates may promote synthesis of unsaturated FA and long-chain FA.…”

Section: Discussionsupporting

confidence: 92%

Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice

et al. 2009

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We have used a new ApoA-I transgenic mouse model to identify by global gene expression profiling, candidate genes that affect lipid and lipoprotein metabolism in response to fenofibrate treatment. Multilevel bioinformatical analysis and stringent selection criteria (2-fold change, 0% false discovery rate) identified 267 significantly changed genes involved in several molecular pathways. The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group. However, the treatment increased cholesterol levels to 1.95-fold mainly due to the increase in high-density lipoprotein (HDL) cholesterol. The observed changes in HDL are associated with the upregulation of genes involved in phospholipid biosynthesis and lipid hydrolysis, as well as phospholipid transfer protein. Significant upregulation was observed in genes involved in fatty acid transport and b-oxidation, but not in those of fatty acid and cholesterol biosynthesis, Krebs cycle and gluconeogenesis. Fenofibrate changed significantly the expression of seven transcription factors. The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes.

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Section: Discussionsupporting

confidence: 92%

Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice

et al. 2009

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“…This fact raises that possibility that a closely related enzyme may exist specifically for the glycination of unsaturated long chain fatty acyl-CoAs. In this regard, sequence analysis of cytosolic BACAT revealed 40-45% homology to a group of enzymes known as the acyl-CoA thioesterase I family [40]. These enzymes have not been characterized with respect to glycine conjugating activity; it is possible that one or more may be shown to effectively catalyze the generation of unsaturated long chain fatty acyl glycines.…”

Section: Discussionmentioning

confidence: 99%

In vivo evidence that N-oleoylglycine acts independently of its conversion to oleamide

Chaturvedi

Driscoll

Elliot

et al. 2006

Prostaglandins & Other Lipid Mediators

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Oleamide (cis-9-octadecenamide) is a member of an emerging class of lipid-signaling molecules, the primary fatty acid amides. A growing body of evidence indicates that oleamide mediates fundamental neurochemical processes including sleep, thermoregulation, and nociception. Nevertheless, the mechanism for oleamide biosynthesis remains unknown. The leading hypothesis holds that oleamide is synthesized from oleoylglycine via the actions of the peptide amidating enzyme, peptidylglycine alpha amidating monooxygenase (PAM). The present study investigated this hypothesis using pharmacologic treatments, physiologic assessments, and measurements of serum oleamide levels using a newly development enzyme-linked immunosorbant assay (ELISA). Oleamide and oleoylglycine both induced profound hypothermia and decreased locomotion, over equivalent dose ranges and time courses, whereas, closely related compounds, stearamide and oleic acid, were essentially without effect. While the biologic actions of oleamide and oleoylglycine were equivalent, the two compounds differed dramatically with respect to their effects on serum levels of oleamide. Oleamide administration (80 mg/kg) elevated blood-borne oleamide by eight-fold, whereas, the same dose of oleoylglycine had no effect on circulating oleamide levels. In addition, pretreatment with the established PAM inhibitor, disulfiram, produced modest reductions in the hypothermic responses to both oleoylglycine and oleamide, suggesting that the effects of disulfiram were not mediated through inhibition of PAM and a resulting decrease in the formation of oleamide from oleoylglycine. Collectively, these findings raise the possibilities that: (1) oleoylglycine possesses biologic activity that is independent of its conversion to oleamide, and (2) the increased availability of oleoylglycine as a potential substrate does not drive the biosynthesis of oleamide.

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“…This enzyme is the mouse homologue of human PTE1 (26), which was first identified by the yeast two-hybrid system as hACTEIII and hTE, a HIV-1 Nef-binding protein (27,28). There is a lot of confusion regarding the nomenclature of acyl-CoA thioesterases, and based on a recent attempt to accomplish a more uniform terminology (16), we propose the name PTE-2 for this acyl-CoA thioesterase, as the nomenclature PTE-I has already been assigned to two enzymes that are members of a novel multigene family, with other members in mitochondria and cytosol (25) (Table III). However, the rule applied to the nomenclature of yeast enzymes states that they remain known by the name applied when they were first identified, therefore this enzyme will remain known as PTE1.…”

Section: Fig 3 Pte-2 Is a Peroxisomal Matrix Proteinmentioning

confidence: 99%

“…To date, several peroxisomal acyl-CoA thioesterases have been cloned from yeast, mouse, and human. PTE-Ia and -Ib have been cloned from mouse, which belong to a novel family of Type I acyl-CoA thioesterases, with related enzymes also in cytosol and mitochondria (25). Acyl-CoA thioesterases have been identified in yeast and human peroxisomes, named PTE1 (26).…”

mentioning

confidence: 99%

Characterization of an Acyl-CoA Thioesterase That Functions as a Major Regulator of Peroxisomal Lipid Metabolism

Hunt

Solaas

Kase

et al. 2002

Journal of Biological Chemistry

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144

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Peroxisomes function in ␤-oxidation of very long and long-chain fatty acids, dicarboxylic fatty acids, bile acid intermediates, prostaglandins, leukotrienes, thromboxanes, pristanic acid, and xenobiotic carboxylic acids. These lipids are mainly chain-shortened for excretion as the carboxylic acids or transported to mitochondria for further metabolism. Several of these carboxylic acids are slowly oxidized and may therefore sequester coenzyme A (CoASH). To prevent CoASH sequestration and to facilitate excretion of chain-shortened carboxylic acids, acyl-CoA thioesterases, which catalyze the hydrolysis of acyl-CoAs to the free acid and CoASH, may play important roles. Here we have cloned and characterized a peroxisomal acyl-CoA thioesterase from mouse, named PTE-2 (peroxisomal acyl-CoA thioesterase 2). PTE-2 is ubiquitously expressed and induced at mRNA level by treatment with the peroxisome proliferator WY-14,643 and fasting. Induction seen by these treatments was dependent on the peroxisome proliferator-activated receptor ␣. Recombinant PTE-2 showed a broad chain length specificity with acyl-CoAs from short-and medium-, to long-chain acyl-CoAs, and other substrates including trihydroxycoprostanoyl-CoA, hydroxymethylglutaryl-CoA, and branched chain acyl-CoAs, all of which are present in peroxisomes. Highest activities were found with the CoA esters of primary bile acids choloyl-CoA and chenodeoxycholoyl-CoA as substrates. PTE-2 activity is inhibited by free CoASH, suggesting that intraperoxisomal free CoASH levels regulate the activity of this enzyme. The acyl-CoA specificity of recombinant PTE-2 closely resembles that of purified mouse liver peroxisomes, suggesting that PTE-2 is the major acyl-CoA thioesterase in peroxisomes. Addition of recombinant PTE-2 to incubations containing isolated mouse liver peroxisomes strongly inhibited bile acidCoA:amino acid N-acyltransferase activity, suggesting that this thioesterase can interfere with CoASH-dependent pathways. We propose that PTE-2 functions as a key regulator of peroxisomal lipid metabolism.Peroxisomes are cellular organelles present in all eukaryotic cells. They play an indispensable role in the metabolism of a variety of lipids including very long-chain fatty acids, dicarboxylic fatty acids, bile acids, prostaglandins, leukotrienes, thromboxanes, pristanic acid, and xenobiotic fatty acids (for review, see Refs. 1 and 2). The peroxisomal ␤-oxidation system contains two sets of enzymes, one of which is involved in the oxidation of branched chain fatty acids and intermediates in the hepatic bile acid biosynthetic pathway and consists of one or two branched-chain acyl-CoA oxidase(s), a D-specific bifunctional protein and the sterol carrier-like protein x (SCPx). The second pathway is involved in the oxidation of very long straight-chain fatty acids, CoA esters of prostaglandins, leukotrienes, and thromboxanes (prostanoids) and dicarboxylic acids. This system is composed of a straight-chain acyl-CoA oxidase, an L-specific bifunctional protein and straight-chain 3-ke...

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Peroxisome Proliferator-induced Long Chain Acyl-CoA Thioesterases Comprise a Highly Conserved Novel Multi-gene Family Involved in Lipid Metabolism

Cited by 98 publications

References 45 publications

Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice

Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice

In vivo evidence that N-oleoylglycine acts independently of its conversion to oleamide

Characterization of an Acyl-CoA Thioesterase That Functions as a Major Regulator of Peroxisomal Lipid Metabolism

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