Expression of the Hydrogen Peroxide-Generating Enzyme Fatty Acyl CoA Oxidase Activates NF-kappa B

Li, Yixin; Tharappel, Job C.; Cooper, Simon; Glenn, Michelle; Glauert, Howard P.; Spear, Brett T.

doi:10.1089/104454900314627

Cited by 49 publications

(39 citation statements)

References 37 publications

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“…The antioxidants vitamin E and catalase inhibited this activation (28). Conversely, specific inhibition of catalase resulted in peroxisome-derived oxidative imbalance, which rapidly impaired mitochondrial function and caused mitochondrial damage (29).…”

Section: Discussionmentioning

confidence: 99%

Specific Inhibition of Acyl-CoA Oxidase-1 by an Acetylenic Acid Improves Hepatic Lipid and Reactive Oxygen Species (ROS) Metabolism in Rats Fed a High Fat Diet

Zeng

Deng

Wang

et al. 2017

Journal of Biological Chemistry

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Edited by Dennis R. VoelkerA chronic high fat diet results in hepatic mitochondrial dysfunction and induction of peroxisomal fatty acid oxidation (FAO); whether specific inhibition of peroxisomal FAO benefits mitochondrial FAO and reactive oxygen species (ROS) metabolism remains unclear. In this study a specific inhibitor for the rate-limiting enzyme involved in peroxisomal FAO, acyl-CoA oxidase-1 (ACOX1) was developed and used for the investigation of peroxisomal FAO inhibition upon mitochondrial FAO and ROS metabolism. Specific inhibition of ACOX1 by 10,12-tricosadiynoic acid increased hepatic mitochondrial FAO via activation of the SIRT1-AMPK (adenosine 5-monophosphateactivated protein kinase) pathway and proliferator activator receptor ␣ and reduced hydrogen peroxide accumulation in high fat diet-fed rats, which significantly decreased hepatic lipid and ROS contents, reduced body weight gain, and decreased serum triglyceride and insulin levels. Inhibition of ACOX1 is a novel and effective approach for the treatment of high fat dietor obesity-induced metabolic diseases by improving mitochondrial lipid and ROS metabolism. Hepatic lipid and reactive oxygen species (ROS)2 accumulation due to hyperlipidemia and obesity are critical factors associated with the prevalence of metabolic and cardiovascular diseases (1, 2). Decreased mitochondrial fatty acid oxidation (FAO) and increased lipogenesis are major contributors to lipid accumulation in liver and other tissues (3). Excessive hepatic ROS generation and decreased cellular antioxidative activity lead to oxidative stress and hepatic oxidative injury (2, 4). Agents that are able to promote mitochondrial fatty acid oxidation or have antilipogenic and antioxidative effects will improve lipid and ROS metabolism and attenuate hepatic steatosis and oxidative injury.Peroxisomes are subcellular respiratory organelles that are critical for the metabolism of long chain and branched-chain fatty acids (5). Peroxisomes are sensitive to external signals and are easy to proliferate under conditions of high fat diet (HFD) (6, 7), diabetes (8), or hypolipidemic drug treatment (9); peroxisomal FAO is induced, oxidation capacity is increased by 2-10-fold, and peroxisomal FAO is regulated by the peroxisome proliferator activator receptor ␣ isoform (PPAR␣) (5).Acyl-CoA oxidase-1 (ACOX1, EC 1.3.3.6) is a flavoenzyme that catalyzes the initial and rate-determining reaction of the classical peroxisomal FAO using straight-chain fatty acyl-CoAs as the substrates, which donates electrons to molecular oxygen generating hydrogen peroxide; this byproduct is further decomposed by catalase, as shown in Fig. 1. The classical peroxisomal FAO has been known for nearly 40 years (9), but it is still not clear about the exact role of peroxisomal FAO in cellular fatty acid metabolism and especially its effect on mitochondrial fatty acid oxidation. Several lines of evidence have shown that chronic induction of peroxisomal FAO may cause oxidative stress and is potentially detrimental to mitochondrial fa...

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Section: Discussionmentioning

confidence: 99%

Specific Inhibition of Acyl-CoA Oxidase-1 by an Acetylenic Acid Improves Hepatic Lipid and Reactive Oxygen Species (ROS) Metabolism in Rats Fed a High Fat Diet

Zeng

Deng

Wang

et al. 2017

Journal of Biological Chemistry

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“…This cell line has previously been shown to support reporter gene expression for a PKC-dependent promoter that included an AP-1 site (7), and is known to express NF-B (21,22). Moreover, it does not express CXCR2 and normally does not respond to known ligands for KSHV-GPCR.…”

Section: Kshv-gpcr Constitutively Induces Proinflammatory Transcriptimentioning

confidence: 99%

Kaposi’s Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor Constitutively Activates NF-κB and Induces Proinflammatory Cytokine and Chemokine Production Via a C-Terminal Signaling Determinant

Schwarz

Murphy

2001

The Journal of Immunology

167

133

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Kaposi’s sarcoma-associated herpesvirus (KSHV) is believed to be the causative agent of Kaposi’s sarcoma (KS), a multicentric growth factor-dependent tumor common in AIDS patients characterized histopathologically by spindle cell proliferation, angiogenesis, and leukocyte infiltration. Recently, open reading frame 74 of KSHV has been implicated as a major viral determinant of KS. Open reading frame 74 encodes KSHV G protein-coupled receptor (GPCR), a constitutively active chemokine receptor that directly transforms NIH 3T3 cells in vitro and induces multifocal KS-like lesions in KSHV-GPCR-transgenic mice. Interestingly, receptor-positive cells are very rare in lesions from these mice, implicating an indirect mechanism of tumorigenesis. In this regard, here we report that expression of KSHV-GPCR in transfected epithelial, monocytic, and T cell lines induced constitutive activation of the immunoregulatory transcription factors AP-1 and NF-κB. This was associated with constitutive induction of the proinflammatory NF-κB-dependent cytokines IL-1β, IL-6, and TNF-α, and chemokines monocyte chemoattractant protein-1 and IL-8, as well as the AP-1-dependent basic fibroblast growth factor. In addition, IL-2 and IL-4 production was induced in transfected Jurkat T cells. Truncation of the final five amino acids in the cytoplasmic tail of KSHV-GPCR caused complete loss of its transforming and NF-κB-inducing activities, without affecting receptor expression or ligand binding. These data suggest that KS results in part from KSHV-GPCR induction of proinflammatory cytokine and growth factor gene expression, mediated by a signaling determinant within the last five amino acids of the C terminus, a domain that is also critical for direct cell transformation.

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“…Preoxisomal acyl-CoA oxidase 1 (ACOX1) is the first and rate-limiting enzyme in the peroxisomal beta-oxidation pathway catalysing the desaturation of acylCoAs to 2-trans-enoyl-CoAs, thereby producing H 2 O 2 (Fournier et al, 1994;Li et al, 2000). Fan et al (1998) found that homozygous ACOX1-null mice were viable, but growth-retarded and infertile.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization, sequence variation and association with fat deposition traits of <i>ACOX1</i> gene in pigs

Zuo¹,

Yang²,

Wang³

et al. 2007

J. Anim. Feed Sci.

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Preoxisomal acyl-CoA oxidase 1 (ACOX1) catalyses the beta-oxidation of very long chain fatty acids and thus plays an essential role in fatty acid degradation. The objective of this study was to clone a gene encoding ACOX1 and to characterize its association with fat deposition in pigs. The complete coding sequence was 1986bp and encoded a protein of 661 amino acids including the carboxyl-terminal sequence (Ser-Lys-Leu) known as a minimal peroxisome-targeting signal. The predicted porcine ACOX1 amino acid sequence shared 88, 84, 81, 86 and 78% identity to that of human, mouse, rat, bovine and chicken counterparts, respectively. The A/C polymorphism in intron 9 was detected by PCR-PstI-RFLP and the allele frequencies of this polymorphism were significantly different between Chinese fatty type pig breeds (Meishan, Erhualian, Tongcheng and Qinping) and western commercial pig breeds (Landrace, Large White and Duroc). The association analysis between the A/C polymorphism and carcass traits in 298 Large White × Meishan F 2 offspring showed that the single genotype polymorphism (SNP) genotype was significantly associated with traits related to fat deposition such as backfat thickness and carcass fat percentage. The ACOX1 gene was widely expressed in the tissues examined by semi-quantitative reverse transcription (RT) PCR, with the highly abundant in liver, kidney and fat. The present study offered preliminary evidence to further determine the role of the ACOX1 gene in pig fat deposition.

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Expression of the Hydrogen Peroxide-Generating Enzyme Fatty Acyl CoA Oxidase Activates NF-kappa B

Cited by 49 publications

References 37 publications

Specific Inhibition of Acyl-CoA Oxidase-1 by an Acetylenic Acid Improves Hepatic Lipid and Reactive Oxygen Species (ROS) Metabolism in Rats Fed a High Fat Diet

Specific Inhibition of Acyl-CoA Oxidase-1 by an Acetylenic Acid Improves Hepatic Lipid and Reactive Oxygen Species (ROS) Metabolism in Rats Fed a High Fat Diet

Kaposi’s Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor Constitutively Activates NF-κB and Induces Proinflammatory Cytokine and Chemokine Production Via a C-Terminal Signaling Determinant

Molecular characterization, sequence variation and association with fat deposition traits of <i>ACOX1</i> gene in pigs

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