Biochemical characterization of two functional human liver acyl-CoA oxidase isoforms 1a and 1b encoded by a single gene

Oaxaca-Castillo, David; Andreoletti, Pierre; Vluggens, Aurore; Yu, Sangtao; Veldhoven, Paul P. Van; Reddy, Janardan K.; Cherkaoui-Malki, Mustapha

doi:10.1016/j.bbrc.2007.06.059

Cited by 69 publications

(49 citation statements)

References 21 publications

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“…3B). The k cat and K m of ACOX-1 against asc-C9-CoA (4) were of a similar order as those of mammalian acyl-CoA oxidases against fatty acyl-CoA substrates (26) (Table S1). Surprisingly, however, ACOX-1 was not active against any other ascaroside-based substrates, including asc-ωC5-CoA (1) or asc-C7-CoA (3), contrary to what might be expected from the LC-MS/MS data of the acox-1 mutant ( Fig.…”

Section: Resultsmentioning

confidence: 66%

Acyl-CoA oxidase complexes control the chemical message produced by Caenorhabditis elegans

Zhang

Feng

Chinta

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

158

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Caenorhabditis elegans uses ascaroside pheromones to induce development of the stress-resistant dauer larval stage and to coordinate various behaviors. Peroxisomal β-oxidation cycles are required for the biosynthesis of the fatty acid-derived side chains of the ascarosides. Here we show that three acyl-CoA oxidases, which catalyze the first step in these β-oxidation cycles, form different protein homo-and heterodimers with distinct substrate preferences. Mutations in the acyl-CoA oxidase genes acox-1, -2, and -3 led to specific defects in ascaroside production. When the acyl-CoA oxidases were expressed alone or in pairs and purified, the resulting acyl-CoA oxidase homo-and heterodimers displayed different sidechain length preferences in an in vitro activity assay. Specifically, an ACOX-1 homodimer controls the production of ascarosides with side chains with nine or fewer carbons, an ACOX-1/ACOX-3 heterodimer controls the production of those with side chains with seven or fewer carbons, and an ACOX-2 homodimer controls the production of those with ω-side chains with less than five carbons. Our results support a biosynthetic model in which β-oxidation enzymes act directly on the CoA-thioesters of ascaroside biosynthetic precursors. Furthermore, we identify environmental conditions, including high temperature and low food availability, that induce the expression of acox-2 and/or acox-3 and lead to corresponding changes in ascaroside production. Thus, our work uncovers an important mechanism by which C. elegans increases the production of the most potent dauer pheromones, those with the shortest side chains, under specific environmental conditions. dauer | pheromone | ascaroside | beta-oxidation | acyl-CoA oxidase

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Section: Resultsmentioning

confidence: 66%

Acyl-CoA oxidase complexes control the chemical message produced by Caenorhabditis elegans

Zhang

Feng

Chinta

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

158

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“…Human ACOX1a or ACOX1b cDNAs 21 were cloned into the BglII and HindIII sites of pShuttle-CMV expression vector (Quantum Biotechnologies).…”

Section: Materials and Methods Adenoviral Gene Transfermentioning

confidence: 99%

“…[19][20][21] Indeed, alternative splicing of pre-mRNA produces two mRNA sequences harboring exon 3a or exon 3b, which both code for a 54 aminoacid region located near the N terminus. This region is highly conserved in several species with high amino-acid identity.…”

Section: Acox1: One Gene Two Splice Variants With Differential Tissumentioning

confidence: 99%

“…18 The ACOX1 enzyme is encoded by a single gene, which generates two splice variants, including exon 3a or exon 3b, respectively, 19,20 leading to the synthesis of two protein isoforms ACOX1a or ACOX1b. 21 A single homozygous mutation in exon 3b results in the development of the P-NALD disease, 22 suggesting different substrate specificities of the two ACOX1 isoforms. On the other hand, further biochemical analysis of recombinant human ACOX1 isoforms showed that ACOX1a seems to be more labile and exhibits only 50% specific activity toward palmitoyl-CoA as compared with ACOX1b.…”

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confidence: 99%

“…On the other hand, further biochemical analysis of recombinant human ACOX1 isoforms showed that ACOX1a seems to be more labile and exhibits only 50% specific activity toward palmitoyl-CoA as compared with ACOX1b. 21 Therefore, in an attempt to approach the in vivo conditions and to understand the sensing metabolic role of ACOX1 vis-à-vis the hepatic steatosis and the activation of PPARa, we expressed human ACOX1 isoforms in Acox1(À/À) null mice by adenofection. We then analyzed the impact of human ACOX1 expression on the pathophysiological aspects and on the regulation of PPARa and its target genes in the liver samples obtained from Acox1À/À mice.…”

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confidence: 99%

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Functional significance of the two ACOX1 isoforms and their crosstalks with PPARα and RXRα

Vluggens

Andreoletti

Viswakarma

et al. 2010

Laboratory Investigation

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Disruption of the peroxisomal acyl-CoA oxidase 1 (Acox1) gene in the mouse results in the development of severe microvesicular hepatic steatosis and sustained activation of peroxisome proliferator-activated receptor-a (PPARa). These mice manifest spontaneous massive peroxisome proliferation in regenerating hepatocytes and eventually develop hepatocellular carcinomas. Human ACOX1, the first and rate-limiting enzyme of the peroxisomal b-oxidation pathway, has two isoforms including ACOX1a and ACOX1b, transcribed from a single gene. As ACOX1a shows reduced activity toward palmitoyl-CoA as compared with ACOX1b, we used adenovirally driven ACOX1a and ACOX1b to investigate their efficacy in the reversal of hepatic phenotype in Acox1(À/À) mice. In this study, we show that human ACOX1b is markedly effective in reversing the ACOX1 null phenotype in the mouse. In addition, expression of human ACOX1b was found to restore the production of nervonic (24:1) acid and had a negative impact on the recruitment of coactivators to the PPARa-response unit, which suggests that nervonic acid might well be an endogenous PPARa antagonist, with nervonoyl-CoA probably being the active form of nervonic acid. In contrast, restoration of docosahexaenoic (22:6) acid level, a retinoid-X-receptor (RXRa) agonist, was dependent on the concomitant hepatic expression of both ACOX1a and ACOX1b isoforms. This is accompanied by a specific recruitment of RXRa and coactivators to the PPARa-response unit. The human ACOX1b isoform is more effective than the ACOX1a isoform in reversing the Acox1 null phenotype in the mouse. Substrate utilization differences between the two ACOX1 isoforms may explain the reason why ACOX1b is more effective in metabolizing PPARa ligands.

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Diesel and biodiesels induce hepatic palmitoyl‐coa oxidase enzymatic activity through different molecular mechanisms in rats

Pelletier

Rigden

Poon

2012

J Biochem & Molecular Tox

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Induction of palmitoyl-CoA oxidase enzymatic activity in rat liver suggests that ingestion of diesel and biodiesels can cause mild hepatic peroxisomal proliferation. Surprisingly, quantification by immunochemistry of the enzyme itself (ACOX1) revealed that palmitoyl-CoA oxidase enzymatic activity correlates with ACOX1 protein level following exposure to diesel, but not following exposure to biodiesels. Quantification of CYP4A1, another biomarker of peroxisomal proliferation, further indicates that contrary to diesel, the effects of biodiesels appear to be independent of this pathway. There are two ACOX1 protein isoforms that exhibit different enzymatic activities depending on the substrate. The results of our enzymatic assays performed on substrates presenting different carbon chain lengths (octanoyl-CoA and palmitoyl-CoA) are compatible with the hypothesis of a differential regulation of the ACOX1 isoforms by diesel and biodiesels. Further studies will be required to precisely determine the molecular mechanisms by which diesel and biodiesels induce palmitoyl-CoA oxidase activity in rat liver.

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Biochemical characterization of two functional human liver acyl-CoA oxidase isoforms 1a and 1b encoded by a single gene

Cited by 69 publications

References 21 publications

Acyl-CoA oxidase complexes control the chemical message produced by Caenorhabditis elegans

Acyl-CoA oxidase complexes control the chemical message produced by Caenorhabditis elegans

Functional significance of the two ACOX1 isoforms and their crosstalks with PPARα and RXRα

Diesel and biodiesels induce hepatic palmitoyl‐coa oxidase enzymatic activity through different molecular mechanisms in rats

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