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Arachidonic acid downregulates acyl-CoA synthetase 4 expression by promoting its ubiquitination and proteasomal degradation

ACSL4 is a member of the long-chain acyl-CoA synthetase (ACSL) family with a marked preference for arachidonic acid (AA) as its substrate. Although an association between elevated levels of ACSL4 and hepatosteatosis has been reported, the function of ACSL4 in hepatic FA metabolism and the regulation...

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Autores principales: Kan, Chin Fung Kelvin, Singh, Amar Bahadur, Stafforini, Diana M., Azhar, Salman, Liu, Jingwen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Biochemistry and Molecular Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109760/
https://www.ncbi.nlm.nih.gov/pubmed/24879802
http://dx.doi.org/10.1194/jlr.M045971
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author Kan, Chin Fung Kelvin
Singh, Amar Bahadur
Stafforini, Diana M.
Azhar, Salman
Liu, Jingwen
author_facet Kan, Chin Fung Kelvin
Singh, Amar Bahadur
Stafforini, Diana M.
Azhar, Salman
Liu, Jingwen
author_sort Kan, Chin Fung Kelvin
collection PubMed
description ACSL4 is a member of the long-chain acyl-CoA synthetase (ACSL) family with a marked preference for arachidonic acid (AA) as its substrate. Although an association between elevated levels of ACSL4 and hepatosteatosis has been reported, the function of ACSL4 in hepatic FA metabolism and the regulation of its functional expression in the liver remain poorly defined. Here we provide evidence that AA selectively downregulates ACSL4 protein expression in hepatic cells. AA treatment decreased the half-life of ACSL4 protein in HepG2 cells by approximately 4-fold (from 17.3 ± 1.8 h to 4.2 ± 0.4 h) without causing apoptosis. The inhibitory action of AA on ACSL4 protein stability could not be prevented by rosiglitazone or inhibitors that interfere with the cellular pathways involved in AA metabolism to biologically active compounds. In contrast, treatment of cells with inhibitors specific for the proteasomal degradation pathway largely prevented the AA-induced ACSL4 degradation. We further show that ACSL4 is intrinsically ubiquitinated and that AA treatment can enhance its ubiquitination. Collectively, our studies have identified a novel substrate-induced posttranslational regulatory mechanism by which AA downregulates ACSL4 protein expression in hepatic cells.
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spelling pubmed-41097602014-08-01 Arachidonic acid downregulates acyl-CoA synthetase 4 expression by promoting its ubiquitination and proteasomal degradation Kan, Chin Fung Kelvin Singh, Amar Bahadur Stafforini, Diana M. Azhar, Salman Liu, Jingwen J Lipid Res Research Articles ACSL4 is a member of the long-chain acyl-CoA synthetase (ACSL) family with a marked preference for arachidonic acid (AA) as its substrate. Although an association between elevated levels of ACSL4 and hepatosteatosis has been reported, the function of ACSL4 in hepatic FA metabolism and the regulation of its functional expression in the liver remain poorly defined. Here we provide evidence that AA selectively downregulates ACSL4 protein expression in hepatic cells. AA treatment decreased the half-life of ACSL4 protein in HepG2 cells by approximately 4-fold (from 17.3 ± 1.8 h to 4.2 ± 0.4 h) without causing apoptosis. The inhibitory action of AA on ACSL4 protein stability could not be prevented by rosiglitazone or inhibitors that interfere with the cellular pathways involved in AA metabolism to biologically active compounds. In contrast, treatment of cells with inhibitors specific for the proteasomal degradation pathway largely prevented the AA-induced ACSL4 degradation. We further show that ACSL4 is intrinsically ubiquitinated and that AA treatment can enhance its ubiquitination. Collectively, our studies have identified a novel substrate-induced posttranslational regulatory mechanism by which AA downregulates ACSL4 protein expression in hepatic cells. The American Society for Biochemistry and Molecular Biology 2014-08 /pmc/articles/PMC4109760/ /pubmed/24879802 http://dx.doi.org/10.1194/jlr.M045971 Text en http://creativecommons.org/licenses/by/3.0/ Author's Choice—Final version full access. Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/) applies to Author Choice Articles
spellingShingle Research Articles
Kan, Chin Fung Kelvin
Singh, Amar Bahadur
Stafforini, Diana M.
Azhar, Salman
Liu, Jingwen
Arachidonic acid downregulates acyl-CoA synthetase 4 expression by promoting its ubiquitination and proteasomal degradation
title Arachidonic acid downregulates acyl-CoA synthetase 4 expression by promoting its ubiquitination and proteasomal degradation
title_full Arachidonic acid downregulates acyl-CoA synthetase 4 expression by promoting its ubiquitination and proteasomal degradation
title_fullStr Arachidonic acid downregulates acyl-CoA synthetase 4 expression by promoting its ubiquitination and proteasomal degradation
title_full_unstemmed Arachidonic acid downregulates acyl-CoA synthetase 4 expression by promoting its ubiquitination and proteasomal degradation
title_short Arachidonic acid downregulates acyl-CoA synthetase 4 expression by promoting its ubiquitination and proteasomal degradation
title_sort arachidonic acid downregulates acyl-coa synthetase 4 expression by promoting its ubiquitination and proteasomal degradation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109760/
https://www.ncbi.nlm.nih.gov/pubmed/24879802
http://dx.doi.org/10.1194/jlr.M045971
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