TY - JOUR
T1 - Functional significance of the two ACOX1 isoforms and their crosstalks with PPARα and RXRα
AU - Vluggens, Aurore
AU - Andreoletti, Pierre
AU - Viswakarma, Navin
AU - Jia, Yuzhi
AU - Matsumoto, Kojiro
AU - Kulik, Wim
AU - Khan, Mushfiquddin
AU - Huang, Jiansheng
AU - Guo, Dongsheng
AU - Yu, Sangtao
AU - Sarkar, Joy
AU - Singh, Inderjit
AU - Rao, M. Sambasiva
AU - Wanders, Ronald J.
AU - Reddy, Janardan K.
AU - Cherkaoui-Malki, Mustapha
N1 - Funding Information:
Financial support for this study was received from a grant from the European Union project ‘Peroxisome’ LSHG-CT 2004–512018, The Institut National de la Santé et de la Recherche Médicale, the Regional Council of Burgundy, the Ministère de l’enseignement Supérieur et de la Recherche and from the National Iinstitut of Health GM 23750.
PY - 2010/5
Y1 - 2010/5
N2 - 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-α (PPARα). 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 Β-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(-/-) 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 PPARα-response unit, which suggests that nervonic acid might well be an endogenous PPARα 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 (RXRα) agonist, was dependent on the concomitant hepatic expression of both ACOX1a and ACOX1b isoforms. This is accompanied by a specific recruitment of RXRα and coactivators to the PPARα-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 PPARα ligands.
AB - 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-α (PPARα). 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 Β-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(-/-) 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 PPARα-response unit, which suggests that nervonic acid might well be an endogenous PPARα 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 (RXRα) agonist, was dependent on the concomitant hepatic expression of both ACOX1a and ACOX1b isoforms. This is accompanied by a specific recruitment of RXRα and coactivators to the PPARα-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 PPARα ligands.
KW - Fatty acids oxidation
KW - Hepatic steatosis
KW - PPARα
KW - Peroxisome proliferation
KW - RXRα
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U2 - 10.1038/labinvest.2010.46
DO - 10.1038/labinvest.2010.46
M3 - Article
C2 - 20195242
AN - SCOPUS:77951781514
VL - 90
SP - 696
EP - 708
JO - Laboratory Investigation
JF - Laboratory Investigation
SN - 0023-6837
IS - 5
ER -