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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-alpha (PPARalpha). 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 beta-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 PPARalpha-response unit, which suggests that nervonic acid might well be an endogenous PPARalpha 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 (RXRalpha) agonist, was dependent on the concomitant hepatic expression of both ACOX1a and ACOX1b isoforms. This is accompanied by a specific recruitment of RXRalpha and coactivators to the PPARalpha-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 PPARalpha ligands.

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-alpha (PPARalpha). 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 beta-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 PPARalpha-response unit, which suggests that nervonic acid might well be an endogenous PPARalpha 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 (RXRalpha) agonist, was dependent on the concomitant hepatic expression of both ACOX1a and ACOX1b isoforms. This is accompanied by a specific recruitment of RXRalpha and coactivators to the PPARalpha-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 PPARalpha ligands.

Human acyl-CoA oxidase 1 (ACOX1) is a rate-limiting enzyme in peroxisomal fatty acids β-oxidation and its deficiency is associated with a lethal, autosomal recessive disease, called pseudoneonatal-adrenoleukodystrophy. Two mRNA variants, transcribed from a single gene encode ACOX1a or ACOX1b isoforms, respectively. Recently, a mutation in a splice site has been reported [H. Rosewich, H.R. Waterham, R.J. Wanders, S. Ferdinandusse, M. Henneke, D. Hunneman, J. Gartner, Pitfall in metabolic screening in a patient with fatal peroxisomal β-oxidation defect, Neuropediatrics 37 (2006) 95–98.], which results in the defective peroxisomal fatty acids β-oxidation. Here, we show that these mRNA splice variants are expressed differentially in human liver. We investigated the biochemical role of the two human ACOX1 isoforms by heterologous expression of the catalytically active ACOX1a and ACOX1b enzymes in Escherichia coli. ACOX1a seems to be more labile and exhibits only 50% specific activity toward palmitoyl-CoA as compared to ACOX1b.