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Papers In Press, published online ahead of print September 18, 2003
Pathology Dept., Northwestern University, Feinberg School of Medicine, Chicago, IL 60611
Corresponding Author: jkreddy{at}northwestern.edu
Peroxisomal b-oxidation system consists of peroxisome proliferator-activated receptor a (PPARa)-inducible pathway capable of catalyzing straight-chain acyl-CoAs, and a second noninducible pathway catalyzing the oxidation of 2-methyl-branched fatty acyl-CoAs. Disruption of the inducible b-oxidation pathway in mice at the level of fatty acyl-CoA oxidase (AOX), the first and rate limiting enzyme, results in spontaneous peroxisome proliferation and sustained activation of PPARa leading to the development of liver tumors, whereas disruptions of this classical pathway or of the noninducible system at the level of the second enzyme, had no such discernible effects. We now show that mice with complete inactivation of peroxisomal b-oxidation at the level of the second enzyme, enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase (L-PBE) of the inducible pathway and D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase (D-PBE) of the noninducible pathway (L-PBE-/-D-PBE-/-), exhibit severe growth retardation and postnatal mortality with none surviving beyond weaning. L-PBE-/-D-PBE-/- mice that survived exceptionally beyond the age of 3 weeks, exhibited microvesicular hepatic steatosis, mitochondrial structural abnormalities, and paucity of peroxisomes in hepatocytes. L-PBE-/-D-PBE-/- mice also showed overexpression of PPARa regulated genes in liver, despite the absence of morphological evidence of peroxisome proliferation. These studies establish that peroxisome proliferation in rodent liver is highly correlatable with the induction mostly of the L- and D-PBE genes. We conclude that disruption of peroxisomal fatty acid b-oxidation at the level of second enzyme in mice leads to the induction of many of the PPARa target genes independently of peroxisome proliferation in hepatocytes raising the possibility that very long-chain acyl-CoAs and enoyl-CoAs can act as ligands for PPARa.
J. Biol. Chem, 10.1074/jbc.M306363200
Submitted on June 16, 2003
Revised on September 18, 2003
Accepted on September 18, 2003
Overexpression of PPARa regulated genes in liver in the absence of peroxisome proliferation in mice deficient in both L- and D- forms of enoyl-CoA hydratase/dehydrogenase enzymes of peroxisomal b-oxidation system
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