Peroxisomal very long chain fatty acid beta-oxidation activity is determined by the level of adrenodeukodystrophy protein (ALDP) expression

Impaired peroxisomal beta-oxidation of saturated very long chain fatty acid s (VLCFA, greater than or equal to C22:0) results in increased VLCFA levels in the tissues and body fluids of patients with disorders of peroxisomal b iogenesis (i.e., Zellweger syndrome and neonatal adrenoleukodystrophy) and single peroxisomal protein defects (i.e., X-linked adrenoleukodystrophy (X- ALD) and acyl-CoA oxidase deficiency). We show that SV40T transformation al so results in impaired peroxisomal beta-oxidation and VLCFA accumulation de spite the presence of abundant peroxisomes, To explore the mechanism respon sible for this observation, we have examined expression of key components o f peroxisomal VLCFA beta-oxidation, We found that expression of both acyl-C oA oxidase, the rate limiting enzyme of peroxisomal VLCFA beta-oxidation an d the adrenoleukodystrophy protein (ALDP), the defective gene product in X- ALD, are reduced after SV40T transformation. Surprisingly, ALDP overexpress ion by itself restores peroxisomal VLCFA beta-oxidation in SV40T-transforme d control and X-ALD cells. These results demonstrate that ALDP is a fundame ntal component in VLCFA peroxisomal beta-oxidation and may serve as a "gate keeper" for VLCFA homeostasis, (C) 1999 Academic Press.