Braiterman L T, Watkins P A, Moser A B, Smith K D
Kennedy Krieger Research Institute, 707 N. Broadway, Baltimore, Maryland, 21205, USA.
Mol Genet Metab. 1999 Feb;66(2):91-9. doi: 10.1006/mgme.1998.2789.
Impaired peroxisomal beta-oxidation of saturated very long chain fatty acids (VLCFA, >/=C22:0) results in increased VLCFA levels in the tissues and body fluids of patients with disorders of peroxisomal biogenesis (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 also results in impaired peroxisomal beta-oxidation and VLCFA accumulation despite the presence of abundant peroxisomes. To explore the mechanism responsible for this observation, we have examined expression of key components of peroxisomal VLCFA beta-oxidation. We found that expression of both acyl-CoA oxidase, the rate limiting enzyme of peroxisomal VLCFA beta-oxidation and the adrenoleukodystrophy protein (ALDP), the defective gene product in X-ALD, are reduced after SV40T transformation. Surprisingly, ALDP overexpression by itself restores peroxisomal VLCFA beta-oxidation in SV40T-transformed control and X-ALD cells. These results demonstrate that ALDP is a fundamental component in VLCFA peroxisomal beta-oxidation and may serve as a "gatekeeper" for VLCFA homeostasis.
过氧化物酶体对饱和超长链脂肪酸（VLCFA，≥C22:0）的β-氧化受损，会导致过氧化物酶体生物发生障碍（即泽尔韦格综合征和新生儿肾上腺脑白质营养不良）以及单个过氧化物酶体蛋白缺陷（即X连锁肾上腺脑白质营养不良（X-ALD）和酰基辅酶A氧化酶缺乏症）患者的组织和体液中VLCFA水平升高。我们发现，尽管存在丰富的过氧化物酶体，但SV40T转化也会导致过氧化物酶体β-氧化受损和VLCFA积累。为了探究导致这一现象的机制，我们检测了过氧化物酶体VLCFAβ-氧化关键成分的表达。我们发现，过氧化物酶体VLCFAβ-氧化的限速酶酰基辅酶A氧化酶以及X-ALD中的缺陷基因产物肾上腺脑白质营养不良蛋白（ALDP）在SV40T转化后表达均降低。令人惊讶的是，单独过表达ALDP可恢复SV40T转化的对照细胞和X-ALD细胞中的过氧化物酶体VLCFAβ-氧化。这些结果表明，ALDP是VLCFA过氧化物酶体β-氧化的基本成分，可能作为VLCFA稳态的“守门人”。
