ENZYMATIC REGULATION OF VERY LONG CHAIN FATTY ACID

Hugo W. Moser Res Inst Kennedy Krieger, Baltimore MD

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Abstract

Elevated tissue levels of very long-chain fatty acids (VLCFA) are associated with human diseases such as X-linked adrenoleukodystrophy (X-ALD). Fibroblasts from X-ALD patients have impaired peroxisomal VLCFA beta-oxidation and reduced activity of peroxisomal very long-chain acyl-CoA synthetase (VLCS). An earlier hypothesis suggested that ALD, the protein defective in X-ALD, controlled VLCFA degradation by interacting with peroxisomal VLCS. New data indicate that ALDP may a more general role in VLCFA homeostasis. The former hypothesis implies a role of peroxisomal VLCS and the latter a role for extraperoxisomal VLCS. Irrespective of which hypothesis provides correct, enzymes with VLCS activity are necessary for activation and subsequent metabolism of VLCFA. We cloned cDNAs encoding several proteins with VLCS activity. We hypothesize that two of these enzymes play significant roles in VLCFA homeostasis and may be involved in X-ALD pathogenesis. In Aim 1 we will study the biochemical function of human and mouse BG, a primarily cytoplasmic enzyme first described in a Drosophila mutant ("bubblegum") with neurodegeneration and elevated VLCFA levels, and related enzymes. BG activates VLCFA and several essential brain fatty acids, and is expressed almost exclusively in tissues pathologically affected in X-ALD (brain, testis and adrenal gland). Elucidation of BG's function will be facilitated by producing a mouse knockout model in Aim 2. Because BG is primarily found in brain, we hypothesize that BG functions critically in other aspects of brain fatty acid homeostasis such as docosahexenoic acid synthesis and acylation of myelin proteolipid protein. In Aim 3, we will study a recently produced VLCS knockout mouse model. VLCS differs from BG in that the former is expressed primarily in liver and kidney and localizes to peroxisomes and endoplasmic reticulum. We will test hypothesis that VLCS as critical roles in VLCFA, beta-oxidation, complex lipid synthesis, branched-chain fatty acid catabolism and bile acid synthesis. In Aim 4, biochemical studies of lipid metabolism will be undertaken to probe the role(s) of BG, VLCS, ALDP (the peroxisomal membrane ABC transporter defective in X-ALD) and related peroxisomal ABC transporters in X-ALD patient fibroblasts and in double and triple-knockout animal models produced by mating mice form Aims 2 and 3 of this Project with those from other projects.