Fundamental knowledge concerning the metabolism and function of very long chain fatty acids (VLFA) in man is lacking. Current interest in VLFA metabolism has been heightened by the demonstration that patients with the X-linked inherited disease adrenoleukodystrophy (ALD) accumulate VLFA in various tissues, including cultured fibroblasts. Long-term objectives of the proposed research are to establish the biochemical basis for VLFA accumulation in ALD, determine whether genetic heterogeneity is responsible for phenotypic variability in affected individuals, and uncover the pathogenetic mechanisms resulting in organ dysfunction. Accordingly, we will investigate the rate and control of VLFA synthesis and turnover in normal and ALD fibroblasts using radio-chemical techniques. These methods will be used to clarify the mechanism whereby VLFA accumulation in ALD fibroblasts is decreased by incubation in the presence of oleic acid. The relative contribution of peroxisomal and mitochondrial pathways to total VLFA oxidation will be determined in cultured fibroblasts, adrenocortical cells, hepatocytes, and glioma cells. Individual VLFA Beta-oxidation enzymatic activities will be characterized in rat liver, and these assays will be applied to normal and ALD fibroblasts in an attempt to identify the putative enzymatic defect in ALD. Genetic complementation studies with fibroblasts will be used to investigate possible genetic heterogeneity in ALD, and the ALD gene will be further mapped on the X-chromosome by chromosome-mediated gene transfer techniques. The pathophysiologic basis for adrenal insufficiency in ALD will be investigated in a model system employing adrenocortical cells cultured in the presence of VLFA. These studies will provide fundamental information about normal VLFA metabolism and the deranged VLFA metabolism in ALD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033914-04
Application #
3232320
Study Section
Biochemistry Study Section (BIO)
Project Start
1984-04-01
Project End
1988-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
4
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Zenger-Hain, J; Craft, D A; Rizzo, W B (1992) Diagnosis of inborn errors of phytanic acid oxidation using tritiated phytanic acid. Prog Clin Biol Res 375:399-407
Roesel, R A; Carroll, J E; Rizzo, W B et al. (1991) Dyggve-Melchior-Clausen syndrome with increased pipecolic acid in plasma and urine. J Inherit Metab Dis 14:876-80
Boles, D J; Craft, D A; Padgett, D A et al. (1991) Clinical variation in X-linked adrenoleukodystrophy: fatty acid and lipid metabolism in cultured fibroblasts. Biochem Med Metab Biol 45:74-91
Jensen, M E; Sawyer, R W; Braun, I F et al. (1990) MR imaging appearance of childhood adrenoleukodystrophy with auditory, visual, and motor pathway involvement. Radiographics 10:53-66
Proud, V K; Rizzo, W B; Patterson, J W et al. (1990) Fatty acid alterations and carboxylase deficiencies in the skin of biotin-deficient rats. Am J Clin Nutr 51:853-8
Rizzo, W B; Leshner, R T; Odone, A et al. (1989) Dietary erucic acid therapy for X-linked adrenoleukodystrophy. Neurology 39:1415-22
Rizzo, W B; Dammann, A L; Craft, D A et al. (1989) Sjogren-Larsson syndrome: inherited defect in the fatty alcohol cycle. J Pediatr 115:228-34