The aim of this investigation is to examine cholesterol and cholestanol metabolism in patients with cerebrotendinous xanthomatosis (CTX), atherosclerosis and gallstones. Specially we shall continue to define the clinical and biochemical abnormalities in the rare inherited lipid storage diseases, CTX. In CTX, a defect in bile acid synthesis leads to excessive production and tissue accumulation of cholesterol and cholestanol. A major goal is to suppress the abnormal bile acid synthetic pathway with chenodeoxycholic acid and evaluate changes in the clinical and biochemical course of the disease. Further the site of cholestanol formation and its regulation will be investigated. In addition, the pathway of side chain oxidation of cholesterol to bile acid will be examined to determine whether the side chain cleavage proceeds via 26- or 25-hydroxylated derivatives. In other experiments, the metabolism of plant sterols (campesterol and sitosterol) and cholesterol will be evaluated in sitosterolemia with xanthomatosis, a newly discovered lipid storage disease in which plant sterols (campesterol and sitosterol) along with cholesterol accumulate in the body. We intend to measure sitosterol and cholesterol turnover by the isotope kinetic method, conversion of sitosterol to bile acids and to assess the intestinal absorption of both sitosterol and cholesterol by the plasma dual isotope ratio method, which is not dependent on fecal balance measurements.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL017818-14
Application #
3335458
Study Section
Metabolism Study Section (MET)
Project Start
1977-12-01
Project End
1987-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
14
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
Schools of Medicine
DUNS #
605799469
City
Newark
State
NJ
Country
United States
Zip Code
07107
Honda, A; Salen, G; Matsuzaki, Y et al. (2001) Differences in hepatic levels of intermediates in bile acid biosynthesis between Cyp27(-/-) mice and CTX. J Lipid Res 42:291-300
Honda, M; Tint, G S; Honda, A et al. (2000) Regulation of cholesterol biosynthetic pathway in patients with the Smith-Lemli-Opitz syndrome. J Inherit Metab Dis 23:464-74
Xu, G; Shneider, B L; Shefer, S et al. (2000) Ileal bile acid transport regulates bile acid pool, synthesis, and plasma cholesterol levels differently in cholesterol-fed rats and rabbits. J Lipid Res 41:298-304
Honda, A; Salen, G; Shefer, S et al. (2000) Regulation of 25- and 27-hydroxylation side chain cleavage pathways for cholic acid biosynthesis in humans, rabbits, and mice. Assay of enzyme activities by high-resolution gas chromatography;-mass spectrometry. J Lipid Res 41:442-51
Honda, A; Salen, G; Honda, M et al. (2000) 3-Hydroxy-3-methylglutaryl-coenzyme A reductase activity is inhibited by cholesterol and up-regulated by sitosterol in sitosterolemic fibroblasts. J Lab Clin Med 135:174-9
Xu, G; Salen, G; Shefer, S et al. (1999) Increasing dietary cholesterol induces different regulation of classic and alternative bile acid synthesis. J Clin Invest 103:89-95
Batta, A K; Datta, S C; Tint, G S et al. (1999) A convenient synthesis of dinorbile acids: oxidative hydrolysis of norbile acid nitriles. Steroids 64:780-4
Honda, A; Salen, G; Shefer, S et al. (1999) Bile acid synthesis in the Smith-Lemli-Opitz syndrome: effects of dehydrocholesterols on cholesterol 7alpha-hydroxylase and 27-hydroxylase activities in rat liver. J Lipid Res 40:1520-8
Ertel, N H; Dayal, B; Rao, K et al. (1999) Anomalous enantioselectivity in the sharpless asymmetric dihydroxylation reaction of 24-nor-5beta-cholest-23-ene-3alpha,7alpha,12alpha-triol: synthesis of substrates for studies of cholesterol side-chain oxidation. Lipids 34:395-405
Batta, A K; Salen, G; Rapole, K R et al. (1999) Highly simplified method for gas-liquid chromatographic quantitation of bile acids and sterols in human stool. J Lipid Res 40:1148-54

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