The aim of this investigation is to examine cholestanol, cholesterol, and bile acid metabolism in patients with cerebrotendinous xanthomatosis (CTX), sitosterolemia with xanthomatosis, atherosclerosis and gallstones. Specifically, we shall continue to define the clinical and biochemical abnormalities in the rare inherited lipid storage diseases, CTX and sitosterolemia. In CTX, a defect in bile acid synthesis leads to the overproduction and accumulation of cholesterol and cholestanol in tissues. A major goal is (1) to suppress abnormal bile acid synthesis with chenodeoxycholic acid and evaluate long term changes in the clinical and biochemical course of the disease. Comparison with other promising treatments such as cholic acid and the HMG CoA reductase inhibitor Mevinolin will be made. (2) Quantitative information on the mechanism of side- chain oxidation in cholic acid biosynthesis will be sought using 3 alpha, 7 alpha, 12 alpha-trihydroxycoprostanoic acid, a C-27 bile acid, as a putative precursor. (3) By defining the quantitative mechanism of side chain cleavage (either 25- or 26 hydroxy pathways) in bile acid synthesis, the specific bile acid enzymatic defect in CTX will be ascertained. (4) The pathway of cholestanol biosynthesis will be investigated in both CTX and sitosterolemia to determine if the bile acid precurcors, 7 alpha- hydroxycholesterol or 4-cholesten-3-one, are intermediates in these diseases where cholestanol accumulates. (5) The metabolism of plant sterols (campesterol and sitosterol) and cholestanol will be compared to cholesterol in sitosterolemia with xanthomatosis. In this disease, plant sterol absorption is increased and coupled to decreased hepatic sterol and bile acid secretion. We propose to measure (a) sitosterol and cholesterol turnover by isotope kinetic methods, (b) the conversion of sitosterol to bile acids, (c) the possibility that plant sterols may competitively block normal bile acid synthesis (suppress cholesterol 7 alpha-hydroxylase activity) and (d) intestinal absorption of sitosterol and cholesterol will be measured by plasma dual isotope ratio method which is independent of fecal measurements.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL017818-22
Application #
2215079
Study Section
Special Emphasis Panel (NSS)
Project Start
1977-12-01
Project End
1996-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
22
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Internal Medicine/Medicine
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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