Niemann-Pick disease type C (NP-C) is an autosomal recessive disorder characterized by the sequestration and trapping of endocytosed cholesterol in lysosomes. The NPC1 gene on chromosome 18 was recently identified but its physiological function remains unknown. We have studied the lipid compositions of cultured human NP-C fibroblasts and mouse SPM-3T3 cell line derived from the C57BL/KsJ NP-C model mouse, which belongs to the same complementation group. Fibroblasts derived from apparently normal age-matched individuals and a subline of SPM-3T3 cells which restores cholesterol metabolism by transfer of human chromosome 18 were used as controls. Levels of free cholesterol in whole cell homogenates increased about 1.5-fold in human NP-C fibroblasts and mouse SPM-3T3 cells, while in the plasma membrane, cholesterol content did not significantly change in NP-C fibroblasts but rather decreased in SPM-3T3 cells. The total phospholipid content did not significantly change; however, among phospholipid head groups, increases in sphingomyelin and decreases in other classes were observed in human NP-C fibroblasts and mouse SPM-3T3 cells. The ratios of saturated fatty acids to unsaturated fatty acids increased in both human and mouse cells. The increase was also confirmed in the plasma membrane fraction of SPM-3T3 cells. Membrane fluidity was examined using a 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescent probe. The DPH anisotropy values were markedly increased in NP-C fibroblasts and in SPM-3T3 cells. The results suggest that a NP-C mutation causes complex alterations in cellular lipid contents and biophysical properties of the membrane.

The effect of chitosan feeding (for 21 days) on intestinal bile acids was studied in male rats. Serum cholesterol levels in rats fed a commercial diet low in cholesterol were decreased by chitosan supplementation. Chitosan inhibited the transformation of cholesterol to coprostanol without causing a qualitative change in fecal excretion of these neutral sterols. Increased fiber consumption did not increase fecal excretion of bile acids, but caused a marked change in fecal bile acid composition. Lithocholic acid increased significantly, deoxycholic acid increased to a lesser extent, whereas hyodeoxycholic acid and the 6 beta-isomer and 5-epimeric 3 alpha-hydroxy-6-keto-cholanoic acid(s) decreased. The pH in the cecum and colon became elevated by chitosan feeding which affected the conversion of primary bile acids to secondary bile acids in the large intestine. In the cecum, chitosan feeding increased the concentration of alpha-,beta-, and omega-muricholic acids, and lithocholic acid. However, the levels of hyodeoxycholic acid and its 6 beta-isomer, of monohydroxy-monoketo-cholanoic acids, and of 3 alpha, 6 xi, 7 xi-trihydroxy-cholanoic acid decreased. The data suggest that chitosan feeding affects the metabolism of intestinal bile acids in rats.

Metabolism of 26-hydroxycholesterol to 3 beta-hydroxychol-5-en-24-oic acid and other C24-bile acids has been expected to occur by way of 3 beta-hydroxycholest-5-en-26-oic acid in studies in vitro. 3 beta-Hydroxycholest-5-en-26-oic acid was infused intravenously into bile fistula hamsters and the following C24-bile acids were identified: 3 beta-hydroxychol-5-en-24-oic acid, lithocholic acid, chenodeoxycholic acid, and a small amount of cholic acid.

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