Comparative effects of cholestanol and cholesterol on hepatic sterol and bile acid metabolism in the rat.

Abstract

Abstract. Large amounts of cholestanol, the 5a-dihydro derivative of cholesterol are found in tissues of patients with the rare inherited sterol storage disease cerebrotendinous xanthomatosis. Although small amounts of cholestanol are present in virtually every tissue of normal man, little is known about its metabolism and effect on cholesterol and bile acid formation. The purpose of this study is to investigate the absorption and metabolism of cholestanol and its early effects on hepatic morphology and on the rate-limiting enzymes of cholesterol and bile acid biosynthesis. After 2 wk on a diet supplemented with 2% cholestanol, total liver sterol content increased by 48% (3.26 vs. 2.20 mg/g), and resulted in a significant rise in hepatic cholestanol concentration to 1.4 mg/g. However, cholestanol was less efficiently absorbed from the intestine than cholesterol and interfered with cholesterol absorption. Furthermore, hepatic hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase activity rose 2.6-fold (from 150.3 to 397.0 pmol/mg per min) during cholestanol feeding, and was associated with a marked proliferation of the smooth endoplasmic reticulum of the centrilobular areas. In addition, significant amounts of allocholic acid (16%) and allochenodeoxycholic acid (5%) were formed from cholestanol and excreted in the bile. These results show that cholestanol is absorbed from the intestine, interferes with cholesterol absorption, and is deposited in the liver. However, in contrast to cholesterol, cholestanol feeding was associated with a marked elevation of HMG-CoA

Determination of serum cholestanol by semi‐micro high‐performance liquid chromatography with electrochemical detection

“…mice showed a 20-fold increase (303 ± 14.7 μM) compared with the control mice (14.4 ± 20.4 μM). These results are in good agreement with the previous results of Shefer et al (1984), Buchmann and Clausen (1986) and Byun et al (1988). Therefore, our results indicate that the current method is useful to monitor experimental hypercholestanolemia in mice, allowing for a proper diagnosis of these animal models of CTX.…”

On the mechanism of cerebral accumulation of cholestanol in patients with cerebrotendinous xanthomatosis

“…In fact, there was some tendency toward an upregulation of enzyme activity. In agreement with these findings, Shefer and collaborators (28), in a comparative study of the effects of cholestanol and cholesterol on hepatic sterol metabolism in the rat, reported a 2.6-fold upregulation of HMG-CoA reductase activity. Therefore, it is evident that despite the structural similarity between cholesterol and its 5a-saturated derivative, cholestanol does not exert the same strong feedback inhibition on cholesterol biosynthesis as cholesterol.…”

Competitive inhibition of bile acid synthesis by endogenous cholestanol and sitosterol in sitosterolemia with xanthomatosis. Effect on cholesterol 7 alpha-hydroxylase.

“…However, cholesterol 7a-hydroxylase activity reflects the rate of bile acid synthesis since increased or decreased enzyme activity, as measured in vitro, correlates with higher or lower bile acid production rates determined in vivo (2,33). The conversion of sitosterol and cholestanol to primary bile acids has been demonstrated in humans (34) and rats (35,36) …”