Cerebrotendinous xanthomatosis (CTX) is a rare familial
sterol storage disease, causing multiple
xanthomas in tendons and the brain. The underlying biochemical defect is a lack of the hepatic mitochondrial
cholesterol 27-hydroxylase involved in the normal biosynthesis of
bile acid, resulting in reduced biosynthesis of
chenodeoxycholic acid (CDCA). It has been reported that administration of CDCA to CTX patients improves
neurological disorders and
xanthomas of the Achilles tendon. The present study investigated the effect of CDCA on the mechanism of
cholesterol accumulation in macrophages, the major cells in
xanthoma. The
LDL from the patients in this study was significantly more susceptible to oxidative modification than normal
LDL, and supplement
therapy with CDCA resulted in an improvement in the susceptibility to oxidative modification. In the incubation of CDCA with plasma, 13% of the CDCA added to serum was recovered in the
LDL fraction. In addition, supplementation with CDCA enhanced
cholesteryl ester transfer protein (CETP) activity and reduced
high-density-lipoprotein cholesterol levels in the plasma. This evidence suggests that the multiple
xanthomas observed in CTX may be induced by increased
oxidized LDL and the low activity of CETP, both of which are caused by a lack of CDCA.