title: Enhanced susceptibility of LDL to oxidative modification in a CTX patient:- role of chenodeoxycholic acid in xanthoma formation.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan. makkino@med.teikyo-u.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Kawamura
authors.forename: Mineko
authors.initials: M
authors.lastname: Fujita
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hirota
authors.forename: Takaoki
authors.initials: T
authors.lastname: Suda
authors.forename: Masanari
authors.initials: M
authors.lastname: Taki
authors.forename: Jyun
authors.initials: J
authors.lastname: Kusano
authors.forename: Kosuke
authors.initials: K
authors.lastname: Takao
authors.forename: Hideki
authors.initials: H
authors.lastname: Takenaka
authors.forename: Shunichiro
authors.initials: S
authors.lastname: Kubota
authors.forename: Tamio
authors.initials: T
authors.lastname: Teramoto
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000008:administration & dosage*; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL / Q000187:drug effects / Q000378:metabolism*; D005765:Gastrointestinal Agents / Q000008:administration & dosage*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D016896:Treatment Outcome; D014973:Xanthomatosis / Q000503:physiopathology; D019294:Xanthomatosis, Cerebrotendinous / Q000188:drug therapy / Q000378:metabolism*
chemical_list: C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL; D005765:Gastrointestinal Agents; D006023:Glycoproteins; D002635:Chenodeoxycholic Acid