title: Negative feedback loop of cholesterol regulation is impaired in the livers of patients with Alagille syndrome.
abstract: OBJECTIVE
  To characterize cholesterol regulation in the liver of patients with Alagille syndrome (AGS).
  
  
  METHODS
  Serum total cholesterol (TC) and total bile acid (TBA) levels were measured in 23 AGS patients. The expressions of genes involved in cholesterol regulation, including low-density lipoprotein receptor (LDLR), scavenger receptor class B type I (SR-BI), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), cholesterol 7α-hydroxylase (CYP7A1), ATP-binding cassette transporter (ABC) A1, and ABCG1/5/8, were measured in liver tissues from five of these patients. Expression of regulators for these genes, including farnesoid X receptor/small heterodimer partner (SHP), liver X receptor α (LXRα) and mature Sterol regulatory element-binding protein 2 (SREBP2) was measured. The expression of mature SREBP2 protein was also examined.
  
  
  RESULTS
  Serum TC and TBA levels were correlated in the AGS patients. Liver cholesterol was also increased compared with controls, and correlated with bile acid contents. LDLR, SR-BI, HMGCR, and ABCGs mRNA expression were upregulated, while CYP7A1 mRNA expression was downregulated in AGS livers. SHP and LXRα mRNA expression was also increased, but maturation of SREBP2 was not suppressed in the patients.
  
  
  CONCLUSIONS
  The major upregulators of liver cholesterol might be increased in AGS patients, indicating an impaired negative feedback mechanism and accelerated liver cholesterol accumulation.
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Miyahara
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Bessho
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka, Japan. Electronic address: kondou@ped.med.osaka-u.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kondou
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka, Japan.
authors.forename: Kie
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Department of Pediatric Gastroenterology, Nutrition and Endocrinology, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodou, Izumi City, Osaka, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Ida
authors.affiliation: Department of Transplant Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke City, Tochigi, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ihara
authors.affiliation: Department of Transplant Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke City, Tochigi, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Mizuta
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Miyoshi
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
mesh_terms: D000293:Adolescent; D016738:Alagille Syndrome / Q000378:metabolism* / Q000503:physiopathology; D001647:Bile Acids and Salts / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism; D007223:Infant; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D001647:Bile Acids and Salts; C573412:LDLR protein, human; D011973:Receptors, LDL; C495124:SCARB1 protein, human; C497390:SREBF2 protein, human; D051122:Scavenger Receptors, Class B; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase
keywords: 3-hydroxy-3-methylglutaryl coenzyme A reductase; Alagille syndrome; Hypercholesterolemia; Low-density lipoprotein receptor; Scavenger receptor class B type I