title: Fluctuation of lipoprotein metabolism linked with bile acid-activated liver nuclear receptors in Alagille syndrome.
abstract: Alagille syndrome (AGS) is a rare hereditary disorder exhibiting fluctuating cholestasis and dyslipidemia. Farnesoid X receptor (FXR) and liver X receptor (LXR) are hepatic nuclear receptors that regulate bile acid and lipoprotein metabolism. To investigate whether cholestasis is related to dyslipidemia and hepatic nuclear receptor expression in AGS patients, we determined the blood levels of total bile acid (TBA) and lipoprotein parameters, and examined hepatic nuclear receptor expression in three AGS children and their three incomplete AGS parents repeatedly over several years. In the AGS children, TBA level showed significant positive correlations with low-density lipoprotein-cholesterol, apolipoprotein E (apoE)-rich high-density lipoprotein-cholesterol (HDL-C), apoA-I, apoE, and cholesteryl ester transfer protein (CETP) concentrations, but negative correlation with apoE-poor HDL-C concentration. Western blot analysis of liver biopsy specimens revealed that FXR and LXR expression increased in parallel with TBA level. CETP- and ATP-binding cassette transporter A1 expression also increased with TBA level, while scavenger receptor class B type-I expression showed the opposite response. However, apoA-I expression was similar to the control level at any TBA level. In the incomplete AGS parents, TBA and lipoprotein parameters showed little fluctuation. In summary, cholestasis is closely related to dyslipidemia and hepatic nuclear receptor expression in AGS patients.
authors.affiliation: Division of Metabolism, Chiba Children's Hospital, Chiba 266-0007, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Nagasaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Miida
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hirano
authors.forename: Akemi
authors.initials: A
authors.lastname: Ota
authors.forename: Kei
authors.initials: K
authors.lastname: Murayama
authors.forename: Tohru
authors.initials: T
authors.lastname: Yorifuji
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Tomozumi
authors.initials: T
authors.lastname: Takatani
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tsukahara
authors.forename: Shu-Ping
authors.initials: SP
authors.lastname: Hui
authors.forename: Masaki
authors.initials: M
authors.lastname: Takayanagi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Chiba
mesh_terms: D000328:Adult; D016738:Alagille Syndrome / Q000378:metabolism* / Q000473:pathology; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D000071518:Liver X Receptors; D008297:Male; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated