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: Hironori Nagasaka, Takashi Miida, Ken-ichi Hirano, Akemi Ota, Kei Murayama, Tohru Yorifuji, Kunihiko Kobayashi, Tomozumi Takatani, Hirokazu Tsukahara, Shu-Ping Hui, Masaki Takayanagi, Hitoshi Chiba
• Journal: Atherosclerosis (Atherosclerosis) Vol. 198 Issue 2 Pg. 434-40 (Jun 2008) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 18430427 (Publication Type: Journal Article)

Chemical References

• Bile Acids and Salts
• DNA-Binding Proteins
• Lipoproteins
• Liver X Receptors
• Orphan Nuclear Receptors
• Receptors, Cytoplasmic and Nuclear
• Transcription Factors
• farnesoid X-activated receptor

Topics

• Adult
• Alagille Syndrome (metabolism, pathology)
• Bile Acids and Salts (blood, metabolism)
• Blotting, Western
• Child
• Child, Preschool
• DNA-Binding Proteins (agonists, metabolism)
• Female
• Humans
• Lipoproteins (blood, metabolism)
• Liver (metabolism, pathology)
• Liver X Receptors
• Male
• Orphan Nuclear Receptors
• Receptors, Cytoplasmic and Nuclear (agonists, metabolism)
• Transcription Factors (agonists, metabolism)