Document Detail


Cholesterol 7-hydroxylase knockout mouse: a model for monohydroxy bile acid-related neonatal cholestasis.
MedLine Citation:
PMID:  9797378     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Cyp 7-/- mice lack a functional cholesterol 7alpha-hydroxylase enzyme and develop cholestasis before up-regulation of 27-hydroxycholesterol 7alpha-hydroxylase activity. Because 7alpha-hydroxylation is not the initial step in this metabolic pathway, we tested the hypothesis that cholesterol 27-hydroxylase is expressed at an earlier step and leads to the production of monohydroxy bile acids. METHODS: Polymerase chain reaction with specific oligonucleotides was used to detect messenger RNA (mRNA) coding for cholesterol 27-hydroxylase in 5-day-old normal and Cyp 7-/- mice. Gas-liquid chromatography-mass spectrometry and reverse isotope dilution were used to identify intermediates in the cholesterol 27-hydroxylase metabolic pathway. Light and electron microscopy were used to evaluate the morphological appearance of the liver. RESULTS: mRNA for cholesterol 27-hydroxylase was identified in the liver and spleen. The monohydroxy bile acids 3beta-hydroxy-5-cholenoate and 3alpha-hydroxy-5beta-cholanoate together with their precursor, 27-hydroxycholesterol, were identified in liver homogenates. Cholestasis, present focally, was manifested as dilated bile canaliculi, partial loss of microvilli, and retention of electron-dense biliary material. CONCLUSIONS: The cholesterol 27-hydroxylase metabolic pathway of bile acid synthesis is expressed in neonatal life. The absence of 7alpha-hydroxylase activities unmasks the cholestatic potential of monohydroxy bile acids. The Cyp 7-/- knockout mouse mimics cholestatic events known to occur in humans and provides a unique opportunity for studying regulatory determinants.
Authors:
R Arnon; T Yoshimura; A Reiss; K Budai; J H Lefkowitch; N B Javitt
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Gastroenterology     Volume:  115     ISSN:  0016-5085     ISO Abbreviation:  Gastroenterology     Publication Date:  1998 Nov 
Date Detail:
Created Date:  1998-11-30     Completed Date:  1998-11-30     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1223-8     Citation Subset:  AIM; IM    
Affiliation:
Division of Pediatric Gastroenterology and Nutrition, Columbia College of Physicians and Surgeons, Columbia University, New York, NY, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Newborn / physiology*
Bile Acids and Salts / physiology*
Bile Canaliculi / pathology,  ultrastructure
Cholestasis / genetics*,  metabolism
Cholic Acids / metabolism
Chromatography, Thin Layer
Cytochrome P-450 Enzyme System / genetics*
Disease Models, Animal
Gas Chromatography-Mass Spectrometry
Hydroxycholesterols / metabolism
Lithocholic Acid / metabolism
Liver / metabolism,  pathology
Mice
Mice, Mutant Strains / genetics*
RNA, Messenger / metabolism
Reference Values
Spleen / metabolism
Steroid 12-alpha-Hydroxylase / genetics*
Grant Support
ID/Acronym/Agency:
DK 32995/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Bile Acids and Salts; 0/Cholic Acids; 0/Hydroxycholesterols; 0/RNA, Messenger; 20380-11-4/27-hydroxycholesterol; 434-13-9/Lithocholic Acid; 5255-17-4/3 beta-hydroxy-delta 5-cholenic acid; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.-/Steroid 12-alpha-Hydroxylase; EC 1.14.99.-/7 alpha-hydroxy-4-cholesten-3-one-12 alpha monooxygenase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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