| Cholesterol 7-hydroxylase knockout mouse: a model for monohydroxy bile acid-related neonatal cholestasis. | |
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MedLine Citation:
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PMID: 9797378 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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R Arnon; T Yoshimura; A Reiss; K Budai; J H Lefkowitch; N B Javitt |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Gastroenterology Volume: 115 ISSN: 0016-5085 ISO Abbreviation: Gastroenterology Publication Date: 1998 Nov |
Date Detail:
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Created Date: 1998-11-30 Completed Date: 1998-11-30 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0374630 Medline TA: Gastroenterology Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 1223-8 Citation Subset: AIM; IM |
Affiliation:
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Division of Pediatric Gastroenterology and Nutrition, Columbia College of Physicians and Surgeons, Columbia University, New York, NY, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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DK 32995/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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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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