| First Author | Arnon R | Year | 1998 |
| Journal | Gastroenterology | Volume | 115 |
| Issue | 5 | Pages | 1223-8 |
| PubMed ID | 9797378 | Mgi Jnum | J:51019 |
| Mgi Id | MGI:1313230 | Doi | 10.1016/s0016-5085(98)70094-0 |
| Citation | Arnon R, et al. (1998) Cholesterol 7-hydroxylase knockout mouse: a model for monohydroxy bile acid-related neonatal cholestasis. Gastroenterology 115(5):1223-8 |
| abstractText | Background & Aims: Cyp 7-/- mice lack a functional cholesterol 7 alpha-hydroxylase enzyme and develop cholestasis before up-regulation of 27-hydroxycholesterol 7 alpha-hydroxylase activity. Because 7 alpha- hydroxylation is not the initial step in this metabolic pathway, we tested the hypothesis that cholesterol 7 alpha- 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 3 beta-hydroxy-5-cholenoate and 27-hydpoxy-5 beta- 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 7 alpha-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. |
