title: Cytochrome P450s in the synthesis of cholesterol and bile acids--from mouse models to human diseases.
abstract: The present review describes the transgenic mouse models that have been designed to evaluate the functions of the cytochrome P450s involved in cholesterol and bile acid synthesis, as well as their link with disease. The knockout of cholesterogenic Cyp51 is embrionally lethal, with symptoms of Antley-Bixler syndrome occurring in mice, whereas the evidence for this association is conflicting in humans. Disruption of Cyp7a1 from classic bile acid synthesis in mice leads to either increased postnatal death or a milder phenotype with elevated serum cholesterol. The latter is similar to the case in humans, where CYP7A1 mutations associate with high plasma low-density lipoprotein and hepatic cholesterol content, as well as deficient bile acid excretion. Disruption of Cyp8b1 from an alternative bile acid pathway results in the absence of cholic acid and a reduced absorption of dietary lipids; however, the human CYP8B1 polymorphism fails to explain differences in bile acid composition. Unexpectedly, apparently normal Cyp27a1(-/-)  mice still synthesize bile acids that originate from the compensatory pathway. In humans, CYP27A1 mutations cause cerebrotendinous xanthomatosis, suggesting that only mice can compensate for the loss of alternative bile acid synthesis. In line with this, Cyp7b1 knockouts are also apparently normal, whereas human CYP7B1 mutations lead to a congenital bile acid synthesis defect in children or spastic paraplegia in adults. Mouse knockouts of the brain-specific Cyp46a1 have reduced brain cholesterol excretion, whereas, in humans, CYP46A1 polymorphisms associate with cognitive impairment. At present, cytochrome P450 family 39 is poorly characterized. Despite important physiological differences between humans and mice, mouse models prove to be an invaluable tool for understanding the multifactorial facets of cholesterol and bile acid-related disorders.
authors: Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors: Gregor
authors: G
authors: Lorbek
authors: Monika
authors: M
authors: Lewinska
authors: Damjana
authors: D
authors: Rozman
mesh_terms: D000328:Adult; D000818:Animals; D054882:Antley-Bixler Syndrome Phenotype / Q000235:genetics; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002635:Chenodeoxycholic Acid / Q000096:biosynthesis; D002648:Child; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D000072556:Cholesterol 24-Hydroxylase; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D019826:Cholic Acid / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072474:Cytochrome P450 Family 7; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics
chemical_list: D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D000072474:Cytochrome P450 Family 7; D000072556:Cholesterol 24-Hydroxylase; C499573:CYP39A1 protein, human; C097207:Cyp7b1 protein, mouse; D053493:Cholestanetriol 26-Monooxygenase; D013253:Steroid 12-alpha-Hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase; D019826:Cholic Acid