Author/Editor		Lorbek, Gregor; Lewinska, Monika; Rozman, Damjana
Title		Cytochromes P450 in Synthesis of Cholesterol and Bile Acids: From Mouse Models to Human Diseases
Type		članek
Source		FEBS J
Vol. and No.		Letnik 279, št. 9 spec issue
Publication year		2012
Volume		str. 1516-33
Language		eng
Abstract		This review describes the transgenic mouse models designed to evaluate the functions of cytochromes P450 involved in cholesterol and bile acid synthesis, and their link to disease. The knockout of cholesterogenic Cyp51 is embrionally lethal with symptoms of Antley-Bixler syndrome in mice, while the evidence for this association is conflicting in humans. Disruption of Cyp7a1 from classic bile acid (BA) synthesis in mice leads to either increased postnatal death or to a milder phenotype with elevated serum cholesterol. The latter is similar to humans, where CYP7A1 mutations associate with high plasma LDL and hepatic cholesterol content, and a deficient BA excretion. Disruption of Cyp8b1 from alternative BA pathway results in absence of cholic acid and a reduced absorption of dietary lipids, however, the human CYP8B1 polymorphism fails to explain differences in BA composition. Surprisingly, the apparently normal Cyp27a1(-/-) mice still synthesize BAs that originate from the compensatory pathway. In humans CYP27A1 mutations cause cerebrotendinous xanthomatosis, suggesting that only mice can compensate for the loss of alternative BA synthesis. In line with this, Cyp7b1 knockouts are also apparently normal while human CYP7B1 mutations cause congenital bile acid synthesis defect in children or spastic paraplegia in adults. Mouse knockouts of the brain-specific Cyp46a1 have reduced brain cholesterol excretion, while in humans CYP46A1 polymorphisms associate with cognitive impairment. CYP39 is at present 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 BA related disorders.
Descriptors		BILE ACIDS AND SALTS CYTOCHROME P-450 CHOLESTEROL CHOLESTEROL 7 ALPHA-MONOOXYGENASE DIETARY FATS POLYMORPHISM (GENETICS) MICE, TRANSGENIC XANTHOMATOSIS MUTATION PARAPLEGIA