Disease relevance of Cyp27a1

• Hepatic synthesis of fatty acids and accumulation of triacylglycerols increases in Cyp27(-/-) mice and is associated with hypertriglyceridemia [1].
• Disruption of the sterol 27-hydroxylase gene in mice results in hepatomegaly and hypertriglyceridemia. Reversal by cholic acid feeding [1].
• Side chain hydroxylations in bile acid biosynthesis catalyzed by CYP3A are markedly up-regulated in Cyp27-/- mice but not in cerebrotendinous xanthomatosis [2].
• Sterol 27-hydroxylase deficiency: a rare cause of xanthomas in normocholesterolemic humans [3].
• In vivo and in vitro regulation of sterol 27-hydroxylase in the liver during the acute phase response. potential role of hepatocyte nuclear factor-1 [4].

High impact information on Cyp27a1

• The mRNA levels for cholesterol 7alpha-hydroxylase, oxysterol 7alpha-hydroxylase, sterol 12alpha-hydroxylase, and sterol 27-hydroxylase, respectively, were comparable in these strains, both on standard and 2% cholesterol chow [5].
• In support of this hypothesis, three potentially toxic sterols (7alpha-hydroxy-4-cholesten-3-one, 5beta-cholestan-3alpha,7alpha,12alpha-triol, and 4-cholesten-3-one), including two that are known to accumulate in Cyp27a1(-/-) mice, are efficacious activators of mouse PXR [6].
• These studies revealed elevated expression levels in B6By liver for key bile acid synthesis proteins, including cholesterol 7alpha-hydroxylase and sterol-27-hydroxylase, and the oxysterol nuclear receptor liver X receptor alpha [7].
• Human sterol 27-hydroxylase (CYP27) overexpressor transgenic mouse model. Evidence against 27-hydroxycholesterol as a critical regulator of cholesterol homeostasis [8].
• Unlike Cyp27(-/-) mice, CYP3A activity was not up-regulated despite marked accumulation of 5beta-cholestane-3alpha,7alpha,12alpha-triol in CTX [2].

Chemical compound and disease context of Cyp27a1

• Cholic acid feeding reverses hepatomegaly and hypertriglyceridemia but not adrenomegaly in Cyp27(-/-) mice [1].

Biological context of Cyp27a1

• We examined lipid metabolism in mice lacking the Cyp27 gene [1].
• The contrast between the biologic effect on cholesterol synthesis by these two C27 hydroxysterols and the wide tissue distribution of both cholesterol 27-hydroxylase and hydroxysterol 7 alpha-hydroxylase implies local regulatory effects prior to their further catabolism in the liver to chenodeoxycholic and cholic acids [9].
• Human sterol 27-hydroxylase cDNAs were isolated from a liver cDNA library by cross-hybridization with a previously cloned rabbit cDNA probe [10].
• DNA sequence analysis of hybridization-positive clones predicted a human sterol 27-hydroxylase consisting of a 33-amino-acid mitochondrial signal sequence followed by a mature protein of 498 amino acids [10].
• Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase expression [11].

Anatomical context of Cyp27a1

• In bile and feces of the cyp27(-/-) mice only traces of bile alcohols were found, and there was no cholestanol accumulation [12].
• A compensatory 2.5-fold increase in whole body cholesterol synthesis occurs in Cyp27(-/-) mice, principally in liver, adrenal, small intestine, lung, and spleen [1].
• RNA blotting experiments demonstrated sterol 27-hydroxylase mRNAs of approximately 1.8 to 2.2 kilobases in liver and fibroblast cells [10].
• Introduction of the sterol 27-hydroxylase cDNA into Simian COS cells resulted in the expression of active enzyme capable of catalyzing multiple oxidation reactions (R-CH3----R-CH2OH----R-COOH) at carbon 27 of sterol intermediates of the bile acid synthesis pathway [10].
• Agents that increase foam cell formation also down-regulate cholesterol 27-hydroxylase and ABCA1 expression [13].

Associations of Cyp27a1 with chemical compounds

• The mRNAs for cholesterol 7alpha-hydroxylase, sterol 27-hydroxylase, and HMG-CoA reductase decreased to 47, 46, and 58% of controls, respectively, on day 7, coinciding with peak FC concentrations [14].
• On normal rodent chow, Cyp27(-/-) mice have 40% larger livers, 45% larger adrenals, 2-fold higher hepatic and plasma triacylglycerol concentrations, a 70% higher rate of hepatic fatty acid synthesis, and a 70% increase in the ratio of oleic to stearic acid in the liver versus Cyp27(+/+) controls [1].
• Sterol 27-hydroxylase is important for the degradation of the steroid side chain in conversion of cholesterol into bile acids and has been ascribed a regulatory role in cholesterol homeostasis [12].
• Mice with a disrupted cyp27 (cyp27(-/-)) had normal plasma levels of cholesterol, retinol, tocopherol, and 1,25-dihydroxyvitamin D [12].
• Mitochondrial 27-hydroxycholesterol and 5beta-cholestane-3alpha,7alpha,12alpha,27-tetrol were virtually absent in both Cyp27(-/-) mice and CTX patients [15].

Other interactions of Cyp27a1

• Long-term (> 4 months) administration of P-407 to C57BL/6 mice appears to have no effect on the biologic activity of S27H and HMG-CoA reductase, but decreases the activity of C7alphaH [16].

References