Disease relevance of Cyp7a1

• Here we report that co-expression of PPARalpha and LXRalpha in hepatoma cells abolishes the stimulation of Cyp7a1 gene promoter in response to their respective agonists [1].
• Gene expression of hepatic Cyp7a1 in both WT and KO mice decreased to less than 5% of the corresponding controls at 6-12 h after treatment with LN (100 mumol/kg body weight, iv) [2].
• Taken together, these data demonstrate a pivotal role for PXR in the regulation of drug-induced hepatomegaly and in the metabolism (CYP3A), transport (Oatp2), biosynthesis (Cyp7a1), and excretion of xenobiotics and bile acids in vivo [3].
• Since a bile acid (cholic acid) is required for the diet induced changes in HDL levels and for atherogenesis in these strains, we examined cholesterol-7-alpha hydroxylase (C7AH) expression [4].
• BACKGROUND & AIMS: Cyp 7-/- mice lack a functional cholesterol 7alpha-hydroxylase enzyme and develop cholestasis before up-regulation of 27-hydroxycholesterol 7alpha-hydroxylase activity [5].

High impact information on Cyp7a1

• The synthesis and excretion of bile acids were found to be dramatically elevated in these mutants, and the expression of 2 key bile acid synthase genes, cholesterol 7alpha-hydroxylase (Cyp7a1) and sterol 12alpha-hydroxylase (Cyp8b1), was strongly upregulated [6].
• Therefore, betaKlotho may stand as a novel contributor to Cyp7a1-selective regulation [6].
• The expression of Cyp7a1 and Cyp8b1 is known to be repressed by dietary bile acids via both SHP-dependent and -independent regulations [6].
• None of these loci were linked to the C7AH structural gene which we mapped to proximal chromosome 4 [4].
• We confirmed previous findings that dietary cholesterol increased mouse Cyp7a1 activity in Het mice but decreased human Cyp7a1 activity in Tg+KO mice [7].

Chemical compound and disease context of Cyp7a1

• Interestingly, hepatic cholestasis was observed in 100% of the bezafibrate-fed (-/-) mice, and this was accompanied by significantly elevated hepatic expression of mRNA encoding bile salt export pump and lower expression of mRNA encoding cytochrome P450 7A1, consistent with enhanced activation of the bile acid receptor, farnesoid X receptor [8].

Biological context of Cyp7a1

• Cholesterol feeding increased the expression of the endogenous modified Cyp7a1 allele but failed to stimulate the human CYP7A1 transgene [9].
• When administered orally to mice, both compounds (BAPA-3>BAPA-6) reduced the bile acid pool size, which was accompanied by up-regulation of hepatic Cyp7a1 and Hmgcr and intestinal Ostalpha/Ostbeta [10].
• ES cells expressing green fluorescent protein (GFP) under the control of the Cyp7a1 enhancer/promoter showed that cultured EBs contained GFP-positive epithelial-like cells [11].
• Among the intercross mice, multiple loci contributed to the regulation of C7AH mRNA levels in response to the diet, the most notable of which coincided with the loci on chromosomes 3, 5, and 11 controlling HDL levels in response to the diet [4].
• Aspects of lipid metabolism in the Cyp7-/- mice are characterized here to deduce the physiological basis of this phenotype [12].

Anatomical context of Cyp7a1

• Expression of the liver-specific gene Cyp7a1 reveals hepatic differentiation in embryoid bodies derived from mouse embryonic stem cells [11].
• The expression of cytochrome P450 7a1, a possible marker for embryonic endoderm-derived mature hepatocytes, was only observed in cES cells that had differentiated in a co-culture with MFLCs [13].
• The report of a novel cytochrome P450 enzyme in mouse hippocampus (cyp7b) with close homology to cholesterol 7 alpha-hydroxylase led us to determine the substrate specificity with respect to 27-hydroxycholesterol, known to be a potent inhibitor of cholesterol synthesis [14].
• Unlike macrophages, the hepatic parenchymal cells express cholesterol-7 alpha-hydroxylase (CYP7A1) which regulates the conversion of cholesterol into bile acids, the major quantitative pathway maintaining cholesterol homeostasis [15].

Associations of Cyp7a1 with chemical compounds

• These results challenge the notion that dietary cholesterol regulation of Cyp7a1 is a major determinant of plasma cholesterol responsiveness [7].
• Cholesterol 7 alpha-hydroxylase (Cyp7a1) plays a central role in the regulation of bile acid and cholesterol metabolism, and transcription of the gene is controlled by bile acids and hormones acting through a complex interaction with a number of potential steroid-hormone-binding sites [16].
• Treatment of mice with phenobarbital or TCPOBOP resulted in decreased hepatic mRNA levels of the reported genes down-regulated by CAR, including Cyp7a1 and Pepck [17].
• Although bile acid pool size contracted markedly in all the Cyp7a1(-/-) mice, the female Cyp7a1(-/-) mice maintained a larger, more cholic acid-rich pool than their male counterparts [18].
• Bile acid synthesis in Cyp7a1(+/+) males and females was increased 2-fold by cholesterol feeding, and 4-fold by cholestyramine treatment, but was not changed in matching Cyp7a1(-/-) mice by either of these manipulations [18].

Enzymatic interactions of Cyp7a1

• Cholesterol 7alpha-hydroxylase (Cyp7a1) catalyzes the rate-limiting step in the intrahepatic conversion of cholesterol to bile acids that may have a role in HDL metabolism [19].

Regulatory relationships of Cyp7a1

• Consistent with this, mice lacking the SHP gene exhibit mild defects in bile acid homeostasis and fail to repress cholesterol 7-alpha-hydroxylase expression in response to a specific agonist for the bile acid receptor FXR [20].
• Several families of nuclear receptor proteins have been shown to modulate this critical process by regulating hepatic cholesterol catabolism and bile acid synthesis through the transcriptional control of cholesterol 7-alpha hydroxylase (CYP7A1) [21].

Other interactions of Cyp7a1

• Upon short-term (2 days) treatment with leptin, a dose-dependent increase was seen in the SR-BI protein and mRNA, whereas the Cyp7a1 protein and mRNA were reduced [22].
• Targeted disruption of the HNF1alpha gene results in decreased Cyp1a2, and Cyp2e1 expression, and increased Cyp4a1 and Cyp7a1 expression, suggesting these enzymes are HNF1alpha target genes [23].
• This was characterized by a reduced expression of Cyp7b1, and elevation of Cyp7a1 and Cyp8b1 expression [24].
• Intestinal cholesterol absorption in the Cyp7a1(-/-) males fell from 46% to 3%, and in the matching females from 58% to 17% [18].
• A sensitive solution hybridization assay using autologous cRNA probes was developed with the aim to study the simultaneous regulation of hepatic mRNA levels, on a quantitative basis, for the LDL receptor (LDLr), HMG-CoA reductase, and cholesterol 7 alpha-hydroxylase (Cho-7-hx) in C57BL/6J mice [25].

Analytical, diagnostic and therapeutic context of Cyp7a1

• Real-time RT-PCR revealed that the okara intake induced down-regulation of the fatty acid synthetase gene and up-regulation of the cholesterol 7 alpha-hydroxylase (CYP7A1) gene in the liver [26].
• Western blot analysis of hepatic microsomal fractions with the PB2a antibody gave three bands, two of which, like cholesterol 7 alpha-hydroxylase, did not inhibit sexual dimorphism [27].
• When fed the atherogenic diet, nontransgenic littermates, but not cholesterol-7-alpha-hydroxylase transgenic mice, accumulated cholesterol and cholesterol esters in their livers and plasma [28].

References