Alternative titles; symbols
HGNC Approved Gene Symbol: CYP7A1
Cytogenetic location: 8q12.1 Genomic coordinates (GRCh38): 8:58,490,178-58,500,163 (from NCBI)
Cholesterol 7-alpha-hydroxylase is a microsomal cytochrome P450 that catalyzes the first step in bile acid synthesis.
Noshiro and Okuda (1990) cloned human CYP7A1, using the rat homolog as probe. The deduced 504-amino acid protein has a calculated molecular mass of 57.6 kD and contains putative heme and steroid-binding domains. The human and rat proteins share 82% sequence identity.
By transfection of reporter constructs, mutation analysis, and DNase footprinting, Molowa et al. (1992) identified areas of the CYP7A1 promoter region that showed hepatocyte-specific activation. They found HNF3 (see 602294) to be an activator of CYP7A1 activity.
Nitta et al. (1999) identified a liver-specific regulatory element within the CYP7A promoter and isolated a transcription factor, CPF (also called LRH1 or NR5A2; 604453), that binds to the promoter of the human CYP7A gene. Cotransfection of a CPF expression plasmid and a CYP7A reporter gene resulted in specific induction of CYP7A-directed transcription. These and other observations suggested that CPF is a key regulator of human CYP7A gene expression in the liver.
In an elegant series of experiments designed to understand the effect of retinoid X receptor (RXR; see 180245) activation on cholesterol balance, Repa et al. (2000) treated animals with the rexinoid LG268. Animals treated with rexinoid exhibited marked changes in cholesterol balance, including inhibition of cholesterol absorption and repressed bile acid synthesis. Studies with receptor-selective agonists revealed that oxysterol receptors (LXRs, see 602423 and 600380) and the bile acid receptor, FXR (603826), are the RXR heterodimeric partners that mediate these effects by regulating expression of the reverse-cholesterol transporter, ABC1 (600046), and the rate-limiting enzyme of bile acid synthesis, CYP7A1, respectively. These RXR heterodimers serve as key regulators in cholesterol homeostasis by governing reverse cholesterol transport from peripheral tissues, bile acid synthesis in liver, and cholesterol absorption in intestine. Activation of RXR/LXR heterodimers inhibits cholesterol absorption by upregulation of ABC1 expression in the small intestine. Activation of RXR/FXR heterodimers represses CYP7A1 expression and bile acid production, leading to a failure to solubilize and absorb cholesterol. Studies have shown that RXR/FXR-mediated repression of CYP7A1 is dominant over RXR/LXR-mediated induction of CYP7A1, which explains why the rexinoid represses rather than activates CYP7A1 (Lu et al., 2000). Activation of the LXR signaling pathway results in the upregulation of ABC1 in peripheral cells, including macrophages, to efflux free cholesterol for transport back to the liver through high density lipoprotein, where it is converted to bile acids by the LXR-mediated increase in CYP7A1 expression. Secretion of biliary cholesterol in the presence of increased bile acid pools normally results in enhanced reabsorption of cholesterol; however, with the increased expression of ABC1 and efflux of cholesterol back into the lumen, there is a reduction in cholesterol absorption and net excretion of cholesterol and bile acid. Rexinoids therefore offer a novel class of agents for treating elevated cholesterol.
Agellon et al. (2002) found that wildtype mice and mice transgenic for human CYP7A1 respond differently to cholesterol feeding. Cholesterol feeding stimulated Cyp7a1 mRNA abundance and enzymatic activity in wildtype mice, but repressed human CYP7A1 mRNA and activity in transgenic mice. In transfected hepatoma cells, cholesterol increased mouse Cyp7a1 gene promoter activity, but had no effect on the human CYYP7A1 gene promoter. By electrophoretic mobility shift assays, Agellon et al. (2002) found interaction of LXR:RXR with the mouse promoter, but no binding to the human promoter.
The catabolism of cholesterol into bile acids is regulated by oxysterols and bile acids, which induce or repress transcription of the pathway's rate-limiting enzyme, CYP7A1. The nuclear receptor LXR-alpha (LXRA, or NR1H3; 602423) binds oxysterols and mediates feed-forward induction. Lu et al. (2000) showed that repression is coordinately regulated by a triumvirate of nuclear receptors, including the bile acid receptor, FXR; the promoter-specific activator, LRH1; and the promoter-specific repressor, SHP (NR0B2; 604630). Feedback repression of CYP7A1 is accomplished by the binding of bile acids to FXR, which leads to transcription of SHP. Elevated SHP protein then inactivates LRH1 by forming a heterodimeric complex that leads to promoter-specific repression of both CYP7A1 and SHP. These results revealed an elaborate autoregulatory cascade mediated by nuclear receptors for the maintenance of hepatic cholesterol catabolism.
Goodwin et al. (2000) used a potent, nonsteroidal FXR ligand to show that FXR induces expression of SHP1, an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP1 represses expression of CYP7A1 by inhibiting the activity of LRH1, an orphan nuclear receptor that regulates CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.
Drover et al. (2002) examined the molecular basis by which triiodothyronine (T3) regulates the human CYP7A1 promoter. T3 decreased chloramphenicol acetyltransferase (CAT) activity in hepatoma cells cotransfected with a plasmid encoding the T3 receptor TR-alpha and a chimeric gene containing nucleotides -372 to +61 of the human CYP7A1 gene fused to the CAT structural gene. DNase I footprinting revealed that recombinant TR-alpha protected 2 regions in this segment of the human CYP7A1 gene promoter. The binding was competed by oligonucleotides bearing an idealized TR-alpha binding motif and abolished by mutation of these elements. The results indicated that T3-dependent repression of human CYP7A1 gene expression is mediated via a novel site in the human CYP7A1 gene promoter.
Inborn errors in bile acid synthesis represent one category of metabolic liver disease. Specific defects are recognized in the enzymes catalyzing reactions responsible for changes to the steroid nucleus of cholesterol and its intermediates in the pathway leading to the formation of cholic and chenodeoxycholic acids: 3-beta-hydroxy-delta-5 ceroid dehydrogenase/isomerase in neonatal giant cell hepatitis (231100) and delta(4)-3-oxysteroid 5-beta-reductase in neonatal cholestatic hepatitis (235555). Other specific defects have been identified in enzymes catalyzing reactions responsible for changes to the side chain of cholesterol and its intermediates in this pathway, e.g., sterol 27-hydroxylase in cerebrotendinous xanthomatosis (213700). These familial conditions are clinically manifest as syndromes of progressive cholestatic liver disease, neurologic disease, and fat-soluble vitamin malabsorption. Early diagnosis is important because patients with these disorders can be successfully treated by oral administration of cholic acid; normalization in serum liver enzymes and bilirubin, and resolution of the histologic lesion are consistent responses to bile acid therapy, and the need for liver transplantation in most cases can be circumvented. Recognition of defects in bile acid synthesis has relied on mass spectrometric analysis of the urine and serum to establish an absence or marked reduction in synthesis of the normal primary bile acids, cholic and chenodeoxycholic acids, concomitant with the presence of excessive amounts of atypical bile acids and sterols that are synthesized as a consequence of the enzyme deficiency.
Cohen et al. (1992) determined that the CYP7 gene spans 10 kb and contains 6 exons. The exon-intron boundaries are completely conserved between human and rat genes. Sequencing of the 5-prime flanking region revealed consensus recognition sequences for a number of liver-specific transcription factors.
Molowa et al. (1992) identified a TATA box and a modified CAAT box in the promoter region of the CYP7 gene. They also identified a modified sterol response element and 3 potential recognition sites for hepatocyte nuclear factor-3 (HNF3A; 602294).
Using both mouse-human somatic cell hybrids and in situ chromosomal hybridization, Cohen et al. (1992) mapped the CYP7 gene to 8q11-q12.
Cohen et al. (1992) found 4 single-stranded conformation-dependent DNA polymorphisms and an Alu sequence-related polymorphism in the CYP7 gene. Of the 20 unrelated Caucasians analyzed, 80% were heterozygous for at least one of these 5 polymorphisms. The localization and characterization of the CYP7 gene as well as the identification of polymorphisms provided molecular tools for investigating the role of the gene in disorders of cholesterol and bile acid metabolism. Paumgartner and Sauerbruch (1991) suggested that cholesterol 7-alpha-hydroxylase is a candidate for a defect in gallstone disease and Angelin et al. (1978, 1987) suggested that it might be involved in familial hypertriglyceridemia. The central role of the enzyme in cholesterol homeostasis renders the CYP7 gene a candidate for determination of both primary hyper- and hypocholesterolemia.
Wang et al. (1998) investigated the relationship between plasma concentrations of low density lipoprotein cholesterol (LDLC) and 3 genes with pivotal roles in LDL metabolism: the low density lipoprotein receptor (LDLR; 606945), apolipoprotein B (APOB; 107730), and CYP7. Their investigation involved sib-pair linkage analyses, variant component linkage analyses, and association studies. Analysis of 150 nuclear families indicated statistically significant linkage between plasma LDLC concentrations and CYP7, but not LDLR or APOB. Further sib-pair analyses using individuals with high plasma LDLC concentrations as probands indicated that the CYP7 locus is linked to high plasma LDLC, but not to low plasma LDLC concentrations. This finding was replicated in an independent sample. DNA sequencing revealed 2 linked polymorphisms in the 5-prime flanking region of CYP7. The allele defined by these polymorphisms was associated with increased plasma LDLC concentrations, both in sib pairs and in unrelated individuals. Common polymorphisms in LDLR and APOB account for little of the heritable variability in plasma LDLC concentrations in the general population. On the other hand, the findings of the study by Wang et al. (1998) indicate that polymorphisms in CYP7 contribute to heritable variability in these concentrations.
Teslovich et al. (2010) performed a genomewide association study for plasma lipids in more than 100,000 individuals of European ancestry and reported 95 significantly associated loci (P = less than 5 x 10(-8)), with 59 showing genomewide significant association with lipid traits for the first time. The newly reported associations included SNPs near known lipid regulators (e.g., CYP7A1; NPC1L1, 608010; and SCARB1, 601040) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contributed not only to normal variation in lipid traits but also to extreme lipid phenotypes and had an impact on lipid traits in 3 non-European populations (East Asians, South Asians, and African Americans).
Agellon, L. B., Drover, V. A. B., Cheema, S. K., Gbaguidi, G. F., Walsh, A. Dietary cholesterol fails to stimulate the human cholesterol 7-alpha-hydroxylase gene (CYP7A1) in transgenic mice. J. Biol. Chem. 277: 20131-20134, 2002. [PubMed: 11967256] [Full Text: https://doi.org/10.1074/jbc.C200105200]
Angelin, B., Einarsson, K., Hellstrom, K., Leijd, B. Bile acid kinetics in relation to endogenous triglyceride metabolism in various types of hyperlipoproteinemia. J. Lipid Res. 19: 1004-1016, 1978. [PubMed: 731122]
Angelin, B., Hershon, K. S., Brunzell, J. D. Bile acid metabolism in hereditary forms of hypertriglyceridemia: evidence for an increased synthesis rate in monogenic familial hypertriglyceridemia. Proc. Nat. Acad. Sci. 84: 5434-5438, 1987. [PubMed: 3474660] [Full Text: https://doi.org/10.1073/pnas.84.15.5434]
Cohen, J. C., Cali, J. J., Jelinek, D. F., Mehrabian, M., Sparkes, R. S., Lusis, A. J., Russell, D. W., Hobbs, H. H. Cloning of the human cholesterol 7-alpha-hydroxylase gene (CYP7) and localization to chromosome 8q11-q12. Genomics 14: 153-161, 1992. [PubMed: 1358792] [Full Text: https://doi.org/10.1016/s0888-7543(05)80298-8]
Drover, V. A. B., Wong, N. C. W., Agellon, L. B. A distinct thyroid hormone response element mediates repression of the human cholesterol 7-alpha-hydroxylase (CYP7A1) gene promoter. Molec. Endocr. 16: 14-23, 2002. [PubMed: 11773435] [Full Text: https://doi.org/10.1210/mend.16.1.0751]
Goodwin, B., Jones, S. A., Price, R. R., Watson, M. A., McKee, D. D., Moore, L. B., Galardi, C., Wilson, J. G., Lewis, M. C., Roth, M. E., Maloney, P. R., Willson, T. M., Kliewer, S. A. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Molec. Cell 6: 517-526, 2000. [PubMed: 11030332] [Full Text: https://doi.org/10.1016/s1097-2765(00)00051-4]
Lu, T. T., Makishima, M., Repa, J. J., Schoonjans, K., Kerr, T. A., Auwerx, J., Mangelsdorf, D. J. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Molec. Cell 6: 507-515, 2000. [PubMed: 11030331] [Full Text: https://doi.org/10.1016/s1097-2765(00)00050-2]
Molowa, D. T., Chen, W. S., Cimis, G. M., Tan, C. P. Transcriptional regulation of the human cholesterol 7 alpha-hydroxylase gene. Biochemistry 31: 2539-2544, 1992. [PubMed: 1312351] [Full Text: https://doi.org/10.1021/bi00124a014]
Nitta, M., Ku, S., Brown, C., Okamoto, A. Y., Shan, B. CPF: an orphan nuclear receptor that regulates liver-specific expression of the human cholesterol 7-alpha-hydroxylase gene. Proc. Nat. Acad. Sci. 96: 6660-6665, 1999. [PubMed: 10359768] [Full Text: https://doi.org/10.1073/pnas.96.12.6660]
Noshiro, M., Okuda, K. Molecular cloning and sequence analysis of cDNA encoding human cholesterol 7 alpha-hydroxylase. FEBS Lett. 268: 137-140, 1990. [PubMed: 2384150] [Full Text: https://doi.org/10.1016/0014-5793(90)80992-r]
Paumgartner, G., Sauerbruch, T. Gallstones: pathogenesis. Lancet 338: 1117-1121, 1991. [PubMed: 1682550] [Full Text: https://doi.org/10.1016/0140-6736(91)91972-w]
Repa, J. J., Turley, S. D., Lobaccaro, J.-M. A., Medina, J., Li, L., Lustig, K., Shan, B., Heyman, R. A., Dletschy, J. M., Mangelsdorf, D. J. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289: 1524-1529, 2000. [PubMed: 10968783] [Full Text: https://doi.org/10.1126/science.289.5484.1524]
Teslovich, T. M., Musunuru, K., Smith, A. V., Edmondson, A. C., Stylianou, I. M., Koseki, M., Pirruccello, J. P., Ripatti, S., Chasman, D. I., Willer, C. J., Johansen, C. T., Fouchier, S. W., and 197 others. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466: 707-713, 2010. [PubMed: 20686565] [Full Text: https://doi.org/10.1038/nature09270]
Wang, J., Freeman, D. J., Grundy, S. M., Levine, D. M., Guerra, R., Cohen, J. C. Linkage between cholesterol 7-alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations. J. Clin. Invest. 101: 1283-1291, 1998. [PubMed: 9502769] [Full Text: https://doi.org/10.1172/JCI1343]