Full text data of CYP7A1
CYP7A1
(CYP7)
[Confidence: low (only semi-automatic identification from reviews)]
Cholesterol 7-alpha-monooxygenase; 1.14.13.17 (CYPVII; Cholesterol 7-alpha-hydroxylase; Cytochrome P450 7A1)
Cholesterol 7-alpha-monooxygenase; 1.14.13.17 (CYPVII; Cholesterol 7-alpha-hydroxylase; Cytochrome P450 7A1)
UniProt
P22680
ID CP7A1_HUMAN Reviewed; 504 AA.
AC P22680; P78454; Q3MIL8; Q7KZ19;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-1994, sequence version 2.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=Cholesterol 7-alpha-monooxygenase;
DE EC=1.14.13.17;
DE AltName: Full=CYPVII;
DE AltName: Full=Cholesterol 7-alpha-hydroxylase;
DE AltName: Full=Cytochrome P450 7A1;
GN Name=CYP7A1; Synonyms=CYP7;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8439551; DOI=10.1016/0167-4781(93)90281-H;
RA Nishimoto M., Noshiro M., Okuda K.;
RT "Structure of the gene encoding human liver cholesterol 7 alpha-
RT hydroxylase.";
RL Biochim. Biophys. Acta 1172:147-150(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, AND VARIANT ASN-347.
RX PubMed=2384150; DOI=10.1016/0014-5793(90)80992-R;
RA Noshiro M., Okuda K.;
RT "Molecular cloning and sequence analysis of cDNA encoding human
RT cholesterol 7 alpha-hydroxylase.";
RL FEBS Lett. 268:137-140(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT SER-100.
RX PubMed=1610352; DOI=10.1016/0006-291X(92)91665-D;
RA Karam W.G., Chiang J.Y.;
RT "Polymorphisms of human cholesterol 7 alpha-hydroxylase.";
RL Biochem. Biophys. Res. Commun. 185:588-595(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-140.
RC TISSUE=Placenta;
RX PubMed=8020987; DOI=10.1006/geno.1994.1177;
RA Wang D.P., Chiang J.Y.;
RT "Structure and nucleotide sequences of the human cholesterol 7 alpha-
RT hydroxylase gene (CYP7).";
RL Genomics 20:320-323(1994).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-25.
RX PubMed=1312351; DOI=10.1021/bi00124a014;
RA Molowa D.T., Chen W.S., Cimis G.M., Tan C.P.;
RT "Transcriptional regulation of the human cholesterol 7 alpha-
RT hydroxylase gene.";
RL Biochemistry 31:2539-2544(1992).
RN [7]
RP INDUCTION BY CHENODEOXYCHOLIC ACID AND CHOLESTYRAMINE, AND TISSUE
RP SPECIFICITY.
RX PubMed=15796896; DOI=10.1016/j.bbrc.2005.02.170;
RA Abrahamsson A., Gustafsson U., Ellis E., Nilsson L.M., Sahlin S.,
RA Bjorkhem I., Einarsson C.;
RT "Feedback regulation of bile acid synthesis in human liver: importance
RT of HNF-4alpha for regulation of CYP7A1.";
RL Biochem. Biophys. Res. Commun. 330:395-399(2005).
RN [8]
RP INDUCTION BY GLUCOSE, AND FUNCTION.
RX PubMed=19965590; DOI=10.1194/jlr.M002782;
RA Li T., Chanda D., Zhang Y., Choi H.S., Chiang J.Y.;
RT "Glucose stimulates cholesterol 7alpha-hydroxylase gene transcription
RT in human hepatocytes.";
RL J. Lipid Res. 51:832-842(2010).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) IN COMPLEX WITH HEME, AND
RP COFACTOR.
RG Structural genomics consortium (SGC);
RT "Crystal structure of human CYP7A1.";
RL Submitted (FEB-2009) to the PDB data bank.
RN [10]
RP VARIANTS SER-233 AND ASN-347.
RX PubMed=12721789; DOI=10.1007/s10038-003-0021-7;
RA Saito S., Iida A., Sekine A., Kawauchi S., Higuchi S., Ogawa C.,
RA Nakamura Y.;
RT "Catalog of 680 variations among eight cytochrome p450 (CYP) genes,
RT nine esterase genes, and two other genes in the Japanese population.";
RL J. Hum. Genet. 48:249-270(2003).
CC -!- FUNCTION: Catalyzes a rate-limiting step in cholesterol catabolism
CC and bile acid biosynthesis by introducing a hydrophilic moiety at
CC position 7 of cholesterol. Important for cholesterol homeostasis.
CC -!- CATALYTIC ACTIVITY: Cholesterol + NADPH + O(2) = 7-alpha-
CC hydroxycholesterol + NADP(+) + H(2)O.
CC -!- COFACTOR: Heme group.
CC -!- PATHWAY: Lipid metabolism; bile acid biosynthesis.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral
CC membrane protein. Microsome membrane; Peripheral membrane protein.
CC -!- TISSUE SPECIFICITY: Detected in liver.
CC -!- INDUCTION: Up-regulated by glucose and by cholestyramine. Down-
CC regulated by chenodeoxycholic acid.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Cholesterol-7 alpha-hydroxylase
CC entry;
CC URL="http://en.wikipedia.org/wiki/Cholesterol_7_alpha-hydroxylase";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CYP7A1ID40254ch8q12.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; X56088; CAA39568.1; -; mRNA.
DR EMBL; M93133; AAA58435.1; -; mRNA.
DR EMBL; BC101777; AAI01778.1; -; mRNA.
DR EMBL; BC112184; AAI12185.1; -; mRNA.
DR EMBL; L13460; AAA61350.1; -; Genomic_DNA.
DR EMBL; M89647; AAA58423.1; -; Genomic_DNA.
DR PIR; S29818; JH0659.
DR RefSeq; NP_000771.2; NM_000780.3.
DR UniGene; Hs.1644; -.
DR PDB; 3DAX; X-ray; 2.15 A; A/B=25-503.
DR PDB; 3SN5; X-ray; 2.75 A; A/B=25-503.
DR PDB; 3V8D; X-ray; 1.90 A; A/B=25-503.
DR PDBsum; 3DAX; -.
DR PDBsum; 3SN5; -.
DR PDBsum; 3V8D; -.
DR ProteinModelPortal; P22680; -.
DR SMR; P22680; 25-503.
DR STRING; 9606.ENSP00000301645; -.
DR PhosphoSite; P22680; -.
DR DMDM; 544084; -.
DR PaxDb; P22680; -.
DR PRIDE; P22680; -.
DR Ensembl; ENST00000301645; ENSP00000301645; ENSG00000167910.
DR GeneID; 1581; -.
DR KEGG; hsa:1581; -.
DR UCSC; uc003xtm.4; human.
DR CTD; 1581; -.
DR GeneCards; GC08M059452; -.
DR HGNC; HGNC:2651; CYP7A1.
DR MIM; 118455; gene.
DR neXtProt; NX_P22680; -.
DR Orphanet; 209902; Hypercholesterolemia due to cholesterol 7alpha-hydroxylase deficiency.
DR PharmGKB; PA132; -.
DR eggNOG; COG2124; -.
DR HOGENOM; HOG000231026; -.
DR HOVERGEN; HBG051100; -.
DR InParanoid; P22680; -.
DR KO; K00489; -.
DR OMA; CQARQEA; -.
DR OrthoDB; EOG7J9VP6; -.
DR PhylomeDB; P22680; -.
DR BioCyc; MetaCyc:HS09659-MONOMER; -.
DR BRENDA; 1.14.13.17; 2681.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P22680; -.
DR UniPathway; UPA00221; -.
DR EvolutionaryTrace; P22680; -.
DR GeneWiki; Cholesterol_7_alpha-hydroxylase; -.
DR GenomeRNAi; 1581; -.
DR NextBio; 6495; -.
DR PRO; PR:P22680; -.
DR Bgee; P22680; -.
DR CleanEx; HS_CYP7A1; -.
DR Genevestigator; P22680; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0008123; F:cholesterol 7-alpha-monooxygenase activity; ISS:UniProtKB.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0006699; P:bile acid biosynthetic process; IDA:UniProtKB.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0071397; P:cellular response to cholesterol; ISS:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IDA:UniProtKB.
DR GO; GO:0006707; P:cholesterol catabolic process; ISS:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; ISS:UniProtKB.
DR GO; GO:0070857; P:regulation of bile acid biosynthetic process; IDA:UniProtKB.
DR GO; GO:0006805; P:xenobiotic metabolic process; TAS:Reactome.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR024204; Cyt_P450_CYP7A1-type.
DR InterPro; IPR002403; Cyt_P450_E_grp-IV.
DR Pfam; PF00067; p450; 1.
DR PIRSF; PIRSF000047; Cytochrome_CYPVIIA1; 1.
DR PRINTS; PR00465; EP450IV.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cholesterol metabolism; Complete proteome;
KW Endoplasmic reticulum; Heme; Iron; Lipid metabolism; Membrane;
KW Metal-binding; Microsome; Monooxygenase; NADP; Oxidoreductase;
KW Polymorphism; Reference proteome; Steroid metabolism;
KW Sterol metabolism.
FT CHAIN 1 504 Cholesterol 7-alpha-monooxygenase.
FT /FTId=PRO_0000051901.
FT METAL 444 444 Iron (heme axial ligand).
FT VARIANT 86 86 H -> N (in dbSNP:rs62621283).
FT /FTId=VAR_059152.
FT VARIANT 100 100 F -> S.
FT /FTId=VAR_001259.
FT VARIANT 233 233 N -> S (in dbSNP:rs8192874).
FT /FTId=VAR_018376.
FT VARIANT 347 347 D -> N (in dbSNP:rs8192875).
FT /FTId=VAR_018377.
FT CONFLICT 385 385 D -> S (in Ref. 2; CAA39568).
FT STRAND 34 41
FT TURN 42 45
FT HELIX 46 48
FT HELIX 52 63
FT STRAND 65 71
FT STRAND 74 79
FT HELIX 82 84
FT HELIX 85 89
FT STRAND 95 98
FT HELIX 99 109
FT HELIX 116 118
FT STRAND 119 121
FT HELIX 125 133
FT HELIX 135 153
FT HELIX 160 163
FT STRAND 167 170
FT HELIX 171 188
FT HELIX 195 197
FT HELIX 198 220
FT HELIX 225 227
FT HELIX 229 241
FT HELIX 244 247
FT HELIX 255 267
FT HELIX 272 287
FT HELIX 290 303
FT HELIX 305 321
FT STRAND 328 331
FT HELIX 337 341
FT HELIX 344 357
FT STRAND 358 360
FT STRAND 362 373
FT STRAND 378 381
FT STRAND 386 389
FT HELIX 392 395
FT TURN 398 400
FT STRAND 401 403
FT TURN 409 412
FT STRAND 417 419
FT HELIX 447 464
FT STRAND 465 469
FT TURN 470 473
FT HELIX 481 483
FT STRAND 485 488
FT STRAND 491 493
FT STRAND 496 501
SQ SEQUENCE 504 AA; 57661 MW; D8067E0FF6342949 CRC64;
MMTTSLIWGI AIAACCCLWL ILGIRRRQTG EPPLENGLIP YLGCALQFGA NPLEFLRANQ
RKHGHVFTCK LMGKYVHFIT NPLSYHKVLC HGKYFDWKKF HFATSAKAFG HRSIDPMDGN
TTENINDTFI KTLQGHALNS LTESMMENLQ RIMRPPVSSN SKTAAWVTEG MYSFCYRVMF
EAGYLTIFGR DLTRRDTQKA HILNNLDNFK QFDKVFPALV AGLPIHMFRT AHNAREKLAE
SLRHENLQKR ESISELISLR MFLNDTLSTF DDLEKAKTHL VVLWASQANT IPATFWSLFQ
MIRNPEAMKA ATEEVKRTLE NAGQKVSLEG NPICLSQAEL NDLPVLDSII KESLRLSSAS
LNIRTAKEDF TLHLEDGSYN IRKDDIIALY PQLMHLDPEI YPDPLTFKYD RYLDENGKTK
TTFYCNGLKL KYYYMPFGSG ATICPGRLFA IHEIKQFLIL MLSYFELELI EGQAKCPPLD
QSRAGLGILP PLNDIEFKYK FKHL
//
ID CP7A1_HUMAN Reviewed; 504 AA.
AC P22680; P78454; Q3MIL8; Q7KZ19;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-1994, sequence version 2.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=Cholesterol 7-alpha-monooxygenase;
DE EC=1.14.13.17;
DE AltName: Full=CYPVII;
DE AltName: Full=Cholesterol 7-alpha-hydroxylase;
DE AltName: Full=Cytochrome P450 7A1;
GN Name=CYP7A1; Synonyms=CYP7;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8439551; DOI=10.1016/0167-4781(93)90281-H;
RA Nishimoto M., Noshiro M., Okuda K.;
RT "Structure of the gene encoding human liver cholesterol 7 alpha-
RT hydroxylase.";
RL Biochim. Biophys. Acta 1172:147-150(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, AND VARIANT ASN-347.
RX PubMed=2384150; DOI=10.1016/0014-5793(90)80992-R;
RA Noshiro M., Okuda K.;
RT "Molecular cloning and sequence analysis of cDNA encoding human
RT cholesterol 7 alpha-hydroxylase.";
RL FEBS Lett. 268:137-140(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT SER-100.
RX PubMed=1610352; DOI=10.1016/0006-291X(92)91665-D;
RA Karam W.G., Chiang J.Y.;
RT "Polymorphisms of human cholesterol 7 alpha-hydroxylase.";
RL Biochem. Biophys. Res. Commun. 185:588-595(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-140.
RC TISSUE=Placenta;
RX PubMed=8020987; DOI=10.1006/geno.1994.1177;
RA Wang D.P., Chiang J.Y.;
RT "Structure and nucleotide sequences of the human cholesterol 7 alpha-
RT hydroxylase gene (CYP7).";
RL Genomics 20:320-323(1994).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-25.
RX PubMed=1312351; DOI=10.1021/bi00124a014;
RA Molowa D.T., Chen W.S., Cimis G.M., Tan C.P.;
RT "Transcriptional regulation of the human cholesterol 7 alpha-
RT hydroxylase gene.";
RL Biochemistry 31:2539-2544(1992).
RN [7]
RP INDUCTION BY CHENODEOXYCHOLIC ACID AND CHOLESTYRAMINE, AND TISSUE
RP SPECIFICITY.
RX PubMed=15796896; DOI=10.1016/j.bbrc.2005.02.170;
RA Abrahamsson A., Gustafsson U., Ellis E., Nilsson L.M., Sahlin S.,
RA Bjorkhem I., Einarsson C.;
RT "Feedback regulation of bile acid synthesis in human liver: importance
RT of HNF-4alpha for regulation of CYP7A1.";
RL Biochem. Biophys. Res. Commun. 330:395-399(2005).
RN [8]
RP INDUCTION BY GLUCOSE, AND FUNCTION.
RX PubMed=19965590; DOI=10.1194/jlr.M002782;
RA Li T., Chanda D., Zhang Y., Choi H.S., Chiang J.Y.;
RT "Glucose stimulates cholesterol 7alpha-hydroxylase gene transcription
RT in human hepatocytes.";
RL J. Lipid Res. 51:832-842(2010).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) IN COMPLEX WITH HEME, AND
RP COFACTOR.
RG Structural genomics consortium (SGC);
RT "Crystal structure of human CYP7A1.";
RL Submitted (FEB-2009) to the PDB data bank.
RN [10]
RP VARIANTS SER-233 AND ASN-347.
RX PubMed=12721789; DOI=10.1007/s10038-003-0021-7;
RA Saito S., Iida A., Sekine A., Kawauchi S., Higuchi S., Ogawa C.,
RA Nakamura Y.;
RT "Catalog of 680 variations among eight cytochrome p450 (CYP) genes,
RT nine esterase genes, and two other genes in the Japanese population.";
RL J. Hum. Genet. 48:249-270(2003).
CC -!- FUNCTION: Catalyzes a rate-limiting step in cholesterol catabolism
CC and bile acid biosynthesis by introducing a hydrophilic moiety at
CC position 7 of cholesterol. Important for cholesterol homeostasis.
CC -!- CATALYTIC ACTIVITY: Cholesterol + NADPH + O(2) = 7-alpha-
CC hydroxycholesterol + NADP(+) + H(2)O.
CC -!- COFACTOR: Heme group.
CC -!- PATHWAY: Lipid metabolism; bile acid biosynthesis.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral
CC membrane protein. Microsome membrane; Peripheral membrane protein.
CC -!- TISSUE SPECIFICITY: Detected in liver.
CC -!- INDUCTION: Up-regulated by glucose and by cholestyramine. Down-
CC regulated by chenodeoxycholic acid.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Cholesterol-7 alpha-hydroxylase
CC entry;
CC URL="http://en.wikipedia.org/wiki/Cholesterol_7_alpha-hydroxylase";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CYP7A1ID40254ch8q12.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; X56088; CAA39568.1; -; mRNA.
DR EMBL; M93133; AAA58435.1; -; mRNA.
DR EMBL; BC101777; AAI01778.1; -; mRNA.
DR EMBL; BC112184; AAI12185.1; -; mRNA.
DR EMBL; L13460; AAA61350.1; -; Genomic_DNA.
DR EMBL; M89647; AAA58423.1; -; Genomic_DNA.
DR PIR; S29818; JH0659.
DR RefSeq; NP_000771.2; NM_000780.3.
DR UniGene; Hs.1644; -.
DR PDB; 3DAX; X-ray; 2.15 A; A/B=25-503.
DR PDB; 3SN5; X-ray; 2.75 A; A/B=25-503.
DR PDB; 3V8D; X-ray; 1.90 A; A/B=25-503.
DR PDBsum; 3DAX; -.
DR PDBsum; 3SN5; -.
DR PDBsum; 3V8D; -.
DR ProteinModelPortal; P22680; -.
DR SMR; P22680; 25-503.
DR STRING; 9606.ENSP00000301645; -.
DR PhosphoSite; P22680; -.
DR DMDM; 544084; -.
DR PaxDb; P22680; -.
DR PRIDE; P22680; -.
DR Ensembl; ENST00000301645; ENSP00000301645; ENSG00000167910.
DR GeneID; 1581; -.
DR KEGG; hsa:1581; -.
DR UCSC; uc003xtm.4; human.
DR CTD; 1581; -.
DR GeneCards; GC08M059452; -.
DR HGNC; HGNC:2651; CYP7A1.
DR MIM; 118455; gene.
DR neXtProt; NX_P22680; -.
DR Orphanet; 209902; Hypercholesterolemia due to cholesterol 7alpha-hydroxylase deficiency.
DR PharmGKB; PA132; -.
DR eggNOG; COG2124; -.
DR HOGENOM; HOG000231026; -.
DR HOVERGEN; HBG051100; -.
DR InParanoid; P22680; -.
DR KO; K00489; -.
DR OMA; CQARQEA; -.
DR OrthoDB; EOG7J9VP6; -.
DR PhylomeDB; P22680; -.
DR BioCyc; MetaCyc:HS09659-MONOMER; -.
DR BRENDA; 1.14.13.17; 2681.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P22680; -.
DR UniPathway; UPA00221; -.
DR EvolutionaryTrace; P22680; -.
DR GeneWiki; Cholesterol_7_alpha-hydroxylase; -.
DR GenomeRNAi; 1581; -.
DR NextBio; 6495; -.
DR PRO; PR:P22680; -.
DR Bgee; P22680; -.
DR CleanEx; HS_CYP7A1; -.
DR Genevestigator; P22680; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0008123; F:cholesterol 7-alpha-monooxygenase activity; ISS:UniProtKB.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0006699; P:bile acid biosynthetic process; IDA:UniProtKB.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0071397; P:cellular response to cholesterol; ISS:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IDA:UniProtKB.
DR GO; GO:0006707; P:cholesterol catabolic process; ISS:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; ISS:UniProtKB.
DR GO; GO:0070857; P:regulation of bile acid biosynthetic process; IDA:UniProtKB.
DR GO; GO:0006805; P:xenobiotic metabolic process; TAS:Reactome.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR024204; Cyt_P450_CYP7A1-type.
DR InterPro; IPR002403; Cyt_P450_E_grp-IV.
DR Pfam; PF00067; p450; 1.
DR PIRSF; PIRSF000047; Cytochrome_CYPVIIA1; 1.
DR PRINTS; PR00465; EP450IV.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cholesterol metabolism; Complete proteome;
KW Endoplasmic reticulum; Heme; Iron; Lipid metabolism; Membrane;
KW Metal-binding; Microsome; Monooxygenase; NADP; Oxidoreductase;
KW Polymorphism; Reference proteome; Steroid metabolism;
KW Sterol metabolism.
FT CHAIN 1 504 Cholesterol 7-alpha-monooxygenase.
FT /FTId=PRO_0000051901.
FT METAL 444 444 Iron (heme axial ligand).
FT VARIANT 86 86 H -> N (in dbSNP:rs62621283).
FT /FTId=VAR_059152.
FT VARIANT 100 100 F -> S.
FT /FTId=VAR_001259.
FT VARIANT 233 233 N -> S (in dbSNP:rs8192874).
FT /FTId=VAR_018376.
FT VARIANT 347 347 D -> N (in dbSNP:rs8192875).
FT /FTId=VAR_018377.
FT CONFLICT 385 385 D -> S (in Ref. 2; CAA39568).
FT STRAND 34 41
FT TURN 42 45
FT HELIX 46 48
FT HELIX 52 63
FT STRAND 65 71
FT STRAND 74 79
FT HELIX 82 84
FT HELIX 85 89
FT STRAND 95 98
FT HELIX 99 109
FT HELIX 116 118
FT STRAND 119 121
FT HELIX 125 133
FT HELIX 135 153
FT HELIX 160 163
FT STRAND 167 170
FT HELIX 171 188
FT HELIX 195 197
FT HELIX 198 220
FT HELIX 225 227
FT HELIX 229 241
FT HELIX 244 247
FT HELIX 255 267
FT HELIX 272 287
FT HELIX 290 303
FT HELIX 305 321
FT STRAND 328 331
FT HELIX 337 341
FT HELIX 344 357
FT STRAND 358 360
FT STRAND 362 373
FT STRAND 378 381
FT STRAND 386 389
FT HELIX 392 395
FT TURN 398 400
FT STRAND 401 403
FT TURN 409 412
FT STRAND 417 419
FT HELIX 447 464
FT STRAND 465 469
FT TURN 470 473
FT HELIX 481 483
FT STRAND 485 488
FT STRAND 491 493
FT STRAND 496 501
SQ SEQUENCE 504 AA; 57661 MW; D8067E0FF6342949 CRC64;
MMTTSLIWGI AIAACCCLWL ILGIRRRQTG EPPLENGLIP YLGCALQFGA NPLEFLRANQ
RKHGHVFTCK LMGKYVHFIT NPLSYHKVLC HGKYFDWKKF HFATSAKAFG HRSIDPMDGN
TTENINDTFI KTLQGHALNS LTESMMENLQ RIMRPPVSSN SKTAAWVTEG MYSFCYRVMF
EAGYLTIFGR DLTRRDTQKA HILNNLDNFK QFDKVFPALV AGLPIHMFRT AHNAREKLAE
SLRHENLQKR ESISELISLR MFLNDTLSTF DDLEKAKTHL VVLWASQANT IPATFWSLFQ
MIRNPEAMKA ATEEVKRTLE NAGQKVSLEG NPICLSQAEL NDLPVLDSII KESLRLSSAS
LNIRTAKEDF TLHLEDGSYN IRKDDIIALY PQLMHLDPEI YPDPLTFKYD RYLDENGKTK
TTFYCNGLKL KYYYMPFGSG ATICPGRLFA IHEIKQFLIL MLSYFELELI EGQAKCPPLD
QSRAGLGILP PLNDIEFKYK FKHL
//
MIM
118455
*RECORD*
*FIELD* NO
118455
*FIELD* TI
*118455 CYTOCHROME P450, SUBFAMILY VIIA, POLYPEPTIDE 1; CYP7A1
;;CYP7;;
CHOLESTEROL 7-ALPHA-HYDROXYLASE;;
read moreCHOLESTEROL 7-ALPHA-MONOOXYGENASE
*FIELD* TX
DESCRIPTION
Cholesterol 7-alpha-hydroxylase is a microsomal cytochrome P450 that
catalyzes the first step in bile acid synthesis.
CLONING
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.
GENE FUNCTION
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.
GENE STRUCTURE
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).
MAPPING
Using both mouse-human somatic cell hybrids and in situ chromosomal
hybridization, Cohen et al. (1992) mapped the CYP7 gene to 8q11-q12.
MOLECULAR GENETICS
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).
*FIELD* RF
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. Noshiro, M.; Okuda, K.: Molecular cloning and sequence analysis
of cDNA encoding human cholesterol 7 alpha-hydroxylase. FEBS Lett. 268:
137-140, 1990.
11. Paumgartner, G.; Sauerbruch, T.: Gallstones: pathogenesis. Lancet 338:
1117-1121, 1991.
12. 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.
13. 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.
14. 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.
*FIELD* CN
Ada Hamosh - updated: 9/27/2010
John A. Phillips, III - updated: 7/9/2002
Patricia A. Hartz - updated: 7/1/2002
Stylianos E. Antonarakis - updated: 10/10/2000
Ada Hamosh - updated: 8/31/2000
Anne M. Stumpf - updated: 2/18/2000
Victor A. McKusick - updated: 11/17/1998
Victor A. McKusick - updated: 4/25/1998
*FIELD* CD
Victor A. McKusick: 9/22/1992
*FIELD* ED
alopez: 09/27/2010
alopez: 9/27/2010
alopez: 7/9/2002
carol: 7/1/2002
ckniffin: 6/5/2002
mgross: 10/10/2000
mgross: 8/31/2000
alopez: 8/11/2000
mcapotos: 3/15/2000
mcapotos: 2/21/2000
mcapotos: 2/18/2000
carol: 4/8/1999
terry: 11/18/1998
terry: 11/17/1998
carol: 6/24/1998
carol: 5/2/1998
terry: 4/25/1998
terry: 5/24/1996
carol: 5/11/1994
carol: 10/23/1992
carol: 9/22/1992
*RECORD*
*FIELD* NO
118455
*FIELD* TI
*118455 CYTOCHROME P450, SUBFAMILY VIIA, POLYPEPTIDE 1; CYP7A1
;;CYP7;;
CHOLESTEROL 7-ALPHA-HYDROXYLASE;;
read moreCHOLESTEROL 7-ALPHA-MONOOXYGENASE
*FIELD* TX
DESCRIPTION
Cholesterol 7-alpha-hydroxylase is a microsomal cytochrome P450 that
catalyzes the first step in bile acid synthesis.
CLONING
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.
GENE FUNCTION
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.
GENE STRUCTURE
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).
MAPPING
Using both mouse-human somatic cell hybrids and in situ chromosomal
hybridization, Cohen et al. (1992) mapped the CYP7 gene to 8q11-q12.
MOLECULAR GENETICS
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).
*FIELD* RF
1. 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.
2. 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.
3. 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.
4. 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.
5. Drover, V. A. B.; Wong, N. C. W.; Agellon, L. B.: A distinct thyroid
hormone response element mediates repression of the human cholesterol
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*FIELD* CN
Ada Hamosh - updated: 9/27/2010
John A. Phillips, III - updated: 7/9/2002
Patricia A. Hartz - updated: 7/1/2002
Stylianos E. Antonarakis - updated: 10/10/2000
Ada Hamosh - updated: 8/31/2000
Anne M. Stumpf - updated: 2/18/2000
Victor A. McKusick - updated: 11/17/1998
Victor A. McKusick - updated: 4/25/1998
*FIELD* CD
Victor A. McKusick: 9/22/1992
*FIELD* ED
alopez: 09/27/2010
alopez: 9/27/2010
alopez: 7/9/2002
carol: 7/1/2002
ckniffin: 6/5/2002
mgross: 10/10/2000
mgross: 8/31/2000
alopez: 8/11/2000
mcapotos: 3/15/2000
mcapotos: 2/21/2000
mcapotos: 2/18/2000
carol: 4/8/1999
terry: 11/18/1998
terry: 11/17/1998
carol: 6/24/1998
carol: 5/2/1998
terry: 4/25/1998
terry: 5/24/1996
carol: 5/11/1994
carol: 10/23/1992
carol: 9/22/1992