CYP7A1 (cytochrome P450, family 7, subfamily A, polypeptide 1)

2010-01-01   Maria Norlin , Kjell Wikvall 

Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Uppsala, Sweden

Identity

HGNC
LOCATION
8q12.1
LOCUSID
ALIAS
CP7A,CYP7,CYPVII

DNA/RNA

Description

The human CYP7A1 DNA maps to NM_000780 (Entrez Gene) and spans a region of 9.98 kB. CYP7A1 is located on chromosome 8 and consists of six exons.

Transcription

The full length CYP7A1 mRNA is 2,875 bp with an open reading frame of 1,512 bp (Noshiro and Okuda, 1990).

Pseudogene

No pseudogenes reported.

Proteins

Description

The human CYP7A1 protein consists of 504 amino acids and has a molecular weight of 57,630 Da (Noshiro and Okuda, 1990). Human CYP7A1 shares 40% sequence identity with CYP7B1, the other member of the CYP7 family.

Expression

Most reports indicate exclusive liver specific expression. One study reports expression of CYP7A1 also in human prostate (Steckelbroeck et al., 2002). The expression of hepatic CYP7A1 in several species has been reported to be low in early life and to increase severalfold with age (Norlin, 2002; Massimi et al., 1998).

Localisation

CYP7A1 is a endoplasmic reticulum membrane enzyme.

Function

CYP7A1 is a cholesterol 7alpha-hydroxylase, catalyzing the first and rate-limiting step in the neutral or classic pathway for bile acid biosynthesis. Bile acid biosynthesis is the predominant pathway for cholesterol catabolism. The enzyme also 7alpha-hydroxylates 27-hydroxycholesterol and other oxysterols (Norlin et al., 2000a, b). Results supporting a role for CYP7A1 as an oxysterol 7alpha-hydroxylase are also reported by others (Dueland et al., 1992; Pandak et al., 2002). Studies on mice with a disruption in the Cyp7a1 gene (Ishibashi et al., 1996; Schwarz et al., 1996) demonstrated a crucial role for this enzyme in bile acid biosynthesis. Mice and humans with cholesterol 7alpha-hydroxylase deficiency exhibit, however, different phenotypes (Norlin and Wikvall, 2007).
Several mechanisms for regulation of CYP7A1 have been described (Chiang, 2004). Bile acids inhibit CYP7A1 gene transcription via negative feedback control. The feedback inhibition by bile acids involve several nuclear receptors such as liver receptor homolog 1 (LRH-1), hepatocyte nuclear factor 4alpha (HNF4alpha), small heterodimer partner (SHP) and the bile acid receptor farnesyl X receptor (FXR). Also the pregnane X receptor (PXR) and the vitamin D receptor (VDR) have been identified as bile acid-activated receptors (Staudinger et al., 2001; Han and Chiang, 2009). Bile acids are also reported to suppress CYP7A1 via stimulation of inflammatory cytokines (tumor necrosis factor alpha and IL-1beta) and mitogen-activated protein kinase (MAPK) signaling pathways leading to the activation of cJun N-terminus kinase (JNK). JNK may phosphorylate and inactivate transcription factors crucial for stimulating the hepatic expression of CYP7A1 (Chiang, 2004; Gupta et al., 2004). Cholestyramine, a drug used in the treatment of hyperlipoproteinemia, induces cholesterol 7alpha-hydroxylase by binding to bile acids in the intestine and preventing their reabsorption to the liver (Brown and Boyd, 1974). Evidence for a posttranscriptional regulation of cholesterol 7alpha-hydroxylase has been reported, but most of the data available suggest that the regulation is predominantly on a transcriptional level (Chiang, 2004; Stroup and Ramsaran, 2005).

Homology

The CYP7A1 gene is conserved in many species, such as chimpanzee, dog, cow, mouse, rat, chicken, and zebrafish.

Mutations

Germinal

A metabolic disorder presenting with elevated plasma cholesterol levels caused by a homozygous deletion mutation in the CYP7A1 gene in a family of English and Celtic origin has been described (Pullinger et al., 2002). The mutation leads to a frameshift resulting in the synthesis of a truncated protein with no enzymatic activity. High levels of LDL cholesterol were seen in three homozygous subjects. The high levels of LDL cholesterol in the CYP7A1-deficient subjects were found to be resistant to treatment with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Two male subjects had hypertriglyceridemia and premature gallstone disease. One subject had premature coronary and peripheral vascular disease. Individuals that are heterozygous for the mutation were also found to be hyperlipidemic, indicating that the disorder is inherited in a codominant fashion (Pullinger et al., 2002). The authors concluded that CYP7A1 deficiency in humans causes hypercholesterolemia. This conclusion is consistent with studies showing an association between cholesterol levels and polymorphisms at the CYP7A1 locus (Wang et al., 1998; Couture et al., 1999).

Implicated in

Entity name
Gallbladder cancer
Note
CYP7A1 promoter polymorphism has been reported to be a genetic risk factor for gallbladder cancer. The association of the polymorphism with gallbladder cancer was more pronounced in female patients, and also in cancer patients who developed gallbladder cancer at advanced age (Srivastava et al., 2008).
Entity name
Colorectal cancer
Note
A link between genetic polymorphism of CYP7A1 and decreased risk of colorectal adenomas has been reported (Tabata et al., 2006). Bile acids have long been implicated in colorectal carcinogenesis. The CC genotype of the CYP7A1 A-203C polymorphism was associated with a decreased risk of proximal colon adenomas. The findings provide further evidence for the role of bile acids in colorectal carcinogenesis. The polymorphism of the CYP7A1 gene probably leads to lower activity of the enzyme synthesizing bile acids (Tabata et al., 2006).
Entity name
Hypercholesterolemia/hyperlipidemia
Note
Due to its important regulatory role in cholesterol catabolism, decreased CYP7A1 levels may lead to hypercholesterolemia. Indeed, high cholesterol levels were seen in subjects having a frameshift mutation in the CYP7A1 gene resulting in the synthesis of a non-functional enzyme. The hypercholesterolemia were resistant to treatment with HMG-CoA reductase inhibitors. Two of the three subjects that were homozygous for this mutation also had elevated plasma triglyceride levels. Six individuals, heterozygous for the mutation were also found to have hypercholesterolemia (Pullinger et al, 2002). An association between plasma cholesterol levels and polymorphisms at the CYP7A1 locus have been shown in some reports (Wang et al., 1998; Couture et al., 1999) whereas another study reported that common polymorphisms in the CYP7A1 gene do not contribute to variations in plasma LDL concentrations (Abrahamsson et al., 2005).
Entity name
Atherosclerosis
Note
One subject with the frameshift mutation in the CYP7A1 gene (as described above) had premature coronary and peripheral vascular disease (Pullinger et al., 2002). Polymorphism in the CYP7A1 gene has been reported to be associated with subclinical atherosclerosis including the presence of atherosclerotic plaques in postmenopausal women (Lambrinoudaki et al., 2008). CYP7A1 polymorphism has also been reported to increase the progression of atherosclerosis and the risk of new clinical events in male patients (Hofman et al., 2005).

Bibliography

Pubmed IDLast YearTitleAuthors
161154732005Common polymorphisms in the CYP7A1 gene do not contribute to variation in rates of bile acid synthesis and plasma LDL cholesterol concentration.Abrahamsson A et al
41531471974The specificity of the rat-liver cholesterol 7alpha-hydroxylase.Brown MJ et al
151233732004Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms.Chiang JY et al
105082081999Association of the A-204C polymorphism in the cholesterol 7alpha-hydroxylase gene with variations in plasma low density lipoprotein cholesterol levels in the Framingham Offspring Study.Couture P et al
14296191992Expression of 7 alpha-hydroxylase in non-hepatic cells results in liver phenotypic resistance of the low density lipoprotein receptor to cholesterol repression.Dueland S et al
146605822004Deoxycholic acid activates the c-Jun N-terminal kinase pathway via FAS receptor activation in primary hepatocytes. Role of acidic sphingomyelinase-mediated ceramide generation in FAS receptor activation.Gupta S et al
191061152009Mechanism of vitamin D receptor inhibition of cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes.Han S et al
157073882005Genetic variation in the rate-limiting enzyme in cholesterol catabolism (cholesterol 7alpha-hydroxylase) influences the progression of atherosclerosis and risk of new clinical events.Hofman MK et al
86634291996Disruption of cholesterol 7alpha-hydroxylase gene in mice. I. Postnatal lethality reversed by bile acid and vitamin supplementation.Ishibashi S et al
187281232008Methylenetetrahydrofolate reductase C677T polymorphism is associated with central adiposity and increased androgenicity in healthy postmenopausal women.Lambrinoudaki I et al
97552441998Cholesterol 7alpha-hydroxylase (CYP7A): patterns of messenger RNA expression during rat liver development.Massimi M et al
108827192000Oxysterol 7 alpha-hydroxylase activity by cholesterol 7 alpha-hydroxylase (CYP7A).Norlin M et al
11013305200024-hydroxycholesterol is a substrate for hepatic cholesterol 7alpha-hydroxylase (CYP7A).Norlin M et al
173461712007Enzymes in the conversion of cholesterol into bile acids.Norlin M et al
119719432002Expression of key enzymes in bile acid biosynthesis during development: CYP7B1-mediated activities show tissue-specific differences.Norlin M et al
23841501990Molecular cloning and sequence analysis of cDNA encoding human cholesterol 7 alpha-hydroxylase.Noshiro M et al
120296252002Regulation of oxysterol 7alpha-hydroxylase (CYP7B1) in primary cultures of rat hepatocytes.Pandak WM et al
120938942002Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype.Pullinger CR et al
86634301996Disruption of cholesterol 7alpha-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7alpha-hydroxylase.Schwarz M et al
181784992008Role of genetic variant A-204C of cholesterol 7alpha-hydroxylase (CYP7A1) in susceptibility to gallbladder cancer.Srivastava A et al
112480852001The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.Staudinger JL et al
123905332002Characterization of the dehydroepiandrosterone (DHEA) metabolism via oxysterol 7alpha-hydroxylase and 17-ketosteroid reductase activity in the human brain.Steckelbroeck S et al
157527492005Cholesterol 7alpha-hydroxylase is phosphorylated at multiple amino acids.Stroup D et al
166301392006Genetic polymorphism of cholesterol 7alpha-hydroxylase (CYP7A1) and colorectal adenomas: Self Defense Forces Health Study.Tabata S et al
95027691998Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations.Wang J et al

Other Information

Locus ID:

NCBI: 1581
MIM: 118455
HGNC: 2651
Ensembl: ENSG00000167910

Variants:

dbSNP: 1581
ClinVar: 1581
TCGA: ENSG00000167910
COSMIC: CYP7A1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000167910ENST00000301645P22680

Expression (GTEx)

0
1
2
3

Pathways

PathwaySourceExternal ID
Primary bile acid biosynthesisKEGGko00120
Steroid hormone biosynthesisKEGGko00140
PPAR signaling pathwayKEGGko03320
Primary bile acid biosynthesisKEGGhsa00120
Steroid hormone biosynthesisKEGGhsa00140
PPAR signaling pathwayKEGGhsa03320
Metabolic pathwaysKEGGhsa01100
Bile secretionKEGGko04976
Bile secretionKEGGhsa04976
Bile acid biosynthesis, cholesterol => cholate/chenodeoxycholateKEGGhsa_M00104
Bile acid biosynthesis, cholesterol => cholate/chenodeoxycholateKEGGM00104
MetabolismREACTOMER-HSA-1430728
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Fatty acid, triacylglycerol, and ketone body metabolismREACTOMER-HSA-535734
Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)REACTOMER-HSA-400206
PPARA activates gene expressionREACTOMER-HSA-1989781
Bile acid and bile salt metabolismREACTOMER-HSA-194068
Synthesis of bile acids and bile saltsREACTOMER-HSA-192105
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterolREACTOMER-HSA-193368
Synthesis of bile acids and bile salts via 27-hydroxycholesterolREACTOMER-HSA-193807
Biological oxidationsREACTOMER-HSA-211859
Phase 1 - Functionalization of compoundsREACTOMER-HSA-211945
Cytochrome P450 - arranged by substrate typeREACTOMER-HSA-211897
Endogenous sterolsREACTOMER-HSA-211976

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA166160055cholic acidChemicalLabelAnnotationassociated
PA448500atorvastatinChemicalClinicalAnnotationassociatedPD15262185, 16103896, 21128988, 26932749

References

Pubmed IDYearTitleCitations
206865652010Biological, clinical and population relevance of 95 loci for blood lipids.1468
128150722003Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis.200
120938942002Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype.110
195982352009Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome.92
191850052009High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis.83
128654252003Coordinated control of cholesterol catabolism to bile acids and of gluconeogenesis via a novel mechanism of transcription regulation linked to the fasted-to-fed cycle.48
218136432011Conversion of 7-dehydrocholesterol to 7-ketocholesterol is catalyzed by human cytochrome P450 7A1 and occurs by direct oxidation without an epoxide intermediate.41
145229882003PGC-1alpha activates CYP7A1 and bile acid biosynthesis.38
125547952003Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-alpha.36
230382642012Nuclear receptors HNF4α and LRH-1 cooperate in regulating Cyp7a1 in vivo.36

Citation

Maria Norlin ; Kjell Wikvall

CYP7A1 (cytochrome P450, family 7, subfamily A, polypeptide 1)

Atlas Genet Cytogenet Oncol Haematol. 2010-01-01

Online version: http://atlasgeneticsoncology.org/gene/40254/cyp7a1