FXR ja atorvastatiini

http://www.ncbi.nlm.nih.gov/pubmed/25278499

Atorvastatin induces bile acid-synthetic enzyme Cyp7a1 by suppressing FXR signaling in both liver and intestine in mice.

Fu ZD¹, Cui JY², Klaassen CD².

Abstract

Statins are effective cholesterol-lowering drugs to treat CVDs. Bile acids (BAs), the end products of cholesterol metabolism in the liver, are important nutrient and energy regulators. The present study aims to investigate how statins affect BA homeostasis in the enterohepatic circulation.

Male C57BL/6 mice were treated with atorvastatin (100 mg/kg/day po) for 1 week, followed by BA profiling by ultra-performance LC-MS/MS.

Atorvastatin decreased BA pool size, mainly due to less BA in the intestine. Surprisingly, atorvastatin did not alter total BAs in the serum or liver.

 Atorvastatin increased the ratio of 12α-OH/non12α-OH BAs.
 Atorvastatin increased the mRNAs of the BA-synthetic enzymes  
cholesterol 7α-hydroxylase (Cyp7a1) (over 10-fold) and 
 cytochrome P450 27a1, (Cyp27a1; Sterol 27-hydroxylase)
 the BA uptake transporters:
 Na⁺/taurocholate cotransporting polypeptide (Ntcp)
and organic anion transporting polypeptide 1b2, (Oatp 1)
and the efflux transporter multidrug resistance-associated protein 2 (Abcc2) ) in the liver.

Noticeably, atorvastatin suppressed the expression of BA nuclear receptor farnesoid X receptor (FXR) target genes,
 namely small heterodimer partner (liver) (Shp, Short heterodimer partner)
 and fibroblast growth factor 15 (ileum). (Fgf15)

 Furthermore, atorvastatin increased
the mRNAs of the organic cation uptake transporter 1
 and cholesterol efflux transporters Abcg5, ( ATP-binding cassette subfamily G member 5)
 and Abcg8 in the liver ( ATP-binding cassette subfamily G member 8).

The increased expression of BA-synthetic enzymes and BA transporters appear to be a compensatory response to maintain BA homeostasis after atorvastatin treatment.
 The Cyp7a1 induction by atorvastatin appears to be due to suppressed FXR signaling in both the liver and intestine.

Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

KEYWORDS:

cholesterol 7α-hydroxylase; farnesoid X receptor signaling; ultra-performance liquid chromatography-tandem mass spectrometry

FXR ja pravastatiini

http://www.ncbi.nlm.nih.gov/pubmed/24463082
Pravastatiini on vesiliukoinen, päinvastoin kuin muut statiinit.

BACKGROUND: 

  Statins are suggested to preserve gallbladder function by suppressing pro-inflammatory cytokines and preventing cholesterol accumulation in gallbladder epithelial cells. They also affect cross-talk among the nuclear hormone receptors that regulate cholesterol-bile acid metabolism in the nuclei of hepatocytes. However, there is controversy over whether or how statins change the expression of peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, liver X receptor alpha (LXRalpha), farnesoid X receptor (FXR), ABCG5, ABCG8, and 7alpha-hydroxylase (CYP7A1) which are directly involved in the cholesterol saturation index in bile.

METHODS: Human Hep3B cells were cultured on dishes. MTT assays were performed to determine the appropriate concentrations of reagents to be used. The protein expression of PPARalpha and PPARgamma was measured by Western blotting analysis, and the mRNA expression of LXRalpha, FXR, ABCG5, ABCG8 and CYP7A1 was estimated by RT-PCR.

RESULTS: In cultured Hep3B cells, pravastatin activated PPARalpha and PPARgamma protein expression, induced stronger expression of PPARgamma than that of PPARalpha, increased LXRalpha mRNA expression, activated ABCG5 and ABCG8 mRNA expression mediated by FXR as well as LXRalpha, enhanced FXR mRNA expression, and increased CYP7A1 mRNA expression mediated by the PPARgamma and LXRalpha pathways, together or independently.

CONCLUSION: Our data suggested that pravastatin prevents cholesterol gallstone diseases via the increase of FXR, LXRalpha and CYP7A1 in human hepatocytes.

PMID:

24463082

[PubMed - indexed for MEDLINE]

Free full text.
Toinen lähde:  

J Gastroenterol Hepatol. 2011 Oct;26(10):1544-51. doi: 10.1111/j.1440-1746.2011.06748.x.

• Pravastatin modulates liver bile acid and cholesterol homeostasis in rats with chronic cholestasis. Kolouchova G¹, Brcakova E,  et al.

BACKGROUND AND AIM: The administration of pravastatin to patients with cholestatic liver disease has suggested the potential of the drug with regard to reducing raised plasma cholesterol and bile acid levels. Information about the mechanisms associated with this effect is lacking. Thus, the aim of the present study is to evaluate pravastatin effects on the liver bile acid and cholesterol homeostasis in healthy and cholestatic rats.

METHODS: Control sham-operated and reversibly bile duct-obstructed (BDO) rats were treated with pravastatin (1 or 5 mg/kg) or the vehicle alone for 7 days after surgery.

RESULTS: Lower doses of pravastatin reduced bile acid plasma concentrations in cholestatic animals. The effect was associated with reduced liver mRNA expression of Cyp7a1, Cyp8b1, Mrp2, Ugt1a1 and the increased expression of Bsep (Abcb11) 

 In addition, BDO-induced increase in the liver content of cholesterol was normalized by pravastatin. The change was accompanied by the reduced liver expression of Hmg-CoA reductase, LDL receptor, and Acat2, and induced the expression of Abca1 and Mdr2. These changes corresponded with the upregulation of nuclear receptors LXRα and PPARα, and the downregulation of FXR, CAR, SREBP-2 (sterol regulatory element.binding protein ) and HNF1α (Hepatic Nuclear Factor).

 High doses of pravastatin lacked any positive effects on bile acids and cholesterol homeostasis, and blocked bile formation through the reduction of the biliary excretion of bile acids.

CONCLUSIONS: Pravastatin rendered a positive reduction in BDO-induced increases in plasma bile acid concentrations and cholesterol liver content, mainly through the transcriptionally-mediated downregulation of genes involved in the synthesis of these compounds in the liver.

© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Comment in

• Effects of statins on cholestasis: good, bad or indifferent? [J Gastroenterol Hepatol. 2011]

FXR ja statiini

http://circ.ahajournals.org/content/130/Suppl_2/A15690.abstract

Statins as Potential Farnesoid X Receptor Modulators in Atrial Cardiomyocytes: A Gender, Age and miR328 Controlled Response

Abstract

... Farnesoid X receptor (FXR) plays an important role in lipid and glucose metabolism and statins are known negative regulators of FXR expression. The role of FXR in atrial fibrillation (AF) has not been defined. MicroRNA-328 (miR-328) a small non-coding RNA contributes to adverse electrical remodeling in AF a common complication after coronary artery bypass grafting (CABG). The present study aimed to examine the levels of FXR mRNA and miR328 in 30 consecutive patients undergoing CABG.

Post reperfusion, mean (S.E.) FXR mRNA levels increased

adjusted the results for the combined confounding effect of age, gender and statin therapy.
...FXR mRNA post-pre CABG in patients under statin therapy were -2.6 units lower (95% C.I.-4.43,-0.80) than in patients not taking statins (p=0.007).
 Each additional year of age results in FXR mRNA being 0.27 units higher (95% C.I. 0.04, 0.48) (p=0.018). Female patient FXR mRNA was 2.10 units higher (95% C.I. 0.12, 4,09) than their male counterparts
... These results suggest that FXR regulation during CABG is dependent on statin therapy, is gender specific and increases with age. Also the inverse relation of FXR mRNA with miR-328 suggests a possible interplay between metabolic and electrical substrate alterations for the atrial myocardium during CABG.

FXR Gene

http://www.ncbi.nlm.nih.gov/gene/9971

Official Symbol

NR1H4provided by HGNC

Official Full Name

nuclear receptor subfamily 1 group H member 4provided by HGNC

Primary source

HGNC:HGNC:7967

See related

Ensembl:ENSG00000012504; HPRD:04827; MIM:603826; Vega:OTTHUMG00000170359

Gene type

protein coding

RefSeq status

REVIEWED

Organism

Homo sapiens

Lineage

Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo

Also known as

BAR; FXR; HRR1; HRR-1; RIP14

Summary

This gene encodes a ligand-activated transcription factor that shares structural features in common with nuclear hormone receptor family members. This protein functions as a receptor for bile acids, and when bound to bile acids, binds to DNA and regulates the expression of genes involved in bile acid synthesis and transport. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Feb 2016]

Orthologs Hiiri

Bibliography

Related articles in PubMed

1. Association of FXR gene variants with cholelithiasis. Hirobe-Jahn S, et al. Clin Res Hepatol Gastroenterol, 2015 Feb. PMID 25242139
2. Genome-wide binding and transcriptome analysis of human farnesoid X receptor in primary human hepatocytes. Zhan L, et al. PLoS One, 2014. PMID 25198545, Free PMC Article
3. A farnesoid X receptor polymorphism predisposes to spontaneous bacterial peritonitis. Lutz P, et al. Dig Liver Dis, 2014 Nov. PMID 25086996
4. Promoter DNA methylation of farnesoid X receptor and pregnane X receptor modulates the intrahepatic cholestasis of pregnancy phenotype. Cabrerizo R, et al. PLoS One, 2014. PMID 24498169, Free PMC Article
5. Differential activation of the human farnesoid X receptor depends on the pattern of expressed isoforms and the bile acid pool composition. Vaquero J, et al. Biochem Pharmacol, 2013 Oct 1. PMID 23928191

See all (184) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. Three FXR gene variants (rs35724, rs11110385, rs11110386) were identified as potential susceptibility factors for cholelithiasis in a German cohort in gender- and weight-dependent manners
2. these data demonstrate that copper-mediated nuclear receptor dysfunction disrupts liver function in WD and potentially in other disorders associated with increased hepatic copper levels.
3. FXR agonist, GW4064, upregulates adipokine expression in preadipocytes and HepG2 cells.
4. NHR1H4 genotype increases the risk for spontaneous bacterial peritonitis in live cirrhosis patients.
5. Results show that HRG is a novel transcriptional target gene of FXR in human hepatoma cells, human upcyteVR primary hepatocytes and 3D human liver microtissues in vitro and in mouse liver in vivo.
6. established genome-wide human FXR binding and transcriptome profiles. These results will aid in determining the human FXR functions, as well as judging to what level the mouse models could be used to study human FXR functions
7. our data showed that bile acid-activated FXR stimulates miR-22-silenced CCNA2, a novel pathway for FXR to exert its protective effect in the gastrointestinal tract.
8. AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes.
9. Low FXR expression is significantly associated with gastric cancer cell proliferation and invasion.
10. Compared with normal gallbladder tissues, FXR expression was decreased and MCL1 expression was increased in GBC, during progression of tumor node metastasis (TNM) stage

Submit: New GeneRIF Correction See all (149)

Väitöskirja sappiaineenvaihduntaan vaikuttavista tekijöistä

https://gupea.ub.gu.se/handle/2077/40886
Kävin kuuntelemassa tämän väitöstilaisuuden 12.2. 2016 Sahlgrenskan Akatemiassa.
Väitöstyöntekijä on  Sama Islam Sayin. (SI. Sayin)  Vastaväittäjänä toimi  Itävallasta Wienin Yliopistosta Michael Trauner.
Väitöskirja perustuu  kahteen osatyöhön. 
I  Ensimmäinen  on julkaistu vuonna 2013 otsikolla Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occuring FXR antagonist. 
Tässä työryhmässä huomaan myös suomalaisia  olleen mukana kuten S. Jäntti, T. Hyötyläinen. 
II Toinenn työ: Differential FXR-mediated regulation by the gut microbiota in the liver and the intestine.
 
Suomennosta ruotsalaisesta ja englantilaisesta  abstraktista  

 Tausta: 
Suolistoflora, suolistossamme elävä mikrobien moninainen kokoomus on ympäristötekijä, jolla on syvällistä suoraa  vaikutusta  isäntäkehon ( siis meidän ihmisten) niin terveyteen kuin  tautiin. 

Sappihapot ovat  sisäsyntyisiä, endogeenisiä, kolesteroli-johdannaisia, joita suoliston  mikrobiflora voi  muokata,  ja  ne toimivat signaloivina molekyyleinä ihmisen aineenvaihdunta-prosessien säätelyssä. 

Työn tarkoitus:  
Tässä väitöskirjatyössä tutkitaan suolistokasvuston (suolistofloran) osuutta sappihappojen aineenvaihduntaan ja signalointiin käyttämällä apuna suolistobakteerittomia hiiriä, joita vertailtiin normaaliravinnolla kasvatettuihin  hiiriin, joilla oli suolistofloraa. 

Tulos: 

Havaittiin suolistofloran säätelevän sappihappojen aineen-vaihduntaa usealla tasolla, myös  yksittäisten sappihappolajien osuuksilla  ja sappihappojen homeostaasiin osallistuvien geenien ilmentämisellä.

 Havaittiin, että  erityisesti  suolistomikrobit alensivat  hiiren primäärin sappihapon  tauro-beta-murikoolihapon (T-betaMCA)  pitoisuuksia.  Edelleen tunnistettiin, että tämä  sappihappo toimii  FXR-tumareseptorin estäjänä, siis vastavaikuttajana eli antagonistina. 

•  FXR on lyhennys sanoista " Farnesoidi X-reseptori," joka on eräs tumareseptori ( nuclear receptor, NR).   

Farnesoidi-x- reseptori ( FXR) välittää negatiivista  takaisinsyöttöä (negative feed back)   sappihappohomeostaasin  säätelyssä;,  FXR  osallistuu useiden   fysiologisten prosessien säätelyyn. 

Tässä työssä  tutkijat tunnistivat  sappihappoaineenvaihdunnan säätelyn taustalla olevan  molekyylitason mekanismin, kuten   T-betaMCA-sappihapon välittämän  FXR -aktiivisuuden  eston eli inhibition.

 Mutta koska ihmisiltä puuttuu vastaava sappihappo  T-betaMCA, niin tällä  väitöstyöllä on eräs tärkeä osa  selitettämässä   hiiritutkimusten ja kliinisten tutkimusten välisiä eroja, kun  suunnataan terapiaa  FXR- reseptorin toiminnan muuntamiseen  hoidettaessa  gastrointestinaalisia tauteja. 

 Jotta  saataisiin  parempaa ymmärtämystä suolistomikrobien  vaikutuksesta FXR- signalointiin, kehitettiin (germ free)  hiiriä, joilta puuttui funktionaalinen FXR ja kartoitettiin FXR:n kautta tapahtuva geenisäätö.

Tutkittiin  FXR:stä  riippuvaisen geeni-ilmenemän säätö suolistosta ja maksasta.  Tutkittiin  tärkeimmät elimet tässä FXR- välitteisessä sappihappoaineenvaihdunnan säätelyssä. Reseptoria FXR ilmenee maksassa hyvin runsaasti. 

 Havaitsimme, että suolistoflora voi säädellä FXR:n  kohdegeenien ilmenemää suoralla FXR-sitoutumisella promottoreihin. 

Mutta maksassa tapahtuu todennäköisesti  proteiini-proteiini- interaktioita   FXR:n ja muiden  koregulaattorien kesken 

Jöhtopäätöksenä: Tämä tutkimus vahvistaa suolistomikrobit avainasemassa olevaksi vaikuttajaksi sappihappojen aineenvaihdunnassa ja FXR- signaloinnissa, jota tapahtuu  suolessa ja maksassa. 

Näistä löydöistä päätellen mikrobit ovat varteenotettava  tekijä,   kun  hoidetaan gastrointestinaalisia tauteja suuntaamalla  sappihappovälitteiseen FXR-signaloinnin  estämiseen.

 

The collection of microbes in our gastrointestinal tract, the gut microbiota, is an environmental factor that has profound impact on host health and disease. Bile acids are endogenous cholesterol-derived molecules that can be modified by the gut microbiota and function as signaling molecules in regulation of host metabolic processes. This thesis investigates the role of the gut microbiota on bile acid metabolism and signaling by comparing mice that lack microbiota with their conventionally-raised counterparts. We found that the gut microbiota regulates bile acid metabolism at several levels, including proportionalities of individual bile acid species and expression of genes involved in bile acid homeostasis. Specifically, the gut microbiota decreased levels of mouse primary bile acid tauro-beta-muricholic acid (T-βMCA), which we identified as an antagonist of the nuclear receptor farnesoid-x-receptor (FXR). FXR mediates negative feedback regulation of bile acid homeostasis, as well as regulation of several physiological processes.  Hence, we identified the molecular mechanism behind microbial regulation of bile acid homeostasis as T-βMCA mediated inhibition of FXR activity. Since humans lack T-βMCA, this thesis plays an important role in explaining the existing discrepancies between mouse and human studies targeting FXR for treating gastrointestinal diseases. Furthermore, in order to better understand the effect of the microbiota on FXR signaling, we re-derived mice that lacked functional FXR as germ-free and mapped microbial regulation of genes through FXR. We found that the microbiota can regulate expression of FXR target genes through direct FXR binding to promoters in the intestine, while protein-protein interactions between FXR and other co-regulators are likely regulated in the liver.  In conclusion, this study establishes the microbiota as a key player in bile acid metabolism and FXR signaling in the liver and the intestine. The findings from this thesis implicate the microbiota as an important factor that needs to be taken into consideration in treating gastrointestinal diseases by targeting bile-acid mediated FXR signaling.

ISBN:

978-91-628-9703-1 (PDF) 978-91-628-9702-4 (Print)

Tumakalvo, tumalamina, SREBF1

Structure and function of the nuclear lamina. The nuclear lamina lies on the inner surface of the inner nuclear membrane (INM), where it serves to maintain nuclear stability, organize chromatin and bind nuclear pore complexes (NPCs) and a steadily growing list of nuclear envelope proteins (purple) and transcription factors (pink). Nuclear envelope proteins that are bound to the lamina include nesprin, emerin, lamina-associated proteins 1 and 2 (LAP1 and LAP2), the lamin B receptor (LBR) and MAN1. Transcription factors that bind to the lamina include the retinoblastoma transcriptional regulator (RB), germ cell-less (GCL), sterol response element binding protein (SREBP1), FOS and MOK2. Barrier to autointegration factor (BAF) is a chromatin-associated protein that also binds to the nuclear lamina and several of the aforementioned nuclear envelope proteins. Heterochromatin protein 1 (HP1) binds both chromatin and the LBR. ONM, outer nuclear membrane. Coutinho et al. Immunity & Ageing 2009http://www.ncbi.nlm.nih.gov/pubmed/18435918

Kolesterolin homeostaasista hyvä artikkeli.  Se on pitkä olen itse kahlannut sitä vasta puoleenväliin.

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204063/


Eräs olennainen asia: kolesteroli on erittäin tärkeä molekyyli ihmiselle, koska se kuuluu ihmisen suojaan, kalvojen  suojarakenteeseen. Sen takia keho  tuottaa sitä  joka solullaan tarpeen mukaan.. Ainoa haitta kolesterolin automaattiselle homeostaasille   on käytännölllisesti katsoen se . että ihmiset  syövät sitä valmiissa muodossa liikoja, jolloin se on vain eräs  molekyyli, joka pitää  maksan avulla hävittää ja erittää, koska sitä ei voi käyttää energiaksi  ja polttaa lämmöksi,  se on siksi monimutkainen. - tai sitten  synteesin yksipuolisia raaka-aineita syödään  liikaa  siten että koko geneettiinen  lipidikirjotasapino  järkkyy, koska  kolesterolia syntyy  absoluuttisen  välltämättömänä molekyylinä hyvin perustavista elementeistä joita  tulee sokerista ja  kovasta rasvasta.
Tyydyttämättömät öljyt  ylittävät sen  kynnyksen että ne pelkästään rasittaisivat  ja paisuttaisivat kolesterolisynteesitietä koska niistä voi tulla  tasapainoisesti muita kalvolipidejä.

Varsinainen kolesterolin normalisointi pitäisi alkaa  rafiiknnoidun sokerin ja kovien rasvojen vähentämisestä.  Lisäksi  jos haluaa suojata omaa maksaansa ja sappeansa  valmiin kolesterolin detoksiakaatiokuormalta, ei käytä 1 kananmunaa enempää kolesterolia   päivässä.   Hiven  ravintokolesterolia antaa kyllä  pientä tukea endogeeniselle kolesterolitehtaalle- että sen ei tarvitse käydä  ylikierroksilla.  siis noin 300 mg kolesterolia päivässä , kuten  yhdessä  kananmunassa.

Kaikenlaiset kolesterolia alentavat lääkkeet ovat varmaan hyödyksi koska nykyihmiskutna syö todella aivan järkyttävän  epäfysiologisesti.

Jos niistä kolesterolia alentavista lääkkeistä  tulee lihaskipuja,  se saattaa olla paha merkki.  Ei sovi silloin. Parempi koettaa  järkevöidä ravintoa - tosin  nykyajan ylijärkevä ihmiskunta  menee johtopäätöksissään usein  väärään ja  luonnonkansoilla saattaa olla   siinä suhteessa joitain etuja.  ei kai eläinkunnassakaan ole kolesteroli ja lipidiongelmaa muuta kuin ihmisen hoitamilla eläimillä.

Kolesterolivaikutus tumassa ?

https://www.ncbi.nlm.nih.gov/pubmed/26754536

Lipids Health Dis. 2016 Jan 12;15(1):4. doi: 10.1186/s12944-015-0175-2.

Why high cholesterol levels help hematological malignancies: role of nuclear lipid microdomains.

Codini M¹, Cataldi S¹, Lazzarini A², Tasegian A¹, Ceccarini MR¹, Floridi A², Lazzarini R², Ambesi-Impiombato FS³, Curcio F³, Beccari T¹, Albi E⁴.

Author information

Abstract

BACKGROUND:
Diet and obesity are recognized in the scientific literature as important risk factors for cancer development and progression. Hypercholesterolemia facilitates lymphoma lymphoblastic cell growth and in time turns in hypocholesterolemia that is a sign of tumour progression. The present study examined how and where the cholesterol acts in cancer cells when you reproduce in vitro an in vivo hypercholesterolemia condition.
METHODS:
We used non-Hodgkin's T cell human lymphoblastic lymphoma (SUP-T1 cell line) and we studied cell morphology, aggressiveness, gene expression for antioxidant proteins, polynucleotide kinase/phosphatase and actin, cholesterol and sphingomyelin content and finally sphingomyelinase activity in whole cells, nuclei and nuclear lipid microdomains.

RESULTS:

We found that cholesterol changes cancer cell morphology with the appearance of protrusions together to the down expression of β-actin gene and reduction of β-actin protein. The lipid influences SUP-T1 cell aggressiveness since stimulates DNA and RNA synthesis for cell proliferation and increases raf1 and E-cadherin, molecules involved in invasion and migration of cancer cells. Cholesterol does not change GRX2 expression but it overexpresses SOD1, SOD2, CCS, PRDX1, GSR, GSS, CAT and PNKP. We suggest that cholesterol reaches the nucleus and increases the nuclear lipid microdomains known to act as platform for chromatin anchoring and gene expression.

CONCLUSION:

The results imply that, in hypercholesterolemia conditions, cholesterol reaches the nuclear lipid microdomains where activates gene expression coding for antioxidant proteins. We propose the cholesterolemia as useful parameter to monitor in patients with cancer.

PMID:

26754536

[PubMed - in process]

PMCID:

PMC4709975

Free PMC Article

•