Intestinal Bile Acids Can Bind to and Activate the Vitamin D Receptor

BriefCritical Reviews September 2002: 281–288

IntestinalBile Acids Can Bind to and Activate the Vitamin D Receptor

An increasedlevel of colon lithocholic acid,a liver.1 Theunabsorbed portion, representing in the hu- potential tumor promoter, accompanies ahigh-

man20% of the bile acid pool, is metabolized by the Downloaded from https://academic.oup.com/nutritionreviews/article/60/9/281/1891670 by guest on 25 September 2021 fat diet. Lithocholic acidcan bind to the intestinal colonicmicro ora to the secondary bile acids— rst by vitamin Dreceptorand thereby induce the cyto- deconjugation,then by oxidation— todeoxycholic acid, chrome CYP3A, which detoxies lithocholic acid whichis partly reabsorbed, and to lithocholic acid (LCA) bycatabolic reactions. (Figure1), which is almost insoluble and not signi - Key Words: bile acids, lithocholic acid,1,25-di- cantlyreabsorbed. LCA representsapproximately 5% of 1 hydroxyvitamin D 3 ,vitamin Dreceptor,cyto- thetotal bile acid pool. chrome CYP3A, colon. LCAata highconcentration has been found to be a ©2002International Life Sciences Institute powerfultumor promoter, 5 quitelikely by inhibiting DNA repairenzymes. 9 VitaminD, inone of its active Epidemiologicstudies have, with some exceptions, ob- forms (1 -hydroxyvitaminD 3),inhibitedthe tumor-pro- servedan association between high-fat diets and a high motingaction of LCA upontreatment of rats with the 1 riskof coloncancer. Earlytheories as tothe cause have coloncarcinogen N-methyl-N -nitrosourea. 5 suggestedthat free fattyacids, in their ionized state, LCAinthecolon is detoxi ed by the P450 enzyme 2 couldact as tumor promoters. Severalepidemiologic CYP3A,which oxidizes LCA to3-ketolithocholi cacid. 10 studieshave shown an inverse correlation between risk Experimentswith intestinal cells in culture showed that ofcolon cancer and calcium and vitamin D intake. 3 theactive form ofvitaminD, 1,25-dihydroxyvitaminD 3 Calciumions were thoughtto convert the anionic fatty (1,25(OH)2D3),whenliganded to thevitamin D receptor acidsinto neutral soaps and the vitamin would aid in protein(VDR) asaheterodimerwith the receptor RXR, 4 increasingcalcium uptake. Amoredirect action of inducedthe expression of CYP3A. 11 vitaminD insuppressing tumor promotion in colon has Ina recentreport, Makishima et al. 12 tested the 5,6 alsobeen suggested. Itis of interest that the highest hypothesisthat LCA mightactivate VDR, therebyinduc- deathrates of colon cancer occur in areas with a high ingCYP3A andpromoting the detoxi cation of LCA. 3 incidenceof rickets. Themethod the investigators used was aligand-screen- Ahigh-fatdiet is accompanied by an increased ingprocedure developed by the same group. 13 The secretionof bile. For instance,a doublingof the excre- methodmakes use of theinteraction of nuclearreceptors tionof bileacids in fecesin healthyyoung men eating a withtheir coactivators. Upon binding to a ligand(e.g., 7 high-fatdiet was reportedlong ago. Experimentally, 1,25(OH) D ),theensuing conformational change of the 8 2 3 bileacids have been established as tumor promoters. receptorincreases its af nity for itscoactivator. To Bileacids (Figure 1), the end products of cholesterol determinewhich one of a numberof receptors interacts metabolism,are synthesized in the liver as cholic acid witha particularligand, transcriptional activity was as- andchenodeoxychol icacid and secreted in bile conju- sayedwith a luciferasereporter gene. In particular, Mak- gatedwith glycine and taurine (primary bile acids). Their ishimaet al. 12 fusedthe DNA ofthereceptor-interacting functionis to aid in the solubilization, digestion, and domainof the coactivator SRC-1 to that of the DNA- absorptionof lipidsin thegut. More than 95% of the bile bindingdomain of the yeast transcription factor GAL4. acidsare saved from lossin feces by the enterohepatic Thegene of the nuclear receptor to be tested was fused circulation,reabsorption in the ileum and return to the tothe transactivation domain of the herpes virus VP16 DNA. Thenthe expression plasmids for GAL4-SRC1 andthe particular receptor-VP16 were transfectedinto This review was preparedby GeorgeWolf, D.Phil., humankidney cells in culture,together with the plasmid Departmentof Nutritional Sciences and Toxicology, University of California, Berkeley, CA94720-3104, for thereporter, the GAL4-responsive luciferase plasmid. USA.Please address all reprint requests tothe Nutri- Byscreening a numberof known nuclear receptors tion Reviews Editorial Ofce, 711 Washington Street, (includingthe VDR, theliver xenobiotic receptor PXR, Boston, MA02111, USA. theliver farnesoid receptor FXR, theRXR andRAR

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Figure 1. Toprow, left to right: cholic acid; chenodeoxycholic acid. Bottom row, left to right: deoxycholic acid; hyodeoxycholic acid; lithocholicacid. receptors,and others with LCA asligand and SRC1 as reactingwith both LCA and1,25(OH) 2D3 is the VDR. coactivator,investigators found that the only responsive Interestingly,the primary bile acids, though active as receptorswere theVDR andFXR (Figure2). The FXR ligandsfor FXR, were quiteineffective in activating the isanuclearreceptor from liver,where it sensesbile acids VDR. Dosedependence experiments showed that LCA andactivates the “bile acid ef ux pump,” protectingthe showeda medianeffective concentration of 8 M, well organismfrom excessivebile acid levels. 14 The authors12 belowthe pharmacologic range. By means of competi- 3 12 alsoscreened the array of nuclearreceptors with another tionexperiments with [ H]-1,25(OH) 2D3, the authors ligand,1,25(OH) 2D3,andfound that it activated the provedthat LCA actuallybinds to the VDR. VDR, asexpected,but not FXR. Thus,the only receptor Makishima’s12 nextstep in supportof the hypothesis was todemonstrate that LCA, when bound to the VDR couldinduce expression of the LCA-detoxifying enzyme,CYP3A. Thummel et al. 11 hadalready shown that

1,25(OH)2D3 boundto the VDR couldinduce CYP3A in intestinalcells. Makishima et al. 12 testedthe hypothesis

thatLCA (insteadof 1,25(OH) 2D3)boundto the VDR couldalso induce CYP3A. They prepared [ 32P]-labeled oligonucleotidescorresponding to the promoter regions

Figure 2. Receptor-speci cactivationby lithocholicacid. Var- iousnuclear receptors were expressed in HEK293 cells and screenedfor activation by 30 mM lithocholicacid with a mammaliantwo-hybrid GAL4-SRC1 andVP16-receptor lucif- eraseassay. RLU relativelight units, FXR liverfarnesoid Xreceptor,PXR liverxenobiotic X receptor,VDR vitaminD receptor,LXR liverX receptor,RXR retinoid Figure 3. Simpli edschematicdiagram showing activation of Xreceptor,PPAR peroxisomeproliferator –activatedrecep- thevitamin D receptorin intestine by both1,25-dihydoxyvita - tor, RAR retinoicacid receptor, TR thyroidhormone min D3 andby lithocholicacid. The activated receptor induces receptor,ER estrogenreceptor, GR glucocorticoidrecep- thecytochrome P450 enzyme CYP3A, whichcatabolizes litho- tor, LRH-1 liverreceptor homolog-1, SHP short her- cholicacid. 1,25-Dihydroxyvit aminD 3 canalso induce the erodimerpartner (from reference 12, with permission). intestinalcalcium-binding protein, calbindin.

282 NutritionReviews ,Vol. 60,No. 9 ofmouse,rat, and human CYP3A genesand, by meansof azoxymethane-induced intestinal cancer byhigh-fat electrophoreticmobility shift assays, showed that a diet in rats. Cancer Res 1979;39:4956 –9 VDR-RXR heterodimerbound to each of the CYP3A 3. Garland CF,Garland FC,Gorham ED. Calcium and vitamin D:their potentialrolein colonand breastcancer genepromoters. They then inserted the CYP3A-VDR prevention. Ann NYAcad Sci 1999;889:107 –19 responseelements of the CYP3A genesinto a luciferase 4. Newmark HL, WargovichMJ, Bruce WR.Colon reporterplasmid and transfected it, together with VDR cancer and dietaryfat, phosphate and calcium: a andRXR expressionplasmids, into HEK293 cells. They hypothesis. JNatl Cancer Inst 1984;72:1323 –5 observedequally powerful activation of the CYP3A gene 5. Kawaura A,Tanida N,Sawada K,et al.Supplemen- tal administration of1 -hydroxyvitaminD inhibits byadding either 1 nM1,25(OH) 2D3 or10 nM LCA to 3 thecells, thus con rmingthat the vitamin D derivative promotion byintrarectal instillationof lithocholic acid inN-methyl-N-nitrosourea-induced colonictu- couldinduce CYP3A andproving that LCA couldinduce morigenesisin rats. Carcinogenesis 1989;10:647 –9 Downloaded from https://academic.oup.com/nutritionreviews/article/60/9/281/1891670 by guest on 25 September 2021 theenzyme that effects its own detoxi cation.The hu- 6. Mehta RG,Mehta RR.Vitamin Dand cancer. J Nutr man CYP3A geneelement was themost sensitive by Biochem 2002;13:252 – 64 respondingmost strongly to LCA. 7. Cummings JH,WigginsHS, JenkinsDJ, et al.In u- In their nalexperiment, the authors 12 determined ence ofdiets high and lowin animal fat on bowel thein vivoresponse in mouse intestine to 1 -hydroxyvi- habit, gastrointestinaltransit time, fecal micro ora, tamin D (a substitutefor 1,25(OH) D ) and to LCA. bileacid and fat excretion. JClin Invest 1978;61: 3 2 3 953– 63 Theyfed mice by gavage with either the vitamin or the 8. NarisawaT, MagadiaNE, WeisburgerJH, Wynder bileacid for 3daysand isolated intestinal mRNA for EL. Promoting effect ofbile acids on coloncarcino- Northernblot analysis. Both the vitamin and the bile acid genesisafter intrarectal instillationof N-methyl-N - increasedexpression of CYP3A mRNA inintestine.The nitro-N-nitrosoguanidinein rats. JNatl Cancer Inst experiment “demonstratedthat the VDR canfunction as 1974;53:1093 –7 anLCAsensorin vivo,resulting in increased expression 9. OgawaA, Murate T,Suzuki M,et al.Lithocholic acid, ofCYP3A ...andleading to detoxi cationof LCA. ”12 aputative tumor promoterinhibits mammalian DNA polymerasebeta. Jpn JCancer Res 1998;89:1154 –9 Insummary, the work of Makishima et al. 12 re- 10. ArayaZ, WikvallK. 6-Alpha-hydroxylationof tauro- vealedthe pivotal role played by the VDR inintestine chenodeoxycholic acid and lithocholic acid by (Figure 3): CYP3A4 in human livermicrosomes. Biochim Bio- Throughbinding the potentially harmful LCA, VDR phys Acta 1999;1438:47 –54 inducesthe detoxifying enzyme CYP3A, which de- 11. Thummel KE, BrimerC, Yasuda K,et al.Transcrip- toxi es LCA. tional controlof intestinal cytochrome P4503A by1-alpha-25-hydroxyvitamin D . MolPharmacol Throughbinding the active form ofvitamin D, 3 2001;60:1399 –406 1,25(OH)2D3,VDRcanalso induce CYP3A, thus 12. MakishimaM, Lu TT,Xie W,et al.Vitamin Dreceptor possiblyexplaining the antitumor-promoter activity asan intestinal bileacid sensor. Science 2002;296: 5,6 ofvitaminD. 1313–6

Inits classical function, through binding 1,25(OH) 2D3, 13. MakishimaM, Okamoto AY,Repa JJ, et al.Identi- VDR promotesthe intestinal uptake of calcium and cation ofanuclear receptorfor bile acids. Science phosphatenecessary for maintainingserum calcium 1999;284:1362 –5 andphosphate levels and bone mineralization. 15 14. Chawla A,Repa JJ,EvansRM, Mangelsdorf DJ.Nuclear receptorsand lipidphysiology: opening 1. Nagengast FM,Grubben MJAL,van Munster IP. the X-les. Science 2001;294:1866 –70 Roleof bile acids in colorectalcarcinogenesis. Eur J 15. JonesG, Strugnell SA,DeLuca HF.Current under- Cancer 1995;31A:1067 –70 standing ofthe molecular actions ofvitamin D. 2. BullAW, SoullierBK, WilsonPS, et al.Promotion of Physiol Rev 1998;78:1193 –231

TheAge-related Eye DiseaseStudy (AREDS)

Some of the earliest andbest known manifesta- as blindness that results from vitamin Ade - tions of malnutrition involve visual disorders,such ciency. Interest is now being focused onthe role of nutrition in the prevention andtreatment of This review was preparedby Billy R.Hammond, chronic age-relateddisorders. The Age-related Jr., Ph.D., and Mary Ann Johnson, Ph.D., Vision Sci- EyeDisease Study (AREDS)was conductedin ence LaboratoryDepartment of Foodsand Nutrition, orderto determine whether high-dose supple- University ofGeorgia, Athens, GA30602, USA. mentation could in uencethe natural progres-

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