Bile Acids in Gastroenterology

209 Pages·2016·5.6 MB·English

by  Susumu Tazuma

Susumu Tazuma
Hajime Takikawa Editors
Bile Acids in
Gastroenterology
Basic and Clinical
123
Bile Acids in Gastroenterology
Susumu Tazuma (cid:129) Hajime Takikawa
Editors
Bile Acids in
Gastroenterology
Basic and Clinical
Editors
SusumuTazuma HajimeTakikawa
DepartmentofGeneralMedicine DepartmentofMedicine
HiroshimaUniversityHospital TeikyoUniversitySchoolofMedicine
Hiroshima Tokyo
Japan Japan
ISBN978-4-431-56060-9 ISBN978-4-431-56062-3 (eBook)
DOI10.1007/978-4-431-56062-3
LibraryofCongressControlNumber:2017935470
©SpringerJapanKK2017
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Preface
ItisapleasuretointroduceBileAcidsinGastroenterology.Researchhas focused
onbileacidsasakeyplayerinlipidmetabolismaswellasacytotoxicorprotective
agentforhepatobiliaryanddigestivediseases.Bileacidshavelongbeenoneofthe
mostpopulartargetsforbasicandclinical researchingastroenterology,andnum-
bers of reports are still being published in major journals as novel information.
Therefore,themainobjectiveofthisbookistoprovideupdatedinformationonbile
acidsforscientistsandphysicianstotakeadvantageofregardingprogressinbasic
researchandforclinicalapplication.
In principle, bile acids are soluble amphiphilic (detergent-like) molecules
produced by catabolizing cholesterol in the liver, and are essential for secretion
andtransportofcholesterolinbileandforfatdigestionandabsorptioninthesmall
intestine.Inbiologicalterms,bileacidmoleculesarere-absolvedfromtheintestine,
followedbyrecruitingtotheliver.Thisrecyclingsystemisso-calledenterohepatic
circulation, and thanks to such recruitment, the liver synthesizes only enough to
compensateforsmalllossesinthefeces.Accordingly,biliarybileacidsarederived
almostentirelyfromtheenterohepaticcirculation.Bileacidsarethemainconstit-
uentsofbileandarestoredinthegallbladder,flowingintothesmallintestineafter
mealingestion.Intestinalbileacidsfacilitatedigestionandabsorptionoflipidsand
fat-solublevitamins.Thus,bileacidsplayaroleinlipidmetabolism.
Recently there has been intensive interest in the revelation that bile acids are
responsible not only for the digestion and absorption of lipids but also for signal
transductioninvariousmetabolicpathwaysasnaturalligandsfornuclearreceptors,
toparticipateinpathogenesisandmanagementofvariousdiseasessuchascancer,
immunedisorders,andmetabolicsyndrome.Therefore,inthisbook,PartIconsists
mainlyofbiologicalaspectsofbileacidsandincludesthechapters“Metabolismof
Bile Acids”, “Hepatobiliary Transport of Bile Acids”, “Intestinal Absorption of
Bile Acids”, “Nuclear Receptor Regulation of Bile Acids”, and “Bile Acids as
v
vi Preface
TherapeuticAgents”(Chaps.1,2,3,4,and5).Followingtheprecisetreatmentof
thebiologicalaspectsofbileacids,inPartIItherelationshipbetweenbileacidsand
diseases is described according to recent reports in the chapter “Bile Acids and
Gallstones” (Chap. 6)—a traditional theme, but recently updated evidence-based
clinical practice guidelines have accelerated interest in both the basic andclinical
aspects.Similarly,thechapters“BileAcidsandCholestaticLiverDisease,Primary
BiliaryCholangitis(PBC),andPrimarySclerosingCholangitis,(PSC)”,and“Bile
Acids and Non-alcoholic Fatty Liver Diseases/Non-alcoholic Steatohepatitis
(NAFLD/NASH)” and “Bile Acids and Viral Hepatitis and HCC” (Chaps. 7, 8,
10,and11)arealsofocusedonthroughevidence-basedclinicalpracticeguidelines.
Inaddition,otherinterestsincluding“BileAcidsandPancreatitis”,“BileAcidsand
Esophageal Cancer”, and“BileAcids and Colon Cancer” (Chaps. 12, 13,and 14)
are introduced to provide recent findings. Taken together, this book provides
excellent coverage ofthe current knowledge ofbile acids ingastroenterology and
willbeofgreatinteresttoconcernedreaders.
Hiroshima,Japan SusumuTazuma
Tokyo,Japan HajimeTakikawa
18November2016
Contents
PartI BiologicalAspectsofBileAcids
1 MetabolismofBileAcids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
HajimeTakikawa
2 HepatobiliaryTransportofBileAcids. . . . . . . . . . . . . . . . . . . . . 9
TatehiroKagawa
3 IntestinalDigestionandAbsorption. . . . . . . . . . . . . . . . . . . . . . . 27
AkiraHonda,TadashiIkegami,andYasushiMatsuzaki
4 NuclearReceptorRegulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
MakotoMakishima
5 BileAcidasTherapeuticAgents. . . . . . . . . . . . . . . . . . . . . . . . . . 61
YoshihideYamanashi,TappeiTakada,andHiroshiSuzuki
PartII BileAcidsandDiseases
6 BileAcidsandGallstones:Epidemiology,Pathogenesis,
Diagnosis,andManagement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
SusumuTazuma
7 BileAcidsandCholestaticLiverDisease1:PrimaryBiliary
Cholangitis(PBC). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
AtsushiTanaka
8 BileAcidsandCholestaticLiverDisease2:PrimarySclerosing
Cholangitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
TakahiroNakazawa
9 BileAcidsandCholestaticLiverDisease3:InbornErrorsofBile
AcidSynthesis. . . . . .. . . . . . . . .. . . . . . . . . .. . . . . . . . . .. . . . . 135
HiroshiNittono,AkihikoKimura,HajimeTakei,
TakaoKurosawa,andTakashiIida
vii
viii Contents
10 BileAcidsandNAFLD/NASH. . . . . . . . . . . . . . . . . . . . . . . . . . . 145
TsuneoKitamuraandSumioWatanabe
11 BileAcidsandViralHepatitisandHepatocellularCarcinoma. . . 157
YasuakiTakeyamaandShotaroSakisaka
12 BileAcidsandPancreaticDisease.. . . . . . . . .. . . . . . . . . .. . . . . 169
MorihisaHirotaandTooruShimosegawa
13 BileAcidsandEsophagealCancer. . . . . . . . . . . . . . . . . . . . . . . . 177
JuntaroMatsuzakiandHidekazuSuzuki
14 BileAcidandColorectalCancer. . . . . . . . .. . . . . . . . . . .. . . . . . 185
MichiakiUnno
15 BileAcidsandMetabolicSyndrome. . . . . . . . . . . . . . . . . . . . . . . 193
HirokiTaokaandMitsuhiroWatanabe
Part I
Biological Aspects of Bile Acids
Chapter 1
Metabolism of Bile Acids
HajimeTakikawa
Abstract Bile acids are biosynthesized from cholesterol in the liver. Cholic acid
(CA),chenodeoxycholicacid(CDCA),anddeoxycholicacid(DCA)aremajorbile
acidsinhumans.Neutral(classical)pathwayisthemajorpathwayofthebileacid
biosynthesis in adult humans, which starts from 7ɑ-hydroxylation of cholesterol,
catalyzed by cholesterol 7ɑ-hydroxylase (CYP7A1), the rate-limiting step of bile
acid biosynthesis. In the liver, farnesoid X receptor (FXR) induces the negative
nuclear receptor, small heterodimer partner (SHP), which inhibits CYP7A1 and
CYP8B1genetranscription.FXRandSHPareactivatedbybileacidsintheliver.In
the intestine, FXR agonists induce fibroblast growth factor 15 (FGF15; FGF19 in
humans),whichactivatestheliverFGFreceptorinthelivertoinhibitCYP7A1and
CYP8B1 expression. Most bile acids in the bile and serum are conjugated with
glycineortaurine.Inaddition,sulfateandglucuronideconjugatesofbileacidsalso
exist, which are hydrophilic and useful for urinary excretion. Bile acids with less
hydroxylgroupsaresubjectedtotheseconjugations,whichareappropriateforthe
detoxicationoftoxicbileacids.
Keywords Cholesterol 7ɑ-hydroxylase (CYP7A1) • Sterol 12ɑ-hydroxylase
(CYP8B1) • Sterol 27-hydroxylase (CYP27A1) • Oxysterol 7α-hydroxylase
(CYP7B1)•FarnesoidXreceptor(FXR)
1.1 Types of Bile Acids
Bileacidsarebiosynthesizedfromcholesterolintheliver.Thesebileacids,called
primary bile acids, are cholic acid (CA) and chenodeoxycholic acid (CDCA)
(Fig. 1.1) in humans. CA and CDCA are metabolized to deoxycholic acid (DCA)
andlithocholicacid(LCA),respectively,by7ɑ-dehydroxylaseofintestinalbacteria
(Fig. 1.1). CDCA is also metabolized to ursodeoxycholic acid (UDCA) via the
7-oxo-intermediate(Fig.1.1).
H.Takikawa(*)
DepartmentofMedicine,TeikyoUniversitySchoolofMedicine,2-11-1Kaga,Itabashi-ku,
Tokyo173-8605,Japan
e-mail:[email protected]
©SpringerJapanKK2017 3
S.Tazuma,H.Takikawa(eds.),BileAcidsinGastroenterology,
DOI10.1007/978-4-431-56062-3_1