4 Di Ciaula A, et al. , 2017; 16 (Suppl.

1): s4-s14

November, Vol. 16 (Suppl. 1), 2017: s4-s14

The Official Journal of the Mexican Association of Hepatology,

the Latin-American Association for Study of the Liver and
the Canadian Association for the Study of the Liver

Bile Acid Physiology

Agostino Di Ciaula,*,i Gabriella Garruti,†,i Raquel Lunardi Baccetto,‡
Emilio Molina-Molina,‡ Leonilde Bonfrate,‡ David Q.-H. Wang,§ Piero Portincasa‡

* Division of Internal Medicine, Hospital of Bisceglie, Italy.

†
Section of Endocrinology, Department of Emergency and Organ Transplantations,
University of Bari “Aldo Moro” Medical, School, Piazza G. Cesare 11, 70124 Bari, Italy.
§ Department of Medicine, Division of Gastroenterology and Liver Diseases,

Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
‡ Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Bari, Italy.
i The authors provided equal contribution

ABSTRACT

The primary bile acids (BAs) are synthetized from cholesterol in the liver, conjugated to glycine or taurine to increase their solubility,
secreted into bile, concentrated in the gallbladder during fasting, and expelled in the intestine in response to dietary fat. BAs are also
bio-transformed in the colon to the secondary BAs by the gut microbiota, reabsorbed in the ileum and colon back to the liver, and
minimally lost in the feces. BAs in the intestine not only regulate the digestion and absorption of cholesterol, triglycerides, and fat-
soluble vitamins, but also play a key role as signaling molecules in modulating epithelial cell proliferation, gene expression, and lipid
and glucose metabolismby activating farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor-1 (GPBAR-1, also known
as TGR5) in the liver, intestine, muscle and brown adipose tissue. Recent studies have revealed the metabolic pathways of FXR and
GPBAR-1 involved in the biosynthesis and enterohepatic circulation of BAs and their functions as signaling molecules on lipid and
glucose metabolism.

Key words. Bile acids. Microbiota. FXR. Bile.

INTRODUCTION cape from intestinal reabsorption enter the colon, where

they are further transformed into the secondary and, more
Bile acids (BAs), the major lipid components of bile, hydrophilic BAs, by the resident gut microbiota.6
are synthetized from cholesterol in the liver and subse- The role of bile in lipid metabolism goes beyond that
quently conjugated to taurine or glycine, leading to an in- of fat emulsifier. Recent studies have also pointed to BAs
crease in their solubility. Immediately after synthetization, as signaling molecules with metabolic effects via interac-
BAs are secreted into bile, as well as concentrated and tion with the nuclear receptors farnesoid X receptor
stored in the gallbladder. Upon food intake, the gallblad- (FXR), pregnane X receptor (PXR), and vitamin D recep-
der is stimulated by the entero-hormone cholecystokinin tor (VDR), G-protein coupled receptors such as GPBAR-
(CCK) to release bile into the duodenum, where BAs aid 1, and cell signaling pathways such as c-Jun N-terminal
in the digestion and absorption of lipids and fat-soluble kinase (JNK) and extracellular signal-regulated kinase
vitamins.1 Fasting serum BAs concentrations in healthy (ERK). Through these interactions, BAs help to regulate
subjects are 0.2-0.7 —M to increase to 4-5 —M after each energy, glucose, lipids and lipoprotein metabolism.7
meal.2.5 Most of the BAs in the ileum are reabsorbed and In this review, we summarize recent advances in the
return to the liver through the portal vein, and conse- complex BAs physiology, focusing on novel findings about
quently, hepatic BA synthesis is inhibited by a negative the regulatory mechanisms of BAs that are dependent and
feedback regulatory mechanism. However, BAs that es- independent of nuclear FXR. We also briefly discuss the

Manuscript received: September 06, 2017. Manuscript accepted: September 06, 2017.

DOI:10.5604/01.3001.0010.5493

© 2019, Fundación Clínica Médica Sur, A.C. Published by Elsevier España S.L.U. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Bile Acid Physiology. , 2017; 16 (Suppl. 1): s4-s14 5

interaction between host microbiota and dietary intake on num after the meal.8 The aliphatic side chain is conjugat-
BA metabolism. ed in amide linkage (N-acyl amidation) with glycine or
taurine at a ratio of 3:1 to increase water solubility of BAs
BIOSYNTHETIC PATHWAYS (glycine > taurine) in bile and reduce BA toxicity (Fig-
OF BILE ACIDS (BAS) ure 1). 2 In bile, BAs act as cholesterol carriers together
with phospholipids, and in the intestine, BAs act as sur-
BAs belong to a family of closely related acidic sterols factants and help the digestion and absorption of dietary
synthesized from cholesterol, and represent the main cholesterol, triglycerides, and fat-soluble vitamins. 9
catabolic pathway of cholesterol metabolism in humans. Thus, BAs are essential in biliary cholesterol secretion
BAs are classified as soluble amphiphiles because of the and transport in bile, as well as hepatic catabolic prod-
ionized carboxylate or sulfonate group on the side chain ucts of endogenous cholesterol.
that makes BAs water-soluble. In general, BAs possess a About 15% of conjugated BAs escape the absorption of
steroid nucleus of four fused hydrocarbon rings with po- the terminal ileum and enter the colon, where the resi-
lar hydroxyl functions. De novo BA biosynthesis occurs in dent gut microbiota promotes the deconjugation and bi-
the liver as the “primary” BAs, i.e., cholic acid (CA) and otransformation of the primary BAs into the secondary
chenodeoxycholic acid (CDCA). Afterwards, the water BAs such as deoxycholic acid (DCA) and lithocholic acid
solubility of BAs is increased by conjugation to either (LCA) and the tertiary BAs such as ursodeoxycholic acid
taurine or glycine, followed by hepatic secretion of BAs (UDCA), as shown in Figure 2. Approximately 50% of
into bile and release by the gallbladder into the duode- DCA and a small amount of LCA and UDCA are re-ab-

A
Cholestane Cholesterol

Taurine

Glycine

Cholic acid

Figure 1. A. The general structure of cholestane (classified as a saturated 27-carbon tetracyclic triterpene) is shown with numbering of the carbon atoms.
The four fused hydrocarbon rings are labelled as A, B, C, and D. Cholesterol is shown as 3D structure and chemical formula. B. Hepatic cholesterol in the
body is catabolized to bile acids (BAs), and cholic acid (CA) is shown as an example. CA possesses a steroid nucleus of four fused hydrocarbon rings with polar
hydroxyl functions and an aliphatic side chain in amide linkage with taurine or glycine (dotted lines). The two enzymes involved in this process are the BA CoA
synthase and the BA-CoA-amino acid N-acetyltransferase. The hydrophilic (i.e., polar) areas of BAs are the hydroxyl groups (-OH) (orientation of the hydroxyls:
3D, 7D, 12D) and conjugation side chain of either glycine or taurine. The hydrophobic (i.e., nonpolar) area is the ringed steroid nucleus.
6 Di Ciaula A, et al. , 2017; 16 (Suppl. 1): s4-s14

Cholesterol
Liver
Intestine

Primary BAs
Secondary BAs Tertiary BAs
(CYP7A1, CYP27A1)

Classic pathway
Alternative pathway

Intestinal
microbiota
CA
(3
(3AA , 77A A))
A A Desconjutation DCA Liver
Dehydrogenation (3
(3AA , 12
12AA)
7A-dehydroxylation
Epimerization

S-LCA
LCA
( 33A
A)

CDCA
(3A
(3 A , 77A
A)
7-oxo-LCA
UDCA (3
(3AA , 77B
B)

Figure 2. Major primary, secondary, and tertiary BAs of humans. The sites of BA synthesis and metabolism are shown. The “primary” BAs are synthetized in
the liver from cholesterol as precursor.The trihydroxy cholic acid (CA) and the dihydroxy chenodeoxycholic acid (CDCA). Two biosynthetic pathways are in-
volved: the classical pathway is initiated by 7A-hydroxylase (CYP7A1) which stimulates the 7A-hydroxylation of cholesterol with synthesis of 7A-hydroxycholes-
terol. A further step includes the activation of CYP8B1 for CA. CYP7A1 is involved in the synthesis of two primary BAs, CA and CDCA, and contributes to
more than 75% of total BA production. The alternative pathway is initiated by sterol-27-hydroxylase (CYP27A1), which produces the intermediate 27-hydroxyc-
holesterol and mainly CDCA. A further step includes the activation of CYP8B1 for CDCA. In the small and large intestine, the bacterial deconjugation, dehy-
drogenation, 7A-dehydroxylation, and epimerization of the primary BAs produces the “secondary” BAs. CA is converted to the dihydroxy deoxycholic acid (DCA)
and CDCA to the monohydroxy lithocholic acid (LCA). The 7A-dehydrogenation of CDCA form the dihydroxy 7a-oxo-LCA which does not accumulate in bile,
but is metabolized to a “tertiary” BA by hepatic or bacterial reduction to CDCA, mainly in the liver or its 7B-epimer, the dihydroxy ursodeoxycholic acid (UDCA),
primarily by colonic bacteria.2,9 The position and orientation of the hydroxyls for each BA is indicated in parenthesis. 2,9,59

sorbed in the terminal ileum and colon and return to the ileal and liver receptors are depicted in Figure 4. Hepatic
liver via the portal vein. They enter the liver with assist- synthesis of BAs accounts for 0.2-0.6 g/day with an overall
ance of sodium taurocholate cotransporting polypeptide BA pool of about 3 g in the liver and intestine. More than
(NTCP) transporter and organic anion transporting 95% of the secreted BAs are reabsorbed through active ab-
polypeptide (OATP) transporter. The secondary BAs are sorption at the terminal ileum by the specific bile acid
reconjugated with taurine or glycine. By contrast, all BAs transporter apical sodium-dependent bile acid transporter
in feces are deconjugated and consist mainly of DCA and (ASBT) and passive absorption in the colon. These BAs
LCA. are recirculated to the liver via the portal vein, i.e., the so-
BAs constitute about two thirds of the solute mass of called enterohepatic circulation, raising the overall pool to
normal human bile by weight. They belong to the class 3 g with the recirculation of 4-12 cycles per day, i.e., 12-36
of biliary lipids together with cholesterol and phospholi- g/day. Only about 5% (i.e., 0.2-0.6 g per day) of the secret-
pids (Figure 3). The complex scenario related to BA bio- ed BAs are lost in feces, equal to the amount of hepatic
synthesis, enterohepatic circulation and interactions with synthesis (0.2-0.6 g/day).2
Bile Acid Physiology. , 2017; 16 (Suppl. 1): s4-s14 7

Most of BAs remain in the enterohepatic circulation mechanisms.20 Recently, a new role of BAs has been pro-
and only minimum quantity enters the blood circulation posed for regulating transintestinal cholesterol excretion
and is excreted into urine by the kidneys (< 1 —M/day). and reverse cholesterol transport.21
However, biliary secretion of BAs is compromised in
hepatobiliary diseases. To alleviate BA accumulation, BAs BAs AND PHYSICAL
undergo sulfation by the enzyme sulfotransferase 2A1 STATES OF BILIARY LIPIDS
(SULT2A1), mainly in the liver. The sulfated BAs are
more water soluble, and consequently, their absorption BAs tend to self-assemble into micelles in an aqueous
rates in the intestines are decreased, while urinary elimi- solution when the critical micellar concentration (CMC)
nation is increased over 100 times under these condi- is exceeded. Normally, the CMC values of most of BAs
tions.10 The sulfated BAs constitute over 89% of urinary are between 1 and 20 —M, but this value is greatly depend-
BAs, and the majority of them are also amidated with gly- ent on the species of BAs, the ionic strength and composi-
cine or taurine. The degree of sulfation of BAs is inversely tion, and types and concentrations of other solubilized
related to their hydrophobicity, with LCA being almost lipids. Another factor which influences the CMC is the
entirely sulfated in urine, while only half of the CA is progressive bile concentration within the biliary tree and
found to be sulfated. These results point to a critical role especially in the gallbladder, in such a way that BA con-
for this detoxifying mechanism.11 centration steadily exceeds the CMCs.2 As a result, simple
The major physiological functions of BAs include the micelles are formed in bile, which are able to solubilize
digestion and absorption of intestinal cholesterol, triglyc- other types of lipids such as cholesterol and phospholip-
erides, fatty acids,12 and fat-soluble vitamins,13 feedback ids and lead to the formation of mixed micelles in bile.
regulatory mechanisms of hepatic BA biosynthesis, and Cholesterol and lecithins are virtually insoluble in wa-
gallbladder motor function.8 BAs also play a critical role ter, and bile is an aqueous solution. Thus, cholesterol and
in the gut-liver axis in response to inflammation, 14 im- lecithins require BAs for their transport in bile because
mune response,15-17 epithelial cell proliferation,18 intesti- BAs contain both hydrophilic and hydrophobic areas,
nal microbiota19 and gene expression through epigenetic which confer the property of amphiphilicity. The number

Gallbladder

LCA (3D)

UDCA (3D, 7E)

A B. BAs

Phospholipid
BAs
DCA
(3D, 12D) CA
(3D, 7D, 12D) Figure 3. A. Relative com-
position of solutes in hepatic
and gallbladder bile in health.
CDCA
B. Relative composition of
(3D, 7D) BAs in bile: CA: cholic acid;
CDCA: chenodeoxycholic
Cholesterol acid; DCA: deoxycholic acid;
Bilirubin Proteins LCA: lithocholic acid; UDCA:
ursodeoxycholic acid.
8 Di Ciaula A, et al. , 2017; 16 (Suppl. 1): s4-s14

Hepatocyte
6
1 bile BSEP
MRP2
Proximal tubule
T/G

7 ASBT FGFR4/ Oxysterols Cholesterol BAs

Ass
β-Klotho MRP3
≈100umol LXR HNF4α
CYP7A1
CYP7A
C
CY A1 MRP4
CYP8B1 CA OSTα/β

JNK/ERK1/2 LRH-1 C DC
CDCA
MRP2 BAAT/BACS
S
T/G ((I)
I)
I) Portal blood
Metabolic effects MRP3 SHP
MRP4
FXR/RXR
stomach
Brown GPBAR-1
5 GPBAR-1 /FXRE
2 ILEOCYTE
4a
Adipose ≈1-2 umol/day NTCP T/G

tissue filtration OATP

GPBAR-1
G
GPB
PBA
PBAR--1
AR ASBT

≈10-50% - VIP
duodenum
Spillover to peripheral
Muscle GPBAR-1
GPBAR
AR -1
1
FGFR4/ motilin
circulation β-Klotho CCK
GPBAR-1
Portal blood Enterohepatic
FXR
FXR I-BABP
I BABP
circulation
Passive diffusion 4-12 cycles/day
≈15%
OSTα/β
Active transport
≈80%
microbiota
mic
DCA, LCA, UDCA T/G
GLP-1 FGF19
Fecal excretion T/G T/G L cells GLP-2
(II, III)
≈5% ≈100 mM
≈10 PYY
Bile salt hydrolases (BHS) ileum RXR GPBAR-1
Portal blood
colon
4 FXR
≈1 mM (DCA  0.8 mM) GLP-1/2
3 Metabolic
FGF 19/15 PYY effects

Figure 4. Bile acid (BA) biosynthesis, enterohepatic circulation and function through their receptors in the liver and intestine.Complex molecular mechanisms
involve a set of nuclear receptors, i.e., farnesoid X receptor (FXR), retinoid X receptor (RXR), small heterodimer partner (SHP), liver receptor homologous-1
(LRH-1), and liver X receptor (LXR).77 FXR plays a key role as main sensor of BAs and regulator of synthesis, secretion and metabolism of BAs in the liver, ile-
um and colon.78,79 1. In the liver, the primary BAs (CA, CDCA) are mainly synthesized from cholesterol by the rate-limiting microsomal enzyme cholesterol 7A-
hydroxylase (CYP7A1) and by CYP8B1 at a later step (the “classical pathway”) and by the CYP27A1 (the “alternative pathway”). BAs are conjugated to taurine
or glycine mainly via two enzymes, BA CoA synthase (BACS) and BA-CoA-amino acid N-acetyltransferase (BAAT), secreted into bile by the bile salt export
pump (BSEP); the multidrug resistance-associated protein (MRP2) mediates secretion of organic substrates such as bilirubin, and glutathione. 2. Gallbladder:
bile is stored and concentrated because water absorption occurs, as well as periodically released into the duodenum due to gallbladder contraction in the fast-
ing state (about 20% emptying at the end of phase II of the migrating myoelectric complex 80,81 under the control of the vagus and enterohormone motilin 81
and especially after a meal due to the enterohormone cholecystokinin, CCK8). This rythmic activity is also modulated in concert with episodes of gallbladder re-
laxation/refilling due to the effect of the vasointestinal peptide (VIP, released in the duodenum by gastric acid), BAs per se (acting on the gallbladder receptor
GPBAR-1), and the intestinal FGF15/19 (following the BA/FXR interaction in the ileum) acting on the FGF4/B-Klotho receptor also expressed in the gallblad-
der.8,82,83 Fasting serum BAs concentrations in healthy subjects are 0.2-0.7 MM to increase to 4-5 MM after each meal.2-5 3. BAs are efficiently (i.e., > 95%)
reabsorbed in the terminal ileum. The remaining BAs enter the colon, undergo biotransformation to the secondary BAs by the resident gut microbiota, and un-
dergo passive diffusion and reabsorption. Only 5% of BAs are lost in feces every day. The enterohepatic circulation of BAs includes their intestinal re-absorption
and continuous recirculation to the liver through the portal vein. About 10-50% of re-absorbed BAs undergo peripheral spillover into systemic circulation.84 4.
Upon arrival in the terminal ileum, BAs activate FXR and increase the transcription of the enterokine fibroblast growth factor 19 (FGF19 in humans or FGF15
in mice) which enters the portal circulation and regulates both gallbladder (see point 2) and liver effects (see point 5). BAs in the intestine also activate the G
protein-coupled receptor (GPBAR-1) and stimulate the secretion of peptide YY (PYY), glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2), all
of which produce important metabolic effects on glucose metabolism,85 insulin metabolism and appetite acting on GPBAR-1 receptors located in the cells of
brown adipose tissue and muscle. 85 In the ileocyte, BA uptake, intracellular transport and secretion into the portal vein require the apical sodium dependent bile
acid transporter (ASBT), the cellular intestinal BA binding protein (I-BABP), and the basolateral heterodimeric organic solute transporter (OSTA/B), respectively
(see inset 4a for details). 5. The circulating FGF19 binds to hepatic FGF receptor 4 (FGFR4)/B-Klotho to activatec-Jun N-terminal kinase/extracellular signal-
regulated kinase (JNK/ERK) signaling, which inhibits expression of CYP7A1 and CYP8B1 and hepatic BA synthesis, in synergy with the FXR-SHP inhibitory
pathway.70,86 BAs enter the liver by sodium taurocholate cotransporting polypeptide (NTCP) and organic anion transporting polypeptide (OATP) transporters
and act as physiological nuclear ligands for FXR, which regulates target gene transcription by binding toRXRs as a heterodimer. 87 This results in increased
transcription of the small heterodimer partner (SHP) expression. SHP, in turn, inhibits LRH-1, preventing the activation of target genes that participate in BA
and fatty acid synthesis. In the absence of BAs, LRH-1 acts together with LXR to stimulate BA synthesis. 55,88,89 FXR also regulates the enzymatic activity that
is involved in BA conjugation to glycine or taurine, and hepatic BA secretion by of BSEP and hepatic phospholipid secretion by ABCB4. BAs re-entering the liver
also interact with the liver GPBAR-1 expressed in Kupffer cells, in concert with the pathway activated by the FGFR4/B-Klotho. FXR activation also coordinates
BA detoxification enzymes (i.e., cytosolic sulfotransferase 2A1 [SULT2A1], aldol-keto reductase 1 B7 [AKR1B7], cytochrome P450 3A4/3a11 [CYP3A4/
Cyp3a11], and UDP-glycosyltransferase 2B4 [UTG2B4]). 90 6. The events leading to BA excretion from the hepatocyte into the portal vein are shown in the in-
set. Specific transporters are the multidrug resistance protein 3 and 4 (MRP3, MRP4) and OSTA/B. 7. From the peripheral circulation, BAs also undergo renal
uptake by the apical sodium/dependent bile acid transporter (ASBT) in the proximal tubule. Glomerular filtration of BAs are regulated by MRP2, 3, 4 transport-
ers.91 Adapted from Ory, et al.92 and Inagaki, et al.,70 Garruti, et al.,77 Liu, et al.52
Bile Acid Physiology. , 2017; 16 (Suppl. 1): s4-s14 9

and characteristics of hydroxyl groups and side chains more multilamellar vesicles form. If the ratio of choles-
characterize their solubility in water and bile according to terol to phospholipid in vesicles is greater than 1, vesi-
the composition and concentration of other lipids. Thus, cles become increasingly unstable, which could lead to
BA aggregation in bile leads to a transformation from mon- the formation of solid plate-like cholesterol monohy-
omers to simple micelles if concentration exceeds the drate crystals, the first step in cholesterol nucleation.
CMCs (~ 2 mmol/L). The simple micelles can solubilize The following events leading to the formation of solid
cholesterol because the hydrophobic portion of each BA cholesterol crystals and gallstone formation have been
molecule faces in ward and the hydrophilic groups go out- summarized by our group in previous papers.2,30-32
ward, with cholesterol being solubilized within the cen-
tral hydrophobic portion of the micelle. BA simple BAs AND THE MICROBIOTA
micelles appear like disks, ~ 3 nm in diameter. After the
incorporation of phospholipids into simple micelles, The maintenance of an appropriate BA pool in the body
mixed micelles are formed and they are ~ 4-8 nm in diam- is determined by hepatic BA synthesis, biliary secretion,
eter, with the capacity to solubilize 3 times more choles- gallbladder concentration and contraction, intestinal tran-
terol. The mixed (BA-cholesterol-phospholipid) micelles sit, microbial biotransformation, intestinal re-absorption
appear as a lipid bilayer. The hydrophilic groups of the and fecal excretion (Figure 4). Intestinal bacteria play a
BAs and phospholipids are on the “outside” of the bilayer major role in BA metabolism because they are responsible
in contact with the aqueous bile, and cholesterol mole- for the transformation of the primary BAs to the second-
cules are often solubilized by the hydrophobic groups on ary BAs. The involved steps include deconjugation, oxida-
the “inside” of the bilayer. The maximal solubility of cho- tion of hydroxyl groups in 3, 7 and 12 positions, and
lesterol occurs when the molar ratio of phospholipids to 7-dehydroxylation.6 The human gut microbiota is an ex-
BAs is between 0.2 and 0.3, and more cholesterol is solu- tremely dynamic system in both health and disease,33-35
bilized when the concentration of total biliary lipids in- and therefore, has profound effects on the final BA profile.
creases. This process significantly increases the hydrophobicity of
Using quasi-elastic light-scattering spectroscopy and the BA pool, and as a consequence, the risk of potential
electron microscopy, model and native human bile is carcinogenic effects.36
studied22-24 to depict the pathways of biliary cholesterol On the other hand, BAs (mainly DCA) have antimicro-
solubilization, which involve the formation of biliary bial properties and are able to influence the species of gut
unilamellar vesicles25,26 and liquid crystals(i.e., multila- microbiota. This is done by the detergent effects of DCA
mellar vesicles)27,28 as well as cholesterol nucleation and on bacterial cell membranes, which damages the integrity
crystallization in bile.29 The size of unilamellar vesicles of the bacteria and modulates microbial populations.19 The
is ~ 40 to 100 nm in diameter, and they are spherical obstruction of bile flow is a major factor for bacterial
structures with a single bilayer that encircles an aqueous overgrowth and translocations in the intestine. In a mouse
core. These structures are enriched with phospholipids model, this condition is reversed by oral administration of
and cholesterol, but little BAs. Unilamellar vesicles can BAs. This effect is modulated by FXR-induced gene ex-
aggregate and fuse to form large multilamellar vesicles pression, which is associated with the enteral protection
(liquid crystals or liposomes, ~ 500 nm in diameter), and the inhibition of bacteria damage to the intestinal mu-
which consist of multilamellar concentric spherical cosa.37
structures. These vesicles are able to solubilize biliary Furthermore, the gut microbiota can be considered a
cholesterol that cannot be solubilized in simple and privileged interface between the environment (including
mixed micelles. The compositions and proportions of dietary habits at high risk for cancer development,38-40
micelles and vesicles depend on the concentrations of smoking,41 ethanol consumption,42 environmental pollut-
biliary lipids: with a dilute bile (i.e., total lipid concen- ants as heavy metals and pesticides43-46) and BAs-mediated
tration < 3 g/dL), vesicles are stable (i.e.,no aggrega- signaling pathways7 regulating intestinal and metabolic
tionor fusion, or nucleation of solid cholesterol crystals). homeostasis and potentially inducing cancer onset and
For concentrated gallbladder bile (~ 10 g/dL), vesicle growth.36
instability is significantly increased, leading to the pre-
cipitation of solid cholesterol crystals. In the fasting BAs AND DIETARY HABITS
state, hepatic BA output is relatively low and cholesterol
is carried more in vesicles than in micelles. During Diets containing high content of animal proteins and
meals, the BA output is higher, and therefore, more cho- saturated fats increase bile secretion, augmenting BAs in
lesterol is solubilized in micelles. With increasing BA the intestine. These alterations markedly influence the
concentrations (i.e., in concentrated gallbladder bile), gut microbiota40,47,48 by favoring bacteria to increase the
10 Di Ciaula A, et al. , 2017; 16 (Suppl. 1): s4-s14

concentration of hydrophobic BAs (mainly DCA47,48) in liver via the portal vein and reduces expression of hepatic
the total BA pool.39,49 In mice, a high-fat diet decreases cholesterol 7D-hydroxylase and BA synthesis.57
Lactobacillales and increases the Clostridium subcluster BAs also interact with GPBAR-1 that is mainly ex-
XIVa, leading to an increase in serum levels of DCA. The pressed in Kupffer cells, but not hepatocytes.39,58 In this
modified microbiota composition is suppressed by die- case, the rank order of potency is TLCA > TDCA >
tary supplement of agaro-oligosaccharides (a natural TCDCA > TCA.1 In the ileum, activation of GPBAR-1
derivate from agarose).48 In Apcmin/+ mice, treatment increases levels of peptide YY (PYY) with anorexigenic ef-
with DCA alters the gut microbiota composition by fect (i.e., appetite reduction), as well as glucagon-like pep-
causing defective intestinal barrier function, intestinal tide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2). 60
low-grade inflammation, and cancer progression. When GPBAR-1 is also expressed and metabolically active in the
fecal microbiota is transplanted from DCA-treated mice gallbladder, brown adipose tissue, skeletal muscle, macro-
to another group of Apcmin/+ animals, an increased tu- phages, and monocytes1,59 and in the enteroendocrine cells
mor multiplicity is found likely due to activation of the of the intestine.61 In particular, GPBAR-1 signalling in
tumor-associated Wnt/E-catenin signaling pathway. Of skeletal muscle and brown adipose tissue results in local
note, the cancer-promoting effects of BAs are blocked by activation of the type II iodothyronine deiodinase (DIO2)
gut microbiota depletion through antibiotic treatment.36 able to generate or transform the inactive thyroxine (T4)
As demonstrated in animals, the pathways linking a high- to active thyroid hormone (T3, a key regulator of metabo-
fat diet to an alteration in intestinal microbiota are also lism and energy homeostasis). In Kupffer cells and macro-
correlated with increased retention of hydrophobic BAs phages, GPBAR-1 activation inhibits LPS-induced
in the liver, leading to hepatocellular carcinoma in ani- cytokine production.62 Such additional hormonal effects
mals with nonalcoholic steatohepatitis (NASH). This of BAs are cAMP-mediated and might be particularly evi-
pathogenic mechanism isalso supported by an inhibition dent after bariatric surgery with important and beneficial
of key BA transporters secondary to high-fat diet-in- metabolic effects, including increased energy expenditure,
duced liver inflammation and to a down-regulation of increased insulin secretion and/or sensitivity and decrease
the tumor suppressor gene CEBPD.50 inflammatory status.9,57,62 (see also chapter by Garruti, et al.
in the present issue). The mechanisms governing BA bio-
BAs AS SIGNALING MOLECULES synthesis and the composition of the total BA pool are,
therefore, of paramount importance for keeping the over-
As mentioned above, BAs display both hydrophilic and all digestive and metabolic functions of BAs in health.
hydrophobic surfaces, which makes these molecules high- This aspect involves a number of nuclear receptors in the
ly soluble, and detergent-like amphiphilic. The potency of liver and intestine via FXR-dependent and -independent
BAs as detergents depends on the distribution and orienta- mechanisms.
tion of hydroxyl groups around the steroid nucleus of the
molecule, a feature called hydrophobicity, which is quan- FXR-dependent mechanisms
tified by high performance liquid chromatography
(HPLC).2 The hydrophobicity of BAs, which is directly Overall, cholesterol 7D-hydroxylase (CYP7A1) is the
related to cytotoxicity, is the following order: LCA> rate-limiting enzyme for regulating BA synthesis and is a
DCA > CDCA > CA > UDCA. target gene of FXR. Several factors such as BAs, inflamma-
BAs are also being recognized as signaling molecules in tory cytokines, steroid hormones, and insulin may inhibit
the human body because they are able to regulate metabol- CYP7A1 transcription through the 5’-upstream region of
ic and cellular functions by interaction with BA receptors. the promoter.63-65 FXR is critical in this respect as a regu-
BAs interact with the nuclear receptor superfamily such as latory factor of BA metabolism because it down-regulates
ligand-activated FXR and GPBAR-1.1 FXR is a master BA CYP7A1, sterol 12D-hydroxylase (CYP8B1), and sterol 27-
sensor in the liver and ileum.51-53 The BA-FXR interaction hydroxylase (CYP27A1) transcription by a negative feed-
is essential in BA homeostasis: the rank order of potency back mechanism.
is CDCA > LCA = DCA > CA in the conjugated and un- In the hepatocyte, one regulatory mechanism in-
conjugated forms.54 FXR regulates a series of gene expres- volves binding of BAs to FXR in the nucleus, the for-
sion that is involved in the synthesis, uptake, secretion and mation of the FXR/RXR heterodimer, and the
intestinal absorption of BAs, and all these processes are es- activationof small heterodimer partner (SHP), leading
sential in the regulation of intracellular Bas.2,55,56 FXR acti- to an inhibition of the activity of liver receptor homol-
vation in the intestine increases expression of intestinal ogous-1 (LRH-1) and the CYP7A1 transcription. 55,66
fibroblast growth factor 19 (i.e., FGF19 in humans or Furthermore, SHP displaces the promoter factor
FGF15 in mice); in turn, the circulating FGF19 enters the HNF4D from PGC-1D, thus contributing to CYP7A1
Bile Acid Physiology. , 2017; 16 (Suppl. 1): s4-s14 11

and CYP8B1 transcription. FXR also plays a role in de- cholestasis, lipopolysaccharides released by bacteria
creasing BA cytotoxicity because it promotes expres- stimulate the secretion of TNFD (alpha) and IL-1E
sion of the enzymes involved in conjugation of BAs from Kupffer cells, leading to activation of Toll-like
with glycine or taurine, i.e., BA CoA synthase and BA- receptor 4. TNFD and IL-1E may inhibit CYP7A1 tran-
CoA-amino acid N-acetyltransferase. 67,68 Excessive ac- scription by activating the TNF-D receptor and the
cumulation of intrahepatic triglycerides during the MAPK/JNK pathway in the hepatocyte. JNK may in-
sequence non-alcoholic fatty liver, steatohepatitis is as- hibit CYP7A1 and CYP8B1 transcription and BA syn-
sociated with abnormalities of gene expression of FXR thesis by phosphorylating cJun no period 75.76 and
and SHP and BA transporters.69 HNF4D.
In the ileum, a second regulatory mechanism of BA
synthesis involves the secretion of FGF19 and activation CONCLUSIONS
of FGFR4 tyrosine kinase/E-klotho (a co-expressed mem-
brane-bound glycosidase) signaling in the hepatocyte ba- BAs are synthesized mainly in the liver and are the major
solateral membrane.70,71 This pathway involves the lipid components of bile, as well as involved in hepatic cho-
JNK-mediated pathway and suppression of CYP7A1 tran- lesterol catabolism. BAs released by the gallbladder enter the
scription and points to the importance of the BAs/FXR/ gastrointestinal tract during the meal and are key regulators of
FGF19/FGFR4/CYP7A1 signaling cascade which nega- fat emulsion and solubilisation, two essential steps for the
tively regulates BA biosynthesis in the liver in hu- digestion and absorption of cholesterol, triglycerides and fat-
mans.2,72,73 soluble vitamins. BAs also act as signaling molecules by acti-
vating two main sensors in the body: the nuclear receptor
FXR-independent mechanisms FXR and the cell surface receptor GPBAR-1. In this way,
BAs become key regulators of complex homeostatic path-
FXR-independent BA inhibition of CYP7A1 transcrip- ways at a systemic level ranging from their own homeostasis
tion might work by several parallel mechanisms to protect tocholesterol, triglyceride, glucose and energy metabolisms.
against BA toxicity during cholestasis and liver injury. Additional regulations include cell proliferation, inflamma-
tion, and tumor onset and progression.
• Insulin receptor and activation of PI3K and AKT lead Thus, maintaining the precise balance between BA spe-
to phosphorylation of FoxO1 and inhibit CYP7A1 cies and amounts, as well as preventing the accumulation
transcription. of excessive BAs in the body are of importance under-
• Activation of the pregnane X receptor (PXR) and vita- physiological or pathophysiological conditions that in-
min D receptor by LCA and binding to the BA re- volve the liver, intestine, muscle and adipose tissues.
sponse element (BARE)-I sequence in the CYP7A1 In addition, the pathways involving the intestinal
promoter may inhibit CYP7A1 promoter activity.74 microbiota and epigenetic factors regulate gene expres-
• Also, both PXR and vitamin D receptor inhibit sion and act as a common interface between environmen-
CYP7A1 transcription by blocking HNF4D recruit- tal factors (including diet, lifestyle, and exposure to
ment of PGC-1D to CYP7A1 chromatin. environmental toxics) and the molecular events promot-
• BAs also activate epidermal growth factor receptor ing the onset and the progress of disease. The high-fat diet,
(EGFR) and the Raf-1/MEK/ERK signaling pathway, for example, increases the fecal concentration of the sec-
thus inhibiting CYP7A1 transcription. ondary BAs that are a risk factor for the development of
• The hepatocyte growth factor (HGF) is released from colorectal cancer. Of note, intestinal microbiota and the
hepatic stellate cells during liver regeneration and in- epigenome might be modulated by the primary preven-
jury, and HGF stimulates HGF receptor cMet and tion strategies (i.e., changes in dietary habits and lifestyle,
MAPK pathways, leading to inhibition of CYP7A1 and reduced exposure to environmental toxics) and thera-
transcription and BA synthesis. peutic tools. Future studies are needed to better clarify
• Kupffer cells secrete TGFE-1 that activate its receptor how these measures could influence pathogenic mecha-
TREII and the SMAD signaling pathway in the hepato- nisms, disease onset and the efficacy of the available thera-
cyte. SMAD3 enters the nucleus of hepatocyte and peutic tools.
works with HDACs and mSin3A to inhibit HNF4D
activation of CYP7A1 transcription. A tumour sup- ABBREVIATIONS
pressor p53 interacts with HNF4D and inhibits
HNF4D activity. These alterations may inhibit • BAs: bile acids
CYP7A1 transcription. • CA: cholic acid
• Under certain circumstances, i.e., endotoxin-induced • CDCA: chenodeoxycholic acid
12 Di Ciaula A, et al. , 2017; 16 (Suppl. 1): s4-s14

• CMC: critical micellar concentration 12. Wang TY, Liu M, Portincasa P, Wang DQ. New insights into
• CYP7A1: cholesterol 7á-hydroxylase the molecular mechanism of intestinal fatty acid absorption.
Eur J Clin Invest 2013; 43: 1203-23.
• DCA: deoxycholic acid 13. Hofmann AF. The continuing importance of bile acids in liver
• FGF: fibroblast growth factor and intestinal disease. Arch Intern Med 1999; 159: 2647-58.
• FXR: farnesoid X receptor 14. Gong Z, Zhou J, Zhao S, Tian C, Wang P, Xu C, Chen Y, et
• GPBAR-1: G-protein-coupled bile acid receptor-1 al. Chenodeoxycholic acid activates NLRP3 inflammasome
and contributes to cholestatic liver fibrosis. Oncotarget
(also known as TGR5) 2016; 7: 83951-63.
• JNK: c-Jun N-terminal kinase 15. Tremblay S, Romain G, Roux M, Chen XL, Brown K, Gibson
• LCA: lithocholic acid DL, Ramanathan S, et al. Bile Acid Administration Elicits an
• UDCA: ursodeoxycholic acid Intestinal Antimicrobial Program and Reduces the Bacterial
Burden in Two Mouse Models of Enteric Infection. Infect Im-
mun 2017; 85.
CONFLICTS OF INTEREST 16. Guo C, Xie S, Chi Z, Zhang J, Liu Y, Zhang L, Zheng M, et al.
Bile Acids Control Inflammation and Metabolic Disorder
We declare that we have no conflicts of interest. through Inhibition of NLRP3 Inflammasome. Immunity 2016;
45: 802-16.
17. Zhu C, Fuchs CD, Halilbasic E, Trauner M. Bile acids in regu-
ACKNOWLEDGEMENTS lation of inflammation and immunity: friend or foe? Clin Exp
Rheumatol 2016; 34: 25-31.
The present chapter is written in the context of the 18. Dossa AY, Escobar O, Golden J, Frey MR, Ford HR, Gayer
CP. Bile acids regulate intestinal cell proliferation by modulat-
project FOIE GRAS, which has received funding from the ing EGFR and FXR signaling. Am J Physiol Gastrointest Liv-
European Union’s Horizon 2020 Research and Innovation er Physiol 2016; 310: G81-92.
programme under the Marie Sklodowska-Curie Grant 19. Yokota A, Fukiya S, Islam KB, Ooka T, Ogura Y, Hayashi T,
Agreement No. 722619. Raquel Lunardi Baccetto and Hagio M, et al. Is bile acid a determinant of the gut microbiota
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