Bile Acid as Therapeutic Agents

Fig. 5.1
Molecular diagram of chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA), nor-ursodeoxycholic acid (NorUDCA), obeticholic acid (OCA), INT-777, cholestyramine, colestipol, colesevelam-HCl, colestimide, and ezetimibe

Approximately 90–95% of bile acids (except for LCA) in the intestine are reabsorbed in the ilium by apical sodium-dependent bile acid transporter (ASBT; solute carrier (SLC) family 10 member 2 (SLC10A2)) [5, 6], followed by basolateral secretion to the portal blood by a heterodimer of organic solute transporter α and β (OSTα/β; SLC51A/B) [7, 8] (Fig. 5.2). Bile acids in the portal blood are taken up by hepatocytes via Na+-taurocholate cotransporting polypeptide (NTCP; SLC10A1) [9, 10] and, again, secreted into the bile by BSEP (Fig. 5.2). This continuous enterohepatic circulation acts as a recycling system of bile acids and plays an important role in bile acid metabolism and homeostasis. The remaining bile acids (5–10%) escape intestinal reabsorption and are excreted in feces. This loss of bile acids is replenished by de novo bile acid synthesis from cholesterol in the liver to maintain bile acid homeostasis. In humans, about 500 mg bile acids are synthesized per day from cholesterol in the liver, which is one of the important cholesterol elimination processes in our body [11].


Fig. 5.2
Schematic overview of the enterohepatic circulation of bile acids and bile acid signaling in the liver and intestine. BA bile acid, C cholesterol, TG triglyceride

To date, a number of physiological functions of bile acids have been clarified. Bile acids are known to form mixed micelles together with phospholipids and cholesterol. In the intestine, the mixed micelles play an important role in the solubilization of lipophilic compounds such as dietary lipids and fat-soluble vitamins and, thus, regulate their intestinal absorption [11, 12]. Although the detergent property of bile acids is essential to form mixed micelles and to solubilize lipophilic compounds, this property also induces cytotoxicity that promotes cellular apoptosis/necrosis and inflammation [12]. Therefore, bile acids at high concentrations can cause hepatobiliary diseases [13]. Recent findings that bile acids can activate several receptors such as farnesoid X receptor (FXR; nuclear receptor (NR) subfamily 1 group H member 4 (NR1H4)) [14, 15] and G-protein-coupled bile acid receptor 1 (GP-BAR1, also named as TGR5) [16] have provided new insights into the physiological functions of bile acids not only as detergents but also as signaling molecules (Fig. 5.2). Indeed, bile acids regulate several metabolic processes such as lipids, glucose, and energy metabolism via the activation of signaling cascades involving FXR and/or TGR5 [12, 13, 17]. These findings indicate a variety of physiological and pathophysiological functions of bile acids and provide a rationale to target bile acids and/or their related molecules for the treatment of several diseases. In the following sections, we summarized the current knowledge about clinical applications and pharmacological effects of bile acid-related drugs.

5.2 UDCA

UDCA (Fig. 5.1) is a hydrophilic bile acid used for the treatment of gallstone and various cholestatic liver diseases. Normally, endogenous human bile contains UDCA, although its concentration is very low. UDCA represents only 3% of the total amount of bile acids in the body (Fig. 5.3). Unlike in human bile, UDCA is a major component in black bears bile that has been used as a Chinese traditional medicine (Yutan) for the treatment of liver diseases [1820]. In 1927, UDCA was first isolated and crystalized from Yutan [21]. More than 30 years after its isolation, the first report on UDCA pharmacological effects in humans was published by Japanese researchers [22]. An improvement was observed in tests of liver function after UDCA administration in patients with chronic hepatitis. Since then, a variety of clinical and preclinical studies have been conducted worldwide and demonstrated UDCA beneficial effects for several diseases as described in the following sections.


Fig. 5.3
Effects of ursodeoxycholic acid treatment on pool sizes of bile acids. The pool sizes of the major bile acids in humans were quantified before and after ursodeoxycholic acid (UDCA) treatment (Data from Roda et al. [31]. CA cholic acid, CDCA chenodeoxycholic acid, DCA deoxycholic acid, LCA lithocholic acid)

5.2.1 UDCA as a Therapeutic Agent for Gallstone

In the 1970s, the first prospective study of UDCA in patients with gallbladder gallstones demonstrated that UDCA could promote the dissolution of gallstones [23]. It has been recognized that UDCA detergent property might be directly involved in the solubilization of cholesterol from the gallstone surface [20]. In addition, a unique property of UDCA, which promotes the formation of a liquid crystal mesophase of phospholipids and cholesterol, has been thought to facilitate cholesterol solubilization from gallstone [24]. Notably, such a liquid crystal can form even in the bile saturated with cholesterol, which may account for the observation that UDCA can dissolve gallstones even in the cholesterol-saturated bile. Moreover, UDCA has been reported to reduce the cholesterol saturation of the bile by decreasing the biliary excretion of cholesterol [25, 26]. Biliary cholesterol excretion is mediated by a heterodimer of ATP-binding cassette transporter subfamily G members 5 and 8 (ABCG5/G8) [27, 28]. Several studies demonstrated that micellar composition affects the cholesterol efflux activity of ABCG5/G8 [29, 30]. In particular, there is a positive correlation between the concentration of micellar bile acids and the cholesterol efflux activity of ABCG5/G8 [29, 30]. It has been reported that UDCA therapy decreases pool sizes of CA, CDCA, and DCA while increasing that of UDCA (Fig. 5.3) [31], likely because the excess of exogenous UDCA increases fecal loss of endogenous bile acids by competing for ASBT-mediated reabsorption in the intestine [32]. Thus, an altered composition and/or a reduced concentration of biliary bile acids by UDCA therapy may attenuate the cholesterol efflux activity of ABCG5/G8 and, thus, the biliary cholesterol excretion decrease.

Until the 1980s, CDCA (Fig. 5.1) was also used for gallstone therapy because it can solubilize cholesterol from gallstone as UDCA does and even better than UDCA [33, 34]. However, several clinical trials revealed that UDCA is more effective than CDCA for decreasing biliary cholesterol saturation [35, 36]. In addition, diarrhea was observed with high frequency in patients receiving CDCA therapy due to CDCA cytotoxicity to colorectal epithelial cells, while no obvious adverse effects were observed in patients receiving UDCA therapy [37]. Based on these evidences, UDCA rather than CDCA is commonly used for pharmacotherapy of gallstone today.

5.2.2 UDCA as a Therapeutic Agent for Cholestasis

In the 1990s, a number of clinical trials demonstrated UDCA beneficial effects for chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC) [38, 39], intrahepatic cholestasis of pregnancy (ICP) [40], and chronic hepatitis C (CHC) [41, 42]. Currently, UDCA is the only drug approved by the US Food and Drug administration (FDA) for the treatment of PBC. The underlying mechanisms by which UDCA relieves symptoms of these cholestatic liver diseases have not been fully defined. However, a variety of recent studies indicated that at least three pharmacological activities of UDCA might be involved in its beneficial effects: (1) its cytoprotective and antiapoptotic activity, (2) the stimulation of hepatobiliary secretion of bile acids and endogenous toxic compounds, and (3) its immunomodulatory activity. Details of these pharmacological activities are described in the following sections. UDCA Cytoprotective and Antiapoptotic Activity

Detergent properties of bile acids are important for micelle formation and lipid solubillization. However, higher concentrations of bile acids beyond physiological levels disrupt the phospholipid bilayer of the plasma membrane, resulting in damage to hepatocytes and to biliary epithelial cells. Since the detergent effects of bile acids are positively correlated with their hydrophobicity [43], hydrophobic bile acids such as CDCA, DCA, and LCA are more cytotoxic than hydrophilic bile acids such as UDCA (Table 5.1) [44]. In addition, UDCA has been reported to exert cytoprotective effects by stabilizing cellular membranes [45]. Therefore, UDCA treatment, which promotes the replacement of hydrophobic and toxic bile acids with cytoprotective UDCA, could help improving hepatobiliary injury (Fig. 5.3).

Table 5.1
Hydrophobicity indices of individual bile acids

Taurine conjugated

Glycine conjugated


Ursodeoxycholic acid





Cholic acid




Chenodeoxycholic acid




Deoxycholic acid




Lithocholic acid




More hydrophobic

Data from Heuman et al. [44]. Hydrophobicity indices of individual bile acids were determined by measuring the retention of each bile acid in reversed-phase liquid chromatography. A taurine-conjugated cholic acid was used as a standard. NA not available

Excessive hepatic apoptosis is known to cause both acute and chronic liver injury [46]. In vitro studies demonstrated that hydrophobic bile acids such as the glycine conjugate of CDCA (GCDCA) can directly induce apoptosis in rat hepatocytes through the activation of the Fas death receptor and subsequent activation of caspase-8 [47]. In addition, GCDCA and the glycine conjugate of DCA (GDCA) increase mitochondrial membrane permeability, which triggers mitochondrial cytochrome C release with subsequent activation of the caspase-9-dependent apoptotic cascade [48, 49]. In contrast, UDCA inhibits apoptosis by decreasing the cytochrome C release through stabilization of the mitochondrial membrane [48, 49]. Moreover, UDCA activates cell survival signals, which, in part, may account for the antiapoptotic effect of UDCA. Indeed, the taurine conjugate of UDCA (TUDCA) can inhibit GCDCA-induced apoptosis in rat primary hepatocytes by activating survival signaling pathways mediated by mitogen-activated kinase (MAPK) and phosphoinositide-3 kinase (PI3K) [50]. However, since these antiapoptotic activities of UDCA have been demonstrated mainly in vitro, further in vivo studies will be necessary to demonstrate the physiological involvement of UDCA antiapoptotic activity on its beneficial effect against cholestatic liver diseases. Stimulation of Hepatobiliary Excretion of Bile Acids and Endogenous Toxic Compounds by UDCA

Impairment of bile flow causes the hepatic accumulation of hydrophobic bile acids and other endogenous toxic compounds such as bilirubin glucuronides and glutathione conjugates, which results in the exacerbation of liver injury with further cholestasis. In rats, UDCA stimulates biliary excretion of these endogenous toxic compounds and, thus, inhibits the progression of cholestasis [51, 52]. Consistent with the results of animal models, in humans with cholestasis, long-term treatment with UDCA stimulates biliary excretion of bile acids and bilirubin glucuronides, which results in decreasing the elevated serum levels of these compounds [39, 53, 54].

Biliary excretion of bile acids and organic anions including glucuronides and glutathione conjugates is mainly mediated by BSEP and multidrug resistance-associated protein 2 (Mrp2; ABCC2), respectively [2, 3, 55, 56]. In humans, mutations of the gene encoding BSEP cause progressive familial intrahepatic cholestasis type 2 (PFIC2) [2, 3], whereas mutations of the gene encoding MRP2 are causative of Dubin-Johnson syndrome (DJS) characterized by hyperbilirubinemia [55], indicating the physiological importance of these transporters in the liver. In the cholestatic rat liver, TUDCA significantly increases the insertion of BSEP and MRP2 on the canalicular membrane of hepatocytes, resulting in the stimulation of biliary secretion of bile acids and organic anions [51, 57]. The enhanced membrane localization of these transporters might be accounted for by the activity of TUDCA to increase cellular levels of a variety of second messengers such as intracellular Ca2+, conventional protein kinase C (PKC), and cAMP, which promote the exocytic insertion of the membrane transporters [20]. In addition, correct developmental formation of bile canalicular structures is also essential for hepatobiliary excretion of bile acids and endogenous toxic compounds. Interestingly, UDCA, but not CA or CDCA, has the distinctive ability to accelerate bile canalicular formation in cultured cells and rat primary hepatocytes [58]. Consistent with the in vitro observations, UDCA can regenerate bile canalicular structures in rats with chemical-induced liver injury. The effects were dependent on the conventional PKC and p38MAPK signaling molecules in cultured cells and partially dependent on p38MAPK, MAPK/ERK, and conventional PKC in rat primary hepatocytes. Collectively, although the direct molecular target of UDCA remains to be identified, these observations indicate that UDCA stimulates biliary excretion of toxic compounds via multiple signaling pathways. UDCA Immunomodulatory Activity

In autoimmune cholestatic liver diseases such as PBC, humoral and cellular immune responses are exacerbated by bile acids via the following mechanisms [59]. Autoantigen-presenting cells (APCs) stimulate CD4+ helper T lymphocytes (HTLs) to produce and release proinflammatory cytokines such as interleukin (IL)-2, tumor necrosis factor α (TNFα), and interferon-γ (IFN-γ), followed by the activation of B lymphocytes (BLs) and CD8+ cytotoxic T lymphocytes (CTLs) for humoral and cellular response, respectively. The activated BLs produce autoantibodies, while the activated CTLs attack both hepatocytes and cholangiocytes, which induce cellular death by necro-apoptosis. The binding of CTLs to hepatocytes is facilitated by the major histocompatibility complex (MHC) class I, whose expression is induced by the accumulation of bile acids (mainly CDCA) during the cholestatic process. In cholangiocytes, CDCA also induces overexpression of MHC class II, which locally facilitates sequential activation of HTLs and CTLs, resulting in cholangiocyte damages.

In contrast to CDCA, UDCA suppresses the activation of BLs and CTLs. Clinically, UDCA treatment decreased the severity and progression of PBC with reducing biomarkers of autoimmunity such as serum levels of IgM and IgG and antimitochondrial antibody titers [60]. The immunosuppressive effect of UDCA may be, in part, due to the inhibition of the production and release of proinflammatory cytokines such as IL-2, IL-6, and IFN-γ from blood mononuclear cells [61]. Besides the inhibition of cytokine release, UDCA can also inhibit the aberrant overexpression of MHCs in cholestasis. Indeed, UDCA treatment inhibits the overexpression of MHC class I in the liver of patients with PBC [62, 63]. In addition, in vitro studies demonstrated that UDCA inhibited IFN-γ-inducible overexpression of MHC class II via a glucocorticoid receptor (GR; NR3C1)-dependent pathway [64]. Taken together, these findings indicate that UDCA can suppress autoimmune activation in patients with PBC via the inhibition of proinflammatory cytokine release and reversal of the aberrant expression of MHCs. However, it should be noted that the immunomodulatory effect of UDCA observed in patients with PBC was not consistently observed in patients with other inflammatory hepatobiliary diseases. For example, UDCA therapy failed to improve the autoimmune response in patients with primary sclerosing cholangitis (PSC) [65]. Therefore, the immunosuppressive effect of UDCA should be evaluated in the context of each disease and disease pathogenesis.

5.2.3 UDCA as a Therapeutic Agent for NASH

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease characterized by hepatic steatosis, inflammation, and fibrosis. Currently, there is no approved therapy for NASH, and thus, effective agents for the treatment of this disease are highly desired. In this context, UDCA has attracted the attention as a potential therapeutic agent for NASH because of its multiple hepatoprotective activities. To date, several prospective, placebo-controlled clinical trials have been conducted to test the therapeutic effect of UDCA for NASH [66, 67]. These studies demonstrated that UDCA monotherapy at a standard dose (13–15 mg/kg/day) had no positive effect on serum concentrations of liver enzymes in patients with NASH, indicating that UDCA at a standard dose hardly improves hepatic function in NASH. Meanwhile, high dose of UDCA (at 25–30 mg/kg/day) could improve biochemical parameters in patients with NASH [68, 69]. However, histological features of NASH, including liver steatosis, inflammation, and fibrosis, were hardly improved even by treatment with high doses of UDCA. Based on these clinical findings, UDCA monotherapy is no longer recommended for the treatment of NASH [70]. Nevertheless, considering that the pathogenesis of NASH is associated with multiple disease conditions such as obesity, steatosis, insulin resistance, and chronic inflammation, combined therapies using UDCA with other drugs to prevent metabolic and inflammatory disorders might be effective options for the treatment of NASH.

5.2.4 UDCA as a Therapeutic Agent for Colon Cancer

A high-fat diet is a major risk factor of colon cancer. Continuous intake of high-fat foods leads to an increase in colorectal hydrophobic bile acids. These are thought to be major diet-related carcinogenic substances in the colon. Indeed, it has been reported that increased serum and/or fecal concentrations of the hydrophobic bile acid, DCA in particular, are associated with increased adenomas and colon cancer risk in humans [71]. Recent studies demonstrated that DCA increases oxidative DNA damage and causes genomic instability that, in turn, may lead to colorectal carcinogenesis [72]. In addition, DCA activates the EGFR/MAPK pathway. Over-activation of this pathway causes upregulation of various oncogenes such as RAS, RAF, extracellular signal-regulated kinase (ERK) 1/2, and proto-oncogene activator protein 1 (AP-1) as well as EGFR itself [71, 73, 74].

Conversely, UDCA suppresses the development of colon tumor. Several preclinical studies with rats demonstrated that UDCA significantly decreases the size and number of colon tumors induced by chemical carcinogens such as N-methylnitrosourea or azoxymethane [7577]. This antitumor effect of UDCA may be associated with a reduction of colorectal and/or fecal DCA by UDCA therapy [78]. In addition, UDCA itself, which can block the EGFR/MAPK signaling pathway, may directly contribute to its antitumor effect [73, 74].

Consistent with results in animal models, retrospective clinical studies demonstrated a significant decrease in polyp size, decreased adenoma prevalence, and decreased probability of adenoma recurrence in patients treated with UDCA [79, 80]. In addition, a prospective, placebo-controlled, phase III clinical trial was also conducted to examine the tumor-suppressive effect of UDCA [81]. In this study, UDCA was randomly administered orally to 1,285 patients who underwent surgery to remove colorectal adenomas within 6 months prior to the trial. This study indicated a significant decrease in the recurrence of colorectal adenomas in patients who received UDCA [81]. These results strongly indicate that UDCA is a promising agent for colon cancer. Interestingly, further elucidation of the data from the phase III clinical trial revealed that there is a gender difference in the tumor-suppressive effect of UDCA [82]. UDCA caused an overall reduction in the development of adenoma in men, but led to a significantly higher risk of adenoma development in women who were younger (age <65 years), obese (body mass index ≥30 kg/m2), or with high-dietary fat intake (≥56.2 g/day). These findings suggest that there might be some unknown mechanisms underlying the tumor-suppressive effect of UDCA and that further investigations would be necessary to clarify the appropriate population for UDCA therapy against colon cancer.

5.3 Nor-ursodeoxycholic Acid

Nor-ursodeoxycholic acid (NorUDCA) is a side-chain shortened derivate of UDCA (Fig. 5.1). NorUDCA is resistant to conjugation to taurine and glycine [83]. Unconjugated NorUDCA is secreted into the bile and reabsorbed by cholangiocytes to return to the liver. Such a cholehepatic shunt of NorUDCA stimulates bicarbonate secretion into the bile, which results in hypercholeresis [84]. In addition, the cholehepatic shunting helps NorUDCA to target injured bile ducts and, thereby, may facilitate ductal healing by direct antiproliferative, anti-inflammatory, and anti-fibrotic effects. Therapeutic effects of NorUDCA have been reported in the multidrug resistance protein 3 (Mdr3; Abcb4) knockout mouse, which is widely used as a model of cholangiopathy [85, 86]. Mdr3 is predominantly expressed on the canalicular membrane of hepatocytes and acts as a phospholipid translocater involved in biliary excretion of phosphatidylcholine [87]. Phosphatidylcholine in bile facilitates micellar formation of bile acids to reduce their toxicity. Therefore, the absence of biliary phosphatidylcholine promotes bile acid-induced injury to the biliary epithelium, resulting in cholangiopathy. In humans, defects in MDR3 are the cause of progressive familial intrahepatic cholestasis type 3 (PFIC3), an autosomal recessive liver disorder with early-onset cholestasis [88]. In vivo pharmacological studies with Mdr3 knockout mice demonstrated that NorUDCA reversed sclerosing cholangitis [85], while UDCA worsened, rather than improved, the bile infarcts in cholestatic conditions with biliary obstruction [86]. These results suggest that the therapeutic effect of NorUDCA against cholangiocellular cholestasis would be greater than that of UDCA. However, in a model of taurolithocholate-induced hepatocellular cholestasis, NorUDCA failed to counteract cholestasis and hepatocyte apoptosis, while the taurine conjugate of UDCA did [89]. Taken together with the fact that hepatobiliary disorders progressed not only by cholangiocyte but also by hepatocyte dysfunction, these results suggest that combination therapy of NorUDCA with UDCA may be more beneficial than either monotherapy. Currently, a randomized, placebo-controlled phase II clinical trial of NorUDCA in the treatment of PSC is ongoing [83]. Results of this clinical trial will reveal the pharmacological effects of NorUDCA in humans and provide further aspects of the therapeutic potential of NorUDCA.

5.4 Bile Acid Mimetics as FXR and TGR5 Agonists

The discovery of FXR, a nuclear hormone receptor recognizing bile acids as endogenous ligands, gave rise to the idea that bile acids are signaling molecules. In particular, it has been revealed that CDCA, DCA, LCA, and CA, but not UDCA or NorUDCA, present ligand’s ability to activate FXR signaling with the following order of potency: CDCA>DCA>LCA>>CA [17]. FXR is highly expressed in the liver and intestine and plays a key role in bile acid homeostasis. In the liver, binding of bile acids to FXR induces the expression of small heterodimer partner (SHP), which is a transcriptional repressor interfering with the transcription of cholesterol 7α-hydroxyrase (CYP7A1) (Fig. 5.2) [12]. CYP7A1 is a rate-limiting enzyme involved in the conversion of cholesterol to primary bile acids. The expression of CYP7A1 is also negatively regulated via an endocrine mechanism mediated by fibroblast growth factor 19 (FGF19) (human homologue of Fgf15 in rodents), which is secreted from the ileum into the portal circulation in response to the activation of intestinal FXR by bile acids [90] (Fig. 5.2). In the liver, FGF19 activates fibroblast growth factor receptor 4 (FGFR4) with its co-receptor β-Klotho. The FGFR4/β-Klotho signaling cascade then induces the expression of SHP, which, in turn, results in a decrease in CYP7A1 expression [91] (Fig. 5.2). This negative regulation of CYP7A1 expression by bile acids via FXR and FGFR/β-Klotho signaling pathways plays a key role in the feedback regulation of bile acid synthesis. In addition to the CYP7A1 expression, FXR signaling also regulates the expression of bile acid transporters involved in the enterohepatic circulation to maintain bile acid homeostasis [92, 93] (Fig. 5.2). Recent studies indicated that FXR regulates multiple metabolic pathways involved in lipogenesis, gluconeogenesis, tumor suppression, liver regeneration, and liver inflammation as well as bile acid homeostasis, indicating that FXR is a potential therapeutic target for a variety of diseases [1].

Besides FXR, TGR5 acts as a bile acid receptor. TGR5 is a cell surface receptor, abundantly expressed in the liver, bile duct, gallbladder, brown adipose tissue, muscle, and intestine (enteroendocrine L cells, in particular) [17]. In the liver, TGR5 is expressed in Kupffer cells, but not in hepatocytes [94]. Similar to FXR, TGR5 is activated by most endogenous bile acids, including LCA, DCA, CDCA, and CA, but not UDCA, with the following order of potency: LCA>DCA>CDCA>CA [17]. Upon bile acid binding to TGR5, the adenylate cyclase is stimulated, and cellular cAMP levels increase, leading to further downstream signaling events [12]. For example, in enteroendocrine L cells, TGR5 activation stimulates the secretion of glucagon-like peptide 1 (GLP-1), which enhances insulin secretion from the pancreas and improves insulin sensitivity [95, 96] (Fig. 5.2). In Kupffer cells and macrophages, TGR5 activation inhibits lipopolysaccharide-induced production and secretion of proinflammatory cytokines such as IL-1β, IL-6, IFN-γ, and TNFα [94]. In addition, in the brown adipose tissue and skeletal muscle, TGR5 regulates energy homeostasis by activating cAMP-dependent iodothyronine deiodinase 2, an enzyme responsible for the conversion of inactive thyroxine (T4) to active thyroid hormone (T3) [97]. Since T3 is a positive regulator of the basal metabolic rate and energy consumption, TGR5 activation in the muscle and brown adipose tissue results in an increase in energy expenditure. Collectively, these findings indicate that TGR5 and FXR agonists are potential therapeutic agents for several diseases such as diabetes, inflammatory liver diseases, and obesity.

Several mimetics of bile acids have been developed as agonists of these bile acid receptors for the treatment of liver diseases such as PBC, PSC, and NASH [17]. For example, obeticholic acid (OCA) (6α-ethyl-chenodeoxycholic acid) and INT-777 (6α-ethyl-23(S)-methyl-cholic acid) have been developed [98, 99] (Fig. 5.1). Although OCA was developed as a potent and selective FXR agonist, a recent study indicates that it also activates TGR5 with an EC50 value comparable to those of endogenous bile acids [100]. Meanwhile, INT-777 is a highly selective TGR5 agonist with little ability to activate FXR [99, 100]. OCA has been under investigation in clinical trials to examine its beneficial effects for the treatment of PBC. In a phase II clinical trial, OCA monotherapy markedly improved liver functions and inflammation in patients with PBC [101]. However, unexpectedly, this therapy also induced dose-dependent pruritus as a common but serious adverse effect, which results in the discontinuation of the treatment in more than 35% of the patients. For this adverse effect, a phase III clinical trial of OCA has been conducted in a limited number of patients with PBC with inadequate response to standard UDCA therapy [102]. A clinical trial of OCA in NASH patients has also been conducted and demonstrated that OCA treatment improves NASH histological features, although patients developed pruritus with a high frequency [103]. Regarding the selective TGR5 agonist INT-777, preclinical studies revealed that INT-777 administration improves insulin sensitivity and prevents obesity and hepatic steatosis in mice fed a high-fat diet, suggesting multiple pharmacological activities of INT-777 [95]. However, considering the recent finding that bile acid-induced itch may be caused, in part, by the activation of TGR5 [104], it is highly possible that pruritus will be observed with the INT-777 therapy as well as with the OCA therapy. Since bile acids are ligands for multiple receptors, including GR, vitamin D receptor (VDR; NR1I1), and pregnane X receptor (PXR; NR1I2) besides FXR and TGR5 [64, 105, 106], and have multiple biochemical activities, a comprehensive understanding of signaling pathways involving bile acids would be necessary to predict their pharmacological effects accurately.

5.5 Bile Acid Sequestrants

Bile acid sequestrants (BAS) have been used for more than 50 years for the treatment of hypercholesterolemia. Besides such a classical usage, recent advances in understanding multiple physiological functions of bile acid shed light on new medicinal applications of BAS for several metabolic diseases. In this section, we summarized BAS pharmacological activities for the treatment of dyslipidemia and type 2 diabetes mellitus (T2DM).

5.5.1 BAS as Therapeutic Agents for Dyslipidemia

BAS are non-absorbed positively charged resins that can bind to negatively charged bile acids in the intestine. Currently four BAS are available on the market: colestipol (first-generation BAS), cholestyramine, colestimide (available only in Japan), and colesevelam-HCl (Fig. 5.1). Among them, colesevelam-HCl has been specifically engineered to contain long hydrophobic side chains, which increases the affinity and specificity to bind bile acids compared to other traditional BAS [107]. Due to this property, colesevelam-HCl can be used at lower doses compared to other BAS (Table 5.2). Clinically, the efficacy of BAS monotherapies has been proven. BAS decrease total cholesterol levels (by 3–17%) and low-density lipoprotein cholesterol (LDL-C) levels (by 5–26%) without changing or only inducing a little increase in high-density lipoprotein cholesterol (HDL-C) levels (by 0–8%) in a dose-dependent manner (Table. 5.2). The aim of most of cholesterol-lowering therapies is to reduce the risk of atherosclerosis and cardiovascular diseases such as coronary heart disease (CHD). It has been reported that, compared with placebo, cholestyramine as monotherapy and colestipol in combination with lovastatin decrease the percentage of patients with CHD progression and also increase the percentage of patients with CHD regression (Table. 5.2). These results indicate that BAS (either as monotherapy or in combination with other cholesterol-lowering drugs) can reduce the risk of CHD besides improving plasma lipid profiles.

Table 5.2
Effects of bile acid sequestrant therapy on plasma lipid profile


Number of patients


% Change from base line (baseline: mM)






CHD risk (%)

As monotherapy

7.4 years



−1% (7.2)

−3% (5.3)

2% (1.1)

13% (2.0)

Death by CHD: 2.0


Death by MI: 8.3


Cholestyramine (24 g/day)

−8%* (7.3)

−15%* (5.3)

5% (1.1)

17% (2.1)

Death by CHD: 1.6

Death by MI: 6.8

5 years



−1% (7.6)

−5%* (5.9)

2% (1.0)

26%* (1.5)

Progression: 33


Regression: 10


Cholestyramine (24 g/day)

−17%* (8.0)

−26%* (6.3)

8%* (1.0)

28%* (1.8)

Progression: 12

Regression: 12

8 weeks



1% (6.9)

0% (4.9)

0% (1.3)

11%* (1.7)




Colestipol (2 g/day)

−3%* (7.0)

−5%* (4.8)

−1% (1.4)

15%* (1.7)



Colestipol (4 g/day)

−7%* (7.0)

−11%* (4.9)

0% (1.3)

10%* (1.6)



Colestipol (8 g/day)

−13%* (6.8)

−20%* (4.7)

−1% (1.3)

12%* (1.6)



Colestipol (16 g/day)

−17%* (7.0)

−26%* (4.9)

−1% (1.3)

15%* (1.8)


24 weeks



1% (6.3)

0% (4.0)

0% (1.3)

2% (1.9)




Colesevelam-HCl (2.3 g/day)

−4%* (6.3)

−9 %* (4.2)

4%* (1.3)

7%* (1.7)



Colesevelam-HCl (3.0 g/day)

−6%* (6.3)

−12%* (4.1)

4%* (1.2)

4% (1.8)



Colesevelam-HCl (3.8 g/day)

−7%* (6.3)

−15%* (4.1)

4%* (1.2)

9%* (1.9)



Colesevelam-HCl (4.5 g/day)

−10%* (6.2)

−18%* (4.0)

4%* (1.2)

7%* (1.8)


In combination with other cholesterol-lowering drugs

12 weeks


Cholestyramine (8 g/day)

−7%* (6.2)

−13%* (4.5)

3% (1.1)

15% (0.7)




Cholestyramine (8 g/day) + Lovastatin (5 mg/day)

−13%* (6.2)

−25%* (4.5)

5% (1.1)

28%* (0.7)



Lovastatin (20 mg/day)

−13%* (6.2)

−21%* (4.5)

8% (1.1)

−5% (0.7)


12 weeks


Pravastatin (5-10 mg/day)

−7%* (5.4)

−4%* (2.9)

0% (1.4)

−14%* (1.5)




Colestimide (3 g/day) + Pravastatin (5–10 mg/day)

−12%* (5.3)

−20%* (2.9)

11%* (1.4)

27%* (1.5)


2.5 years



−3% (6.8)

−7%* (4.5)

6%* (1.1)

15% (2.6)

Progression: 46


Regression: 11


Colestipol (30 g/day) + Lovastatin (40 mg/day)

−33%* (7.1)

−45%* (5.1)

20%* (1.0)

−9% (2.3)

Progression: 21

Regression: 32

4 weeks



4% (6.8)

3% (4.8)

4%* (1.2)

9% (1.7)




Colesevelam-HCl (3.8 g/day)

−6%* (7.0)

−12%* (4.8)

3%* (1.2)

10% (1.9)



Atorvastatin (10 mg/day)

−27%* (6.9)

−38%* (4.7)

8%* (1.3)

−24%* (2.0)



Colesevelam-HCl (3.8 g/day) + Atorvastatin (10 mg/day)

−31%* (7.0)

−48%* (4.8)

11%* (1.2)

−1% (1.7)



Atorvastatin (80 mg/day)

−39%* (6.9)

−53%* (4.7)

5%* (1.2)

−33%* (1.7)


4 weeks



1% (6.6)

1% (4.4)

1% (1.3)

2% (1.9)




Colesevelam-HCl (2.3 g/day)

−3% (6.6)

−7%* (4.4)

4%* (1.3)

14%* (2.0)



Lovastatin (10 mg/day)

−15%* (6.5)

−22%* (4.3)

3% (1.3)

5% (2.0)



Colesevelam-HCl (2.3 g/day) + Lovastatin (10 mg/day)

−21%* (6.7)

−34%* (4.5)

3% (1.3)

9% (2.0)


6 weeks



−2% (6.9)

−4%* (4.8)

3% (1.2)

6% (2.1)




Colesevelam-HCl (3.8 g/day)

−9%* (7.3)

−16%* (5.1)

2% (1.3)

11%* (1.9)



Simvastatin (10 mg/day)

−19%* (6.9)

−26%* (4.7)

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Sep 30, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Bile Acid as Therapeutic Agents
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