The G Protein-Coupled Bile Acid Receptor, TGR5, Stimulates Gallbladder Filling

Li, Tingting; Holmstrom, Sam R.; Kir, Serkan; Umetani, Michihisa; Schmidt, Daniel R.; Kliewer, Steven A.; Mangelsdorf, David J.

doi:10.1210/me.2010-0460

Cited by 210 publications

(224 citation statements)

References 21 publications

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“…This effect of hydrophobic bile salts will ultimately result in opening K ATP channels, cell membrane hyperpolarization and decreased GBSM contraction. 25,26 Recently, the discovery of interstitial Cajal-like cells (ICLCs) in the gallbladder provides new insight into the pathogenesis of impaired gallbladder motility. [27][28][29] Gallbladder ICLCs are located almost exclusively within the muscularis propria, where they are electrically coupled with GBSM cells.…”

Section: Gallbladder Motilitymentioning

confidence: 99%

Cholesterol gallstone disease: focusing on the role of gallbladder

Chen

Kong

2015

Laboratory Investigation

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Gallstone disease (GSD) is one of the most common biliary tract diseases worldwide in which both genetic and environmental factors have roles in its pathogenesis. Biliary cholesterol supersaturation from metabolic defects in the liver is traditionally seen as the main pathogenic factor. Recently, there have been renewed investigative interests in the downstream events that occur in gallbladder lithogenesis. This article focuses on the role of the gallbladder in the pathogenesis of cholesterol GSD (CGD). Various conditions affecting the crystallization process are discussed, such as gallbladder motility, concentrating function, lipid transport, and an imbalance between pro-nucleating and nucleation inhibiting proteins.

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Section: Gallbladder Motilitymentioning

confidence: 99%

Cholesterol gallstone disease: focusing on the role of gallbladder

Chen

Kong

2015

Laboratory Investigation

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“…GPBA activation of gall bladder smooth muscle promotes relaxation and gall bladder filling with bile (Li et al, 2011). Hydrophobic bile salts activate GPBA on gall bladder smooth muscle, leading to stimulation of cAMP/PKA pathway, opening of KATP channels, and membrane hyperpolarization that decreases contractility (Lavoie et al, 2010).…”

Section: Gpba and Biliary Functionsmentioning

confidence: 99%

“…Hydrophobic bile salts activate GPBA on gall bladder smooth muscle, leading to stimulation of cAMP/PKA pathway, opening of KATP channels, and membrane hyperpolarization that decreases contractility (Lavoie et al, 2010). The treatment of mice with BAs and a GPBA-selective agonist increases gall bladder volume, an effect that is absent from GPBAdeficient mice (Li et al, 2011). These agents also promote relaxation of gall bladder muscle, by a GPBA-mediated process.…”

Section: Gpba and Biliary Functionsmentioning

confidence: 99%

“…BAs also stimulate the proliferation of cholangiocytes by a GPBA-dependent process. Thus, GPBA mediates the secretory and proliferative actions of BAs in the gall bladder, where GPBA may protect against the toxic effects of BAs.GPBA activation of gall bladder smooth muscle promotes relaxation and gall bladder filling with bile (Li et al, 2011). Hydrophobic bile salts activate GPBA on gall bladder smooth muscle, leading to stimulation of cAMP/PKA pathway, opening of KATP channels, and membrane hyperpolarization that decreases contractility (Lavoie et al, 2010).…”

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confidence: 99%

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GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation

Lieu¹,

Jayaweera²,

Bunnett³

2014

British J Pharmacology

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Bile acids (BAs) are digestive secretions that are necessary for the emulsification and absorption of dietary fats. Given the episodic nature of BA secretion and intestinal re-absorption, the circulating and tissue levels of BAs, like those of the gut hormones, fluctuate in fasting and fed states, and BA levels and forms are markedly affected by disease. BAs exert widespread hormonal-like effects by activating receptors in the nucleus and at the plasma membrane. The nuclear steroid receptors mediate the genomic actions of BAs on BA, glucose and lipid homeostasis. GPBA (TGR5) is a G-protein coupled plasma membrane receptor for BAs that mediates many of the rapid, non-genomic actions of BAs. GPBA has been implicated in the control of glucose homeostasis, inflammation and liver functions. Recent observations have revealed an unexpected role for GPBA in the nervous system. GPBA is expressed by enteric neurons and enterochromaffin cells that control peristalsis, and GPBA mediates the prokinetic actions of BAs in the colon that have been known for millennia. GPBA is also present on primary spinal afferent and spinal neurons that are necessary for sensory transduction. BA-induced activation of GPBA in the sensory nervous system promotes scratching behaviours and analgesia, which may contribute to the pruritus and painless jaundice that are observed in some patients with chronic cholestatic disease, where circulating BA concentrations are markedly increased. Thus, GPBA has emerged as an intriguing target for diverse metabolic, inflammatory, digestive and sensory disorders, where agonists and antagonists may be of value. LINKED ARTICLESThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2014.171.issue-5 Abbreviations ADAM, A disintegrin and metalloproteinase domain-containing protein; ASBT, apical sodium-dependent BA transporter; BA, bile acid; CA, cholic acid; CDCA, chenodeoxycholic acid; CGRP, calcitonin gene-related peptide; D2, type 2 iodothyronine deodinase; DCA, deoxycholic acid; GLP-1, glucagon-like peptide 1; GPBA, bile acid receptor; KATP, ATP-dependent potassium channels; LCA, lithocholic acid; OA, oleanolic acid; TDCA, taurodeoxycholic acid; TLCA, taurolithocholic acid; UDCA, ursodeoxycholic acid IntroductionBile acids (BAs), a major component of bile, are digestive secretions that are necessary for the emulsification and absorption of dietary fats. Remarkably, BAs are also signalling molecules. The levels of BAs fluctuate in the circulation under physiological conditions and during disease states, rather like the circulating levels of gut hormones, and BAs can regulate cells throughout the body by activating specific BA receptors in the nucleus and at the plasma membrane. These receptors mediate the effects of BAs on diverse physiological processes, ranging from the control of glucose homeostasis to peristaltic contractions of the digestive tract, and have been implicated in disorders as diverse as obes...

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“…Genetic associations in ulcerative colitis and to a lesser extent PSC at 2q35 encompass several genes [30,31], including TGR5 and IL8RA and IL8RB genes [30,31]. Mechanistically, direct evidence so far available on TGR5 on PSC related aspects seems to concern immunosuppressive effects of receptor activation [32][33][34][35][36], more than aspects of bile homeostasis [17,18,37,38]. Interpretation of the genetic findings at 2q35 in PSC is difficult, since IL8 has also been implicated in cholestasis [39,40].…”

Section: Bile Acid Toxicitymentioning

confidence: 99%

Update on primary sclerosing cholangitis

Karlsen

Schrumpf

Boberg

2010

Digestive and Liver Disease

104

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SummaryPrimary sclerosing cholangitis (PSC) remains one of the most challenging conditions of clinical hepatology. There has been a steady growth in research to overcome this fact and the present review aims at summarizing the most recently published literature. The main emphasis will be put on the link of recent pathogenetic insights to clinical characteristics and patient management. With regard to pathogenesis, there is no consensus yet as to whether immune mediated injury or factors related to bile acid physiology are the most important. It also remains to be clarified whether PSC is a mixed bag of various secondary etiologies yet to be defined, or a disease entity predominantly represented by sclerosing cholangitis in the context of inflammatory bowel disease. Most important, there is no available medical therapy with proven influence on clinical end points, and timing of liver transplantation and patient follow-up are challenging due to the unpredictable and high risk of cholangiocarcinoma. Ó

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The G Protein-Coupled Bile Acid Receptor, TGR5, Stimulates Gallbladder Filling

Cited by 210 publications

References 21 publications

Cholesterol gallstone disease: focusing on the role of gallbladder

Cholesterol gallstone disease: focusing on the role of gallbladder

GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation

Update on primary sclerosing cholangitis

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