TGR5 (GPBAR1) in the Liver

Keitel, Verena; Gertzen, Christoph G. W.; Spomer, Lina; Gohlke, Holger; Häussinger, Dieter

doi:10.1002/9781119436812.ch24

Cited by 13 publications

(17 citation statements)

References 116 publications

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“… 161 Activation of TGR5 triggers the formation of bicarbonate umbrella, promotes the integrity of tight junctions and mediates bile duct bicarbonate secretion via anion exchanger 2, regulates intracellular acid-base balance and protects BECs from BA toxicity. 162 Further studies 163 , 164 have shown that TGR5 activation reduces reactive oxygen species production by inhibiting NF-κB-dependent pro-inflammatory cytokine production and activating Nrf2/HO-1 signaling, and also promotes β-catenin signaling to activate the PI3K/ AKT signaling pathway, thereby inhibiting the inflammatory response to counteract cholestasis. In general, during cholestasis, activation of TGR5 in BECs facilitates the secretion of chloride and bicarbonate, triggers cell proliferation and protects against apoptotic cell death; activation of TGR5 in immune cells suppresses cytokine expression and secretion, thereby reducing systemic as well as hepatic and intestinal inflammation.…”

Section: The Triangular Relationship Of Gut Microbiota-bas-cholestasismentioning

confidence: 99%

Cholestasis: exploring the triangular relationship of gut microbiota-bile acid-cholestasis and the potential probiotic strategies

Liu

Wang

et al. 2023

Gut Microbes

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Cholestasis is a condition characterized by the abnormal production or excretion of bile, and it can be induced by a variety of causes, the factors of which are extremely complex. Although great progress has been made in understanding cholestasis pathogenesis, the specific mechanisms remain unclear. Therefore, it is important to understand and distinguish cholestasis from different etiologies, which will also provide indispensable theoretical support for the development of corresponding therapeutic drugs. At present, the treatment of cholestasis mainly involves several bile acids (BAs) and their derivatives, most of which are in the clinical stage of development. Multiple lines of evidence indicate that ecological disorders of the gut microbiota are strongly related to the occurrence of cholestasis, in which BAs also play a pivotal role. Recent studies indicate that probiotics seem to have certain effects on cholestasis, but further confirmation from clinical trials is required. This paper reviews the etiology of and therapeutic strategies for cholestasis; summarizes the similarities and differences in inducement, symptoms, and mechanisms of related diseases; and provides information about the latest pharmacological therapies currently available and those under research for cholestasis. We also reviewed the highly intertwined relationship between gut microbiota-BA-cholestasis, revealing the potential role and possible mechanism of probiotics in the treatment of cholestasis.

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Section: The Triangular Relationship Of Gut Microbiota-bas-cholestasismentioning

confidence: 99%

Cholestasis: exploring the triangular relationship of gut microbiota-bile acid-cholestasis and the potential probiotic strategies

Liu

Wang

et al. 2023

Gut Microbes

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“…In addition, TGR5 has been identified as a negative regulator of liver inflammation via inhibiting NF-κB signaling [ 128 , 140 – 142 ]. TGR5 activation can induce cholangiocyte regeneration to maintain the integrity of the biliary tree and control the hydrophobicity of BA pools by stimulating bicarbonate secretion [ 28 , 141 , 143 ]. In the BDL and BA-feeding cholestatic mouse models, TGR5 −/− mice appeared to develop more severe inflammation and cholestatic liver injury than WT mice.…”

Section: Bas In Cholestatic Liver Diseasesmentioning

confidence: 99%

Bile acid-mediated signaling in cholestatic liver diseases

Zeng¹,

Fan²,

Zhou³

2023

Cell Biosci

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Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are associated with bile stasis and gradually progress to fibrosis, cirrhosis, and liver failure, which requires liver transplantation. Although ursodeoxycholic acid is effective in slowing the disease progression of PBC, it has limited efficacy in PSC patients. It is challenging to develop effective therapeutic agents due to the limited understanding of disease pathogenesis. During the last decade, numerous studies have demonstrated that disruption of bile acid (BA) metabolism and intrahepatic circulation promotes the progression of cholestatic liver diseases. BAs not only play an essential role in nutrition absorption as detergents but also play an important role in regulating hepatic metabolism and modulating immune responses as key signaling molecules. Several excellent papers have recently reviewed the role of BAs in metabolic liver diseases. This review focuses on BA-mediated signaling in cholestatic liver disease.

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“…146 TGR5 regulates microcirculation, inflammation, regeneration, biliary secretion, proliferation, and gallbladder filling in liver. 146 TGR5 is mainly expressed in hepatic macrophages which is involved in anti-inflammatory and anti-apoptotic processes, affecting the occurrence and development of multiple liver diseases. 147,148 (Figure 3G) The immunomodulatory function inducted by BA-TGR5 signaling was first reported in 2003.…”

Section: Bile Acids-tgr5 Signalingmentioning

confidence: 99%

“…147 Furthermore, TGR5 inhibits the cytokines release from macrophages in LPS-induced damage, preventing cytokines overproduction and liver damage. 153 TGR5 directly play an anti-inflammatory role in the liver, 146 which may be an important means to prevent the progression from NAFLD to NASH. 4.2.3 | TGR5 signaling in the brown and white adipose tissue…”

Section: Bile Acids-tgr5 Signalingmentioning

confidence: 99%

“…In the liver, TGR5 is expressed in non‐parenchymal cells, including sinusoidal endothelial cells, Kupffer cells (a type of liver‐specific macrophage), cholangiocytes, and activated hepatic stellate cells 146 . TGR5 regulates microcirculation, inflammation, regeneration, biliary secretion, proliferation, and gallbladder filling in liver 146 .…”

Section: Bile Acids Signalingmentioning

confidence: 99%

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Physical exercise plays a role in rebalancing the bile acids of enterohepatic axis in non‐alcoholic fatty liver disease

Zhang,

Xiao,

Chen

et al. 2023

Acta Physiologica

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Non‐alcoholic fatty liver disease (NAFLD) is considered as one of the most common diseases of lipid metabolism disorders, which is closely related to bile acids disorders and gut microbiota disorders. Bile acids are synthesized from cholesterol in the liver, and processed by gut microbiota in intestinal tract, and participate in metabolic regulation through the enterohepatic circulation. Bile acids not only promote the consumption and absorption of intestinal fat but also play an important role in biological metabolic signaling network, affecting fat metabolism and glucose metabolism. Studies have demonstrated that exercise plays an important role in regulating the composition and function of bile acid pool in enterohepatic axis, which maintains the homeostasis of the enterohepatic circulation and the health of the host gut microbiota. Exercise has been recommended by several health guidelines as the first‐line intervention for patients with NAFLD. Can exercise alter bile acids through the microbiota in the enterohepatic axis? If so, regulating bile acids through exercise may be a promising treatment strategy for NAFLD. However, the specific mechanisms underlying this potential connection are largely unknown. Therefore, in this review, we tried to review the relationship among NAFLD, physical exercise, bile acids, and gut microbiota through the existing data and literature, highlighting the role of physical exercise in rebalancing bile acid and microbial dysbiosis.

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TGR5 (GPBAR1) in the Liver

Cited by 13 publications

References 116 publications

Cholestasis: exploring the triangular relationship of gut microbiota-bile acid-cholestasis and the potential probiotic strategies

Cholestasis: exploring the triangular relationship of gut microbiota-bile acid-cholestasis and the potential probiotic strategies

Bile acid-mediated signaling in cholestatic liver diseases

Physical exercise plays a role in rebalancing the bile acids of enterohepatic axis in non‐alcoholic fatty liver disease

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