Stimulation of G Protein–Coupled Bile Acid Receptor Enhances Vascular Endothelial Barrier Function via Activation of Protein Kinase A and Rac1

Kida, Taiki; Omori, Keisuke; Hori, Masaru; Ozaki, Hiroshi; Murata, Takahisa

doi:10.1124/jpet.113.209288

Cited by 22 publications

(19 citation statements)

References 34 publications

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“…In metabolically active tissues such as adipose tissues and muscles, GPBAR1 regulates energy expenditure (16) and, in several tissues, exerts anti-inflammatory effects (17). In addition, GPBAR1 is expressed in the vascular system, and its activation by lithocholic acid and deoxycholic acid results in a robust vasodilatory effect (18)(19)(20)(21)(22)(23). This vasodilatory activity is endothelium independent (19)(20)(21) and partially reversed by inhibition of eNos or cystathionine-g-lyase (Cse), 2 enzymes essential for generation of 2 potent gaseous vasodilators, NO and hydrogen sulfide (H 2 S), in the vascular wall (22,23).…”

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confidence: 99%

Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis

et al. 2018

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Nonalcoholic steatohepatitis (NASH) is associated with an increased risk of developing cardiovascular complications and mortality, suggesting that treatment of NASH might benefit from combined approaches that target the liver and the cardiovascular components of NASH. Using genetic and pharmacologic approaches, we show that G protein–coupled bile acid–activated receptor 1 (GPBAR1) agonism reverses liver and vascular damage in mouse models of NASH. NASH is associated with accelerated vascular inflammation representing an independent risk factor for development of cardiovascular diseases and cardiovascular‐related mortality. GPBAR1, also known as TGR5, is a G protein–coupled receptor for secondary bile acids that reduces inflammation and promotes energy expenditure. Using genetic and pharmacologic approaches, we investigated whether GPBAR1 agonism by 6β‐ethyl‐3α,7β‐dihydroxy‐5β‐cholan‐24‐ol (BAR501) reverses liver and vascular damage induced by exposure to a diet enriched in fat and fructose (HFD‐F). Treating HFD‐F mice with BAR501 reversed liver injury and promoted the browning of white adipose tissue in a Gpbar1‐dependent manner. Feeding HFD‐F resulted in vascular damage, as shown by the increased aorta intima‐media thickness and increased expression of inflammatory genes (IL‐6, TNF‐α, iNOS, and F4/80) and adhesion molecules (VCAM, intercellular adhesion molecule‐1, and endothelial selectin) in the aorta, while reducing the expression of genes involved in NO and hydrogen sulfide generation, severely altering vasomotor activities of aortic rings in an ex vivo assay. BAR501 reversed this pattern in a Gpbar1‐dependent manner, highlighting a potential role for GPBAR1 agonism in treating the liver and vascular component of NASH.—Carino, A., Marchianò, S., Biagioli, M., Bucci, M., Vellecco, V., Brancaleone, V., Fiorucci, C., Zampella, A., Monti, M. C., Distrutti, E., Fiorucci, S. Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis. FASEB J. 33, 2809–2822 (2019). http://www.fasebj.org

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confidence: 99%

Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis

et al. 2018

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“…However the precise signal transduction mechanisms, in particular the BA receptors involved, were not investigated in these studies. In contrast, it has been suggested that TGR5‐dependent BA signalling reinforces intestinal and endothelial barriers in mice, 85,86 indicating that BA through multiple signalling pathways may elicit different effects on paracellular permeability, depending on the pathophysiological context and on the cell type involved. As the biliary tract is continuously bathed with BA, we studied the impact of BA signalling on cholangiocyte paracellular permeability.…”

Section: Tgr5‐dependent Protective Responses Against Ba Overloadmentioning

confidence: 99%

“…Early reports on TGR5 expression in endothelial cells pointed that BA through this receptor could elicit nitric oxide (NO) release 41,86,118 and thereby may protect liver parenchyma by modulating sinusoidal blood flow. Further evidence that TGR5 may modulate portal pressure and flow were recently reported, stating that TGR5 would also stimulate the release of other gaseous vasodilators 119 and inhibit endothelin 1 (ET‐1) secretion 120 .…”

Section: Tgr5‐dependent Protective Responses Against Ba Overloadmentioning

confidence: 99%

Hepatoprotective impact of the bile acid receptor TGR5

Merlen

Bidault

Kahale

et al. 2020

Liver International

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During liver repair after injury, bile secretion has to be tightly modulated in order to preserve liver parenchyma from bile acid (BA)-induced injury. The mechanisms allowing the liver to maintain biliary homeostasis during repair after injury are not completely understood. Besides their historical role in lipid digestion, bile acids (BA) and their receptors constitute a signalling network with multiple impacts on liver repair, both stimulating regeneration and protecting the liver from BA overload. BA signal through nuclear (mainly Farnesoid X Receptor, FXR) and membrane (mainly G Protein-coupled BA Receptor 1, GPBAR-1 or TGR5) receptors to elicit a wide array of biological responses. While a great number of studies have been dedicated to the hepato-protective impact of FXR signalling, TGR5 is by far less explored in this context. Because the liver has to face massive and potentially harmful BA overload after partial ablation or destruction, BA-induced protective responses crucially contribute to spare liver repair capacities. Based on the available literature, the TGR5 BA receptor protects the remnant liver and maintains biliary homeostasis, mainly through the control of inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity and sinusoidal blood flow. Mouse experimental models of liver injury reveal that in the lack of TGR5, excessive inflammation, leaky biliary epithelium and hydrophobic BA overload result in parenchymal insult and compromise optimal restoration of a functional liver mass. Translational perspectives are thus opened to target TGR5 with the aim of protecting the liver in the context of injury and BA overload. K E Y W O R D Sbile acids, bile acid pool, hepatoprotection, liver injury, paracellular permeability, TGR5 | B ILE ACIDS AND THE ENTEROHEPATI C C YCLEBile acids, the end products of cholesterol catabolism, are produced in hepatocytes and secreted in the canalicular lumen, flow through the bile ducts towards the duodenum, travel in the intestine until they are massively reabsorbed in the ileum back to the liver along the so-called enterohepatic cycle (EHC). The small BA fraction escaping from ileal reabsorption and flowing through the colon is then transformed by the gut microbiota, resulting in the production of secondary BA which are more hydrophobic -thus more toxic -than primary BA (those produced in hepatocytes). Hydrophobic secondary BA cross passively the colon epithelium and join the other BA

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“…Two endogenous lipid-derived molecules, namely, the phospholipid sphingosine 1-phosphate (S1P) and bile acids (generated from the lipid cholesterol), are known to increase endothelial barrier function. They do so by enhancing Rac1 activity via activation of their respective receptors, S1P receptor type 1 (van Hooren et al, 2014) and the G protein-coupled bile acid receptor (Kida et al, 2014). The sugar, hyaluronan, a glycosaminoglycan that is abundantly present in the extracellular matrix, can be generated in a high-molecular-weight (HMW-HA) or low-molecular-weight (LMW-HA) form and also modulates the endothelial barrier.…”

Section: Role Of Rac1 In the Vasculature Endothelial Cellsmentioning

confidence: 99%

The Ins and Outs of Small GTPase Rac1 in the Vasculature

Marinković

Heemskerk

Buul

et al. 2015

J Pharmacol Exp Ther

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The Rho family of small GTPases forms a 20-member family within the Ras superfamily of GTP-dependent enzymes that are activated by a variety of extracellular signals. The most well known Rho family members are RhoA (Ras homolog gene family, member A), Cdc42 (cell division control protein 42), and Rac1 (Ras-related C3 botulinum toxin substrate 1), which affect intracellular signaling pathways that regulate a plethora of critical cellular functions, such as oxidative stress, cellular contacts, migration, and proliferation. In this review, we describe the current knowledge on the role of GTPase Rac1 in the vasculature. Whereas most recent reviews focus on the role of vascular Rac1 in endothelial cells, in the present review we also highlight the functional involvement of Rac1 in other vascular cells types, namely, smooth muscle cells present in the media and fibroblasts located in the adventitia of the vessel wall. Collectively, this overview shows that Rac1 activity is involved in various functions within one cell type at distinct locations within the cell, and that there are overlapping but also cell type-specific functions in the vasculature. Chronically enhanced Rac1 activity seems to contribute to vascular pathology; however, Rac1 is essential to vascular homeostasis, which makes Rac1 inhibition as a therapeutic option a delicate balancing act.

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Stimulation of G Protein–Coupled Bile Acid Receptor Enhances Vascular Endothelial Barrier Function via Activation of Protein Kinase A and Rac1

Cited by 22 publications

References 34 publications

Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis

Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis

Hepatoprotective impact of the bile acid receptor TGR5

The Ins and Outs of Small GTPase Rac1 in the Vasculature

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