The bile acid receptor TGR5 inhibits platelet activation and thrombus formation
Creators: name: Reusswig, Friedrich
name: Reich, Maria
name: Wienands, Leonard
name: Herebian, Diran
name: Keitel-Anselmino, Verena
name: Elvers, Margitta
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Biochemistry
subject: Medicine
subject: Pharmacology
subject: Chemical Sciences not elsewhere classified
subject: Science Policy
subject: Immunology
subject: FOS: Clinical medicine
subject: Cancer
subject: Hematology
subject: Infectious Diseases
subject: FOS: Health sciences

description: Liver failure and cirrhosis are characterized by abnormal hemostasis with aberrant platelet activation. In particular, the consequences of cholestatic liver disease and molecular mechanisms, including the role of bile acids leading to impaired platelet responses, are not well understood. Here, we demonstrate that bile acids inhibit human and murine platelet activation, adhesion and spreading, leading to reduced thrombus formation under flow conditions. We identified the G-protein coupled receptor TGR5 in platelets and provide support for its role as mediator of bile acid-induced impairment of platelet activation. In the liver, TGR5 couples to Gαs proteins, activates the adenylate cyclase to induce a transient cAMP rise and stimulates the MAPK signaling pathway to regulate cholangiocyte proliferation, hepatocyte survival and inflammation. In this report, we demonstrate that the genetic deficiency of TGR5 in mice led to enhanced platelet activation and thrombus formation, suggesting that TGR5 plays an important role in hemostasis. Mechanistically, platelet inhibition is achieved by TGR5 mediated PKA activation and modulation of AKT and ERK1/2 phosphorylation. Thus, this report provides evidence for the ability of TGR5 ligands to reduce platelet activation and identifies TGR5 agonism as a new target for the prevention of cardiovascular diseases. <b>What is the context?</b>Liver failure or cirrhosis are related to impaired hemostasis and a role of bile acids in impaired platelet responses is known but only less understood.Platelets express the bile acid receptor FXR. Ligand binding to the FXR on platelets causes a shift in platelet reactivity and is atheroprotective suggesting that the FXR is a potential target for the prevention of atherothrombotic diseases. Liver failure or cirrhosis are related to impaired hemostasis and a role of bile acids in impaired platelet responses is known but only less understood. Platelets express the bile acid receptor FXR. Ligand binding to the FXR on platelets causes a shift in platelet reactivity and is atheroprotective suggesting that the FXR is a potential target for the prevention of atherothrombotic diseases. <b>What is new?</b>Treatment of murine and human blood with bile acids in low molecular quantity led to reduced platelet activation, adhesion and thrombus formation.The bile acid receptor TGR5 was identified on human and murine platelets.TGR5 plays an important role in hemostasis because TGR5 deficient mice showed elevated platelet reactivity and enhanced thrombus formation.Loss of TGR5 led to enhanced PKA activation and modulated the phosphorylation of MAPK such as AKT and ERK1/2. Treatment of murine and human blood with bile acids in low molecular quantity led to reduced platelet activation, adhesion and thrombus formation. The bile acid receptor TGR5 was identified on human and murine platelets. TGR5 plays an important role in hemostasis because TGR5 deficient mice showed elevated platelet reactivity and enhanced thrombus formation. Loss of TGR5 led to enhanced PKA activation and modulated the phosphorylation of MAPK such as AKT and ERK1/2. <b>What is the impact?</b>Impairment of platelet activation by bile acids is mediated by TGR5 via the protein kinase A signaling pathway.Our findings provide evidence for the modulation of TGR5 activation as a potential new target of both, anti-platelet therapy in cardiovascular diseases and the restoration of hemostasis upon liver injury. Impairment of platelet activation by bile acids is mediated by TGR5 via the protein kinase A signaling pathway. Our findings provide evidence for the modulation of TGR5 activation as a potential new target of both, anti-platelet therapy in cardiovascular diseases and the restoration of hemostasis upon liver injury.