DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

THE BILE ACID TGR5 RECEPTOR IN LIVER REGENERATION AND REPAIR – BaTiLiRe

Submission summary

Tissue repair is orchestrated by a finely tuned interplay between processes of regeneration, inflammation and cell protection, allowing organisms to restore their integrity after partial loss of cells or organs. In the liver context, even though regeneration capacity is huge, tissue repair after injury (viral, toxic, autoimmune…) can lead to hepatic fibrosis, ultimately leading to cirrhosis with its increased morbidity and mortality. The only definitive treatment at an advanced stage of hepatic fibrosis (cirrhosis) is liver transplant (LT), although the shortage in organ grafts put forward the need for novel therapies to stimulate regeneration, protect liver cells and prevent and/or reverse fibrosis. An important, although largely unexplored feature is that after injury and during liver repair, liver functions have to be maintained to fulfill the peripheral demand. This is particularly critical for bile secretion, which has to be finely tuned in order to preserve liver parenchyma from bile-induced injury. However, mechanisms allowing the liver to maintain biliary homeostasis during repair after injury are not completely understood. Besides cytokines, hormones and growth factors, bile acids (BA) and their receptors constitute an insufficiently explored, although powerful, signaling network during liver regeneration and repair. BA are synthesized by hepatocytes, secreted in bile, and in normal conditions mostly cycle between the liver and the intestine (entero-hepatic cycle). However during liver injury or after partial hepatectomy (PH), BA spillover and subsequent BA overload occur in the liver and in the whole organism, which potential consequences on processes of inflammation, regeneration and biliary homeostasis remain largely ignored. BA signal through both their nuclear (mainly FXR) and membrane (mainly TGR5/GPBAR-1) receptors, which distributions are large in the organism, and which activation elicits a wide array of biological responses. TGR5 is not expressed in hepatocytes but is highly enriched in the biliary tract. While a number of studies have been dedicated to FXR signalling in liver pathophysiology, in particular during liver repair processes, TGR5 remains very poorly explored in the liver context. Our previous studies allowed us i) to demonstrate that PH was followed by an immediate and massive BA overload in rats, mice and humans; ii) that this BA overload participated to the regenerative response, and iii) that the lack of TGR5 in mice resulted in impaired liver regeneration mainly through an alteration of BA homeostasis. Preliminary data indicate that BA signaling through TGR5 has determining impact on survival after extended hepatectomy in mice, and that mechanisms through which TGR5 may act may include crucial regulatory processes for BA pool hydrophobicity on the one hand, and biliary epithelium permeability on the other hand. Based on these data obtained in acute BA overload context, the overall objective of the proposal is to determine the mechanisms by which BA signalling through TGR5, impacts biliary homeostasis during acute and chronic liver repair.
Our proposal will focus on the contribution of TGR5 in: A. Regulation of BA pool hydrophobicity; B. Control of biliary tract permeability; C. Overall hepato-protection during BA overload. These studies will be conducted in experimental mouse models, and in human patients in acute contexts (PH and LT) and in chronic cholestasis, mostly in primary sclerosing cholangitis. Based on collaboration between Inserm UMRS 1174 (T. Tordjmann, UPS, Orsay; Team 1), Inserm U1193 (JC Duclos-Vallée, Hôpital Paul Brousse, Villejuif; Team 2), Inserm U1157 (D. Rainteau, UPMC, Hôpital St-Antoine, Paris; Team 3) and Inserm U938 (C. Housset, Hôpital St-Antoine, Paris; Team 4), new mechanisms and therapeutic options are envisioned to modulate BA pool hydrophobicity and biliary tract permeability in clinical settings involving regeneration, inflammatory processes and BA overload.

Project coordination

Thierry Tordjmann (Interactions cellulaires et physiopathologie hépatique)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

UMR_S 938 Sorbonne Universités, UPMC Univ Paris 06 & Inserm, CDR Saint-Antoine, Equipe Maladies fibro-inflammatoires d'origine métabolique et biliaire du foie
INSERM 1193 PATHOGENESE ET TRAITEMENT DE L'HEPATITE FULMINANTE ET DU CANCER DU FOIE
INSERM U1157 MICROORGANISMES, MOLECULES BIOACTIVES ET PHYSIOPATHOLOGIE INTESTINALE
INSERM U1174 Interactions cellulaires et physiopathologie hépatique

Help of the ANR 561,704 euros
Beginning and duration of the scientific project: September 2015 - 42 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter