The Bile Acid Receptor TGR5 and Liver Regeneration

Abstract

Background: Most of the literature on the bile acid (BA) membrane receptor TGR5 is dedicated to its potential role in the metabolic syndrome, through its regulatory impact on energy expenditure, insulin and GLP-1 secretion, and inflammatory processes. While the receptor was cloned in 2002, very little data are available on TGR5 functions in the normal and diseased liver. However, TGR5 is highly expressed in Kupffer cells and liver endothelial cells, and is particularly enriched in the biliary tract [cholangiocytes and gallbladder (GB) smooth muscle cells]. We recently demonstrated that TGR5 has a crucial protective impact on the liver in case of BA overload, including after partial hepatectomy. Key Messages: TGR5-KO mice after PH exhibited periportal bile infarcts, excessive hepatic inflammation and defective adaptation of biliary composition (bicarbonate and chloride). Most importantly, TGR5-KO mice had a more hydrophobic BA pool, with more secondary BA than WT animals, suggesting that TGR5-KO bile may be harmful for the liver, mainly in situations of BA overload. As GB is both the tissue displaying the highest level of TGR5 expression and a crucial physiological site for the regulation of BA pool hydrophobicity by reducing secondary BA, we investigated whether TGR5 may control BA pool composition through an impact on GB. Preliminary data suggest that in the absence of TGR5, reduced GB filling dampens the cholecystohepatic shunt, resulting in more secondary BA, more hydrophobic BA pool and extensive liver injury in case of BA overload. Conclusions: In the setting of BA overload, TGR5 is protective of the liver through the regulation of not only secretory and inflammatory processes, but also through the control of BA pool composition, at least in part by targeting the GB. Thereby, TGR5 appears to be crucial for protecting the regenerating liver from BA overload.

The role of bile salts in liver regeneration

“…In the liver, Tgr5 is expressed by Kupffer cells and cholangiocytes. PHx in Tgr5 -/-mice resulted in prolonged elevations of circulating and hepatic bile salts, severe necrosis, an aggravated inflammatory response, and delayed liver regeneration [54]. The liver injury observed in hepatectomized Tgr5 -/-mice is likely caused by bile salt-induced toxicity [55].…”

“…Cholestasis is an established risk factor for PLF [59], and patients with jaundice due to bile duct obstruction or parenchymal liver disease have increased morbidity rates following PHx [59,60]. This implicates dysregulated bile salt homeostasis and bile salt toxicity in the defective regenerative response observed in patients with PLF, as mirrored in impaired liver regeneration in Fxr and Tgr5 knockout models [26,47,48,54,55]. Enhanced Kupffer cell activation is thought to occur in PLF, resulting in an excessive inflammatory response and hepatocyte death through pro-inflammatory cytokine triggered pathways [60].…”

Les lésions hépatiques induites par la cholestase : le rôle de S1PR2

“…À l'inverse, l'activation du récepteur TGR5 par les acides biliaires secondaires est connue pour ses propriétés protectrices et favorisant la régénération en condition de surcharge en acides biliaires. Elle pourrait ainsi s'opposer à l'évolution vers la fibrose [4,6] (Figure 2 …”

“…bactériennes comme récemment démon-tré pour S. aureus [10] [3,4]. L'activation de TGR5 par les acides biliaires secondaires stimule la prolifération et inhibe l'apoptose des cholangiocytes [5].…”

“…Au niveau des macrophages, TGR5 limite la production de cytokines pro-inflammatoires [6]. Ainsi, les récepteurs FXR et TGR5 sont aujourd'hui associés à la régénéra-tion et la protection hépatiques en cas de surcharge en acides biliaires [3,4,6], et pourraient représenter des cibles théra-peutiques intéressantes lors de certaines pathologies biliaires. Le récepteur S1PR2, fortement exprimé dans le foie, est l'un des cinq récepteurs membranaires de la S1P (sphingosine-1-phosphate).…”