Bile Acids and Liver Regeneration Dig Dis 2015;33:319–326 DOI: 10.1159/000371668

The Bile Acid Receptor TGR5 and Liver Regeneration Valeska Jourdainne a Noémie Péan a Isabelle Doignon a Lydie Humbert b, c Dominique Rainteau b, c Thierry Tordjmann a a

INSERM U 1174, Université Paris Sud, Orsay, and b ERL INSERM U 1057, Faculté de Médecine Pierre et Marie Curie, and c UMR 7203, ENS, CNRS, UPMC, Paris, France

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 physiolog-

© 2015 S. Karger AG, Basel 0257–2753/15/0333–0319$39.50/0 E-Mail [email protected] www.karger.com/ddi

ical 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. © 2015 S. Karger AG, Basel

Liver Regeneration: A Physiological View

After a two-third partial hepatectomy (PH) or after partial parenchymal destruction, the rodent liver is restored to its initial functional mass within a few days during which a complex array of proliferative and hepatoprotective signaling cascades operate, involving cytokines, growth factors and other paracrine and endocrine agonists [1, 2]. From a molecular point of view, these cascades have been widely explored in the last 30 years. Thierry Tordjmann INSERM U 757 Université Paris Sud FR–91405 Orsay (France) E-Mail Thierry.tordjmann @ u-psud.fr

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Key Words Hepatectomy · Bile acid overload · Bile secretion · G protein-coupled receptor · Inflammation · Gallbladder

BAs and Liver Regeneration

An important, although largely unexplored feature is that after injury and during repair, liver functions have to be maintained both to protect the liver and to fulfill the peripheral demand. This is particularly critical for bile secretion, which has to be finely tuned to preserve liver parenchyma from BA-induced injury. Accordingly, a number of recent papers point to the crucial need for a 320

Dig Dis 2015;33:319–326 DOI: 10.1159/000371668

tight regulation of BA homeostasis after PH or liver injury, unless regeneration would be greatly compromised. While most of these reports converge on a central role for FXR signaling as detailed below [12, 13], other pathways still remain to be deeply explored. Although in the basal state BA are physiologically almost confined within the enterohepatic cycle, significant spillover occurs after partial removal (or chemical destruction) of the liver, allowing BA to massively reach the whole organism through blood circulation (systemic BA overload). As a consequence, intrahepatic BA overload occurs during the first hours after PH [4, 8]. Although systemic diffusion of BA may drive important and mostly unexplored regulatory signaling cascades through their widely expressed receptors in the liver as well as in the whole organism, such a massive overload with potentially harmful detergent BA may also have deleterious effects, especially on liver tissue. Through farnesoid X receptor (FXR) stimulation, BA signals for the need of hepatocyte protection and division after PH or liver injury [14, 15]. On the one hand, the remnant liver adapts to the immediate BA overload by downregulating BA synthesis and uptake via FXR-dependent pathways [16, 17]. On the other hand, FXR-dependent stimulation of the hepatocyte cell cycle progression is also reported as crucial, mainly through the activation of a major transcription factor, FoxM1b [14]. Thus, after partial ablation or destruction of the liver, the remnant liver has to face massive BA overload that could be harmful, putting the FXR-dependent adaptive response in a central position to protect the regenerating organ. The positive impact of BA on liver regeneration has also been reinforced by BA supplementation or BA sequestering resin feeding experiments in different models of liver regeneration [14, 15, 18]. Cholic acid (CA) feeding indeed favors liver regrowth after PH, but BA resins inhibit regeneration, in an FXR-dependent manner [14]. In the acetaminophen-induced liver injury mouse model, CA feeding has also been recently reported as a means to protect the liver and to enhance regeneration [18]. In the same line, BA synthesis which is too small (CYP27–/– mice) [19] or inhibited BA flux in the enterohepatic cycle in rodents (Mrp3–/– [20] or ASBT–/– [9] mice, rat biliary fistula [9]) or in human patients (external biliary drainage [21]) have been reported as being deleterious for the regenerating liver. BA would thus appear as dual messengers, both signaling protection and proliferation in hepatocytes. The inhibition of BA synthesis on its own, which is obviously protective against BA overload as occurring during regeneration, has also been reported to be a crucial step for the initiation of heJourdainne/Péan/Doignon/Humbert/ Rainteau/Tordjmann

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Therefore, although a lot probably remains to be discovered in this field, the different molecular pathways involved in hepatocyte entry into the cell cycle in the regenerating liver have been extensively studied [1, 2]. From a physiological, more integrated point of view, the regenerating liver has been, by far, less explored. However, physiological processes occurring not only in the liver but also in the whole organism during liver regeneration may turn out to be key events for the initiation, course and termination of liver repair. In other words, immediate physiological events, in particular hemodynamic and metabolic, occur in the liver after PH and could be of major impact for triggering regeneration. One of the first major consequences of a two-third removal of the hepatic vascular bed while incoming liver blood flow remains unchanged or even increases is an immediate rise in intrahepatic and portal vein pressure, which potential signaling consequences remain mostly unexplored [3–5]. PH is also immediately followed by an abrupt and massive decrease in liver uptake and synthesis capacity, leading to sharp variations (increases or decreases) in the blood concentration of numerous compounds, otherwise taken up or released by the liver. This has been well described for blood glucose concentrations, the decrease of which has been proposed as an important trigger for hepatocyte proliferation [6, 7]. Another major example is the post-PH bile acid (BA) overload, which occurs immediately after liver parenchymal reduction, and for which signaling consequences inside and outside the liver remain to be closely investigated [4, 8, 9]. After PH or partial liver destruction, BA return from the intestine through the portal circulation becomes suddenly too high for the remnant liver uptake and secretion capacity, leading to an immediate BA rise in the systemic blood. This immediate and prolonged BA overload has been reported in mice and rats [4, 8, 9], as well as humans [4, 10]. In the same line, BA overload has been reported after portal vein embolization in rabbits [11] and humans [10].

TGR5 and Liver Regeneration

Partial hepatectomy/liver injury

– Liver protection

BA flux (BA overload)

– Liver protection

FGF15 CYP7A1 NTCP

Enterocyte

FXR

BSEP Hepatocyte

STAT3

Hepatocyte

FGF15 FoxM1b

Enterocyte

Liver growth

Fig. 1. Schematic overview of FXR involvement in liver regeneration. After PH or liver injury, BA flux is increased and BA overload occurs. FXR activation by BA leads to adaptive responses in the hepatocyte and in the enterocyte. In the hepatocyte, BA synthesis (CYP7A1) and BA entry (NTCP) are downregulated, whereas BA export (BSEP, OSTα/β) is upregulated. FXR also activates hepatocyte proliferation through the transcription factor FoxM1b. In the enterocyte, FGF15 induction both inhibits BA synthesis and stimulates hepatocyte and cholangiocyte proliferation.

As stated above, BA-enriched diets have been reported to induce hepatocyte proliferation, but it is not always clear if this effect is direct or due to a damage-induced regenerative response [32]. It seems that in the normal quiescent liver, hepatocytes would be less responsive to BA than in the injured or regenerative parenchyma [32], as it has been well reported for growth factors [1, 2]. Few studies on the direct effects of BA on isolated hepatocytes have been published, and have provided conflicting results by either stating that BA inhibits or stimulates DNA synthesis [32, 33]. Interestingly, no clear correlation appeared between the hydrophilic/hydrophobic balance and the pro-/antiproliferative properties of BA [33]. Cholangiocyte proliferation appeared to be more clearly impacted by BA challenge, TCA and TLCA being promitogenic whereas UDCA is antimitogenic [34, 35]. Although mechanisms were not completely defined, different signaling pathways have been involved in BA action on cell proliferation in hepatocytes as well as cholangiocytes [36, 37]. The involvement of BA receptors in those effects on liver cell proliferation remains to be precisely explored [38]. As a schematic conclusion for this part, BA likely plays multiple roles during liver regeneration (fig.  1). Because of their ‘physiological’ accumulation after liver removal, they initiate an FXR-dependent adaptive reDig Dis 2015;33:319–326 DOI: 10.1159/000371668

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patocyte proliferation after CCl4 intoxication [22]. Intriguingly, the rapid post-PH CYP7A1 mRNA downregulation has been recently reported as independent from blood BA elevation [9]. It is also important to emphasize that, while powerful, the adaptive face of BA signaling may be overwhelmed if the BA overload would be too high for a remnant liver that is too small. This could be the case especially after extended PH, although only limited reports have been published [23–25, and unpubl. data]. Besides FXR-dependent adaptive responses occurring in hepatocytes, relatively little emphasis has been made about the potential impact of enterocyte adaptation during liver regeneration. Although the total FXR-KO [14] was reported with a more severe post-PH phenotype than either the hepatocyte or ileal-specific FXR-KO, there is evidence that both hepatocyte and ileal FXR contribute to control liver regeneration [26, 27]. While much probably remains to be deciphered in this field, recent studies have provided evidence that the FXR-dependent gut-liver hormone (‘enterokine’) FGF15 in mice (FGF19 in humans) has both protective and proregenerative roles after PH [28, 29]. However, the precise mechanisms by which FGF15 signaling would be activated after PH, and the pathways through which FGF15 would signal to liver cells to enhance regeneration, still remain to be fully explored. FXR-dependent FGF15 synthesis in the ileum is driven by the transenterocytic BA flux from the intestinal lumen toward the basolateral side [30]. Once released in portal blood, FGF15 is mainly reported to regulate BA homeostasis through an FGFR4-dependent CYP7A1 transcriptional inhibition in hepatocytes [30]. Through this inhibitory effect, FGF15, as stated above for other FXR-dependent target genes, may appear as an important factor for liver protection after PH. Indeed, this has been reported recently: FGF15-KO mice exhibited a poor adaptive response after PH, with insufficient repression of BA synthesis presumably leading to excessive BA overload and massive hepatic necrosis after PH [28, 29]. Besides this mechanism, FGF15 may also contribute to liver regeneration through the direct stimulation of hepatocyte and cholangiocyte proliferation [28], potentiating the previously reported direct action of BA on these cells (see below). However, the impact of FGF15 on liver regeneration remains controversial, especially because FGFR4-KO mice do regenerate normally [31]. Moreover, ileal FGF15 mRNA was recently reported to be sharply downregulated after PH in mice and rats, before the moment when CYP7A1 is expected to be suppressed, suggesting that FGF15 would not be crucially responsible for BA synthesis inhibition [9].

–

–

BA flux

Liver protection

Liver protection Cytokine secretion

Kupffer cell HCO3–/Cl– secretion

Kidney TGR5

BA elimination urine

? ‘Bile toxicity’

BA pool hydrophobicity

Cholangiocyte Optimal liver growth

Fig. 2. Schematic overview of TGR5 involvement in liver regeneration. After PH or liver injury, BA flux is increased and BA overload occurs. TGR5 activation may lead to cytokine secretion inhibition in Kupffer cells, stimulation of BA elimination in urine, stimulation of bicarbonate and chloride secretion in cholangiocytes, and reduction in BA pool hydrophobicity. All these processes are protective for the remnant liver against BA overload. Stimulation of bicarbonate and chloride secretion in cholangiocytes together with reduction in BA pool hydrophobicity reduce the overall bile toxicity. By protecting the remnant regenerating liver from BA overload, TGR5 would become crucial for optimal liver growth.

sponse both in hepatocytes and enterocytes. Importantly, this adaptive response intrinsically induces not only protective but also proliferative cascades in the liver, thereby favoring regeneration. It should be noted that beyond a certain threshold of liver resection or injury, BA overload may become more deleterious than beneficial, with yet unrecognized consequences on the fate of the remnant liver. It should also be kept in mind that FXR-independent processes induced by BA, although very poorly explored, may play important roles during regeneration. Apart from FXR, BA also signals through dedicated membrane-bound receptors, mainly represented by the G protein-coupled receptor ‘GPBAR1’ (or TGR5). This BA receptor is expressed in numerous cell types and organs [39, 40], including the liver where its functions essentially remain to be defined [41]. TGR5 activation by BA is coupled with cAMP production in a number of cell types, and coupling to calcium mobilization has also been 322

Dig Dis 2015;33:319–326 DOI: 10.1159/000371668

TGR5 Protects the Liver against BA Overload after PH

In a recent study we provided evidence that, in TGR5KO mice, PH was followed by massive cholestasis and hepatocyte necrosis, and that liver regeneration was markedly delayed as compared with WT mice [8]. After PH, TGR5 may protect the BA-overloaded remnant liver at least in part through control of BA hydrophobicity and through a fine-tuning of inflammatory processes. We also suggested that TGR5 regulates ion exchange in bile and BA efflux in urine, providing further protection against BA overload. As a result, the ability to challenge BA overload before significant cell damage occurs was in some way exceeded in TGR5-KO mice. The mechanisms through which TGR5 would efficiently protect the liver against post-PH BA overload are likely to be multiple (fig. 2). First, the exacerbated postPH induction of cytokines observed in TGR5-KO mice may have contributed to delay regeneration, enhance cholestasis [49] and favor hepatocyte necrosis. TGR5 may thus take part in the known fine-tuning of cytokine production and release after PH in a balanced way to both protect liver cells and promote them for growth factordependent progression into the cell cycle [1, 2]. Second, TGR5-KO mice exhibited a more hydrophobic BA composition, as reported previously [48, 50], suggesting that too much hydrophobic BA accumulating in the TGR5KO liver immediately after PH may have led to liver injury. In line with this hypothesis, the post-PH phenotype was rescued in experiments with a BA resin diet [8]. Jourdainne/Péan/Doignon/Humbert/ Rainteau/Tordjmann

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Partial hepatectomy/liver injury

suggested [42]. As a crucial regulator of energy homeostasis, TGR5 has been reported as a potential target for the treatment of metabolic syndrome and its complications, including NASH, in the context of diabetes and obesity [41–43]. TGR5 has been weakly or not significantly detected in rodent hepatocytes. However, its activation by BA stimulates nitric oxide production by rat liver endothelial cells [44] and decreases lipopolysaccharide-induced cytokine gene induction in rat Kupffer cells [45]. TGR5 is also believed to control cholangiocyte chloride (Cl–) secretion in human gallbladder (GB) [46], and to regulate GB filling [47, 48]. Although some of these reported TGR5-dependent processes (nitric oxide production, cytokine gene induction and energy expenditure regulation) are well known to contribute to the complex regulation of liver regeneration, the precise place of TGR5 had to be investigated.

TGR5 and Liver Regeneration

ing in a weaker ‘trophic pressure’ and reduced liver size. Second, a fraction of TGR5-KO mice (approx. 20%) spontaneously exhibited mild portal inflammation and fibrosis. Although it remains to be explored, this phenotype may be due to excessive gut permeability observed in those mice [61], likely associated with chronic hepatic exposure to abnormally high lipopolysaccharide concentrations together with a BA pool that is too hydrophobic. Both of these harmful factors may potentially create noxious conditions in the portal tract microenvironment and ultimately lead to chronic inflammation and fibrosis.

TGR5 Impact on BA Pool Hydrophobicity: Possible Mechanisms

As already mentioned, BA pool composition was more hydrophobic in TGR5-KO than in WT mice, both before and after PH. This was found in bile, plasma and liver, as well as in feces. Namely, muricholic acid (MCA), a hydrophilic primary BA in mice, as well as the MCA/ CA ratio taken as a marker of hydrophilicity, were strongly reduced in TGR5-KO mice before and after PH as compared with WT mice. It is also important to note that secondary BA was significantly overrepresented in the different tissue compartments from TGR5-KO mice, further increasing the hydrophobic component of the BA pool. Although similar observations were partly reported in previous studies [48, 50], the precise mechanisms linking TGR5 to BA pool composition remain to be elucidated. Among possible avenues, the following hypothesis may be proposed. One is that TGR5 may control BA synthesis in hepatocytes, although this would seem unlikely because of its very weak expression in this cell type [44]; based on our data the different CYP involved in BA synthesis were not differentially expressed in WT and TGR5KO livers [8]. Another is that TGR5 may control BA transformation in the intestine by controlling directly or indirectly the gut microbiota function and/or composition. This hypothesis would need further investigation to be fully explored. Through the control of colonic motility, TGR5 may also indirectly impact secondary BA production by the gut microbiota [61]. An additional hypothesis is that as mentioned above, TGR5 regulates chloride and bicarbonate transport in bile. This may reduce BA protonation, and as a consequence may protect bile duct cells and the liver parenchyma from BA cytotoxicity [55, 56]. Finally, because TGR5 is expressed in Dig Dis 2015;33:319–326 DOI: 10.1159/000371668

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Strengthening the idea that TGR5 may control bile hydrophobicity, bile from TGR5-overexpressing mice was less hydrophobic than WT bile [8]. Previous studies have found that BA pool size and composition were altered after PH [17, 51]. A relative decrease of CDCA and secondary BA as compared with an increase in CA was observed in the first days after PH in the rat, suggesting that the BA pool shifted toward a more hydrophilic composition early during regeneration. Also, the reappearing of more hydrophilic fetal BA (so-called ‘flat BA’) during regeneration has been proposed, although the relevance for liver growth still remains speculative [23, 52]. However, it was not known if the regulation of BA pool hydrophobicity would be crucial for hepatocyte protection and proliferation after PH or injury. Recently, dysregulated BA metabolism with a shift toward a more hydrophobic pool was associated with inhibited liver regeneration [53]. Third, TGR5 appeared to contribute to adapt bile composition in ions after PH, most likely reflecting processes that occur in cholangiocytes, in line with the proposition that TGR5 would control CFTR-dependent Cl– secretion in different epithelial cells [46, 54]. The observed TGR5dependent post-PH increase in biliary HCO3– and Cl– output may be part of an adaptive mechanism enhancing bile secretion and bile fluidity, thereby protecting the overloaded remnant liver from BA toxicity [55, 56]. Such data on the potential modulation of biliary ionic composition after PH had not been previously reported, although biliary bicarbonate output was reported to increase in the days after PH in the rat [57]. Although CFTR and AE2 mRNA were similarly expressed in the basal and post-PH livers and gallbladders from WT and TGR5-KO mice, TGR5 may regulate ion exchange in bile in the posttranslational steps through cAMP-mediated mechanisms [58]. Finally, our data suggest that TGR5 may contribute to BA elimination in urine, through yet unexplored mechanisms. TGR5 may at least control MRP2 and MRP4 gene expression in conditions of BA overload, and thus contribute to protect the organism from BA overload [8]. Deficient urinary BA elimination may thus worsen liver injury in case of BA overload, which is in line with previous reports [59, 60]. Interestingly, apart from the phenotype observed in TGR5-KO mice upon BA overload, we found that the lack of TGR5 impacts basal liver homeostasis. First, the liver weight/body weight ratio is significantly lower in TGR5-KO than in WT mice. As TGR5 is involved in the regulation of energy expenditure, it is possible that in the absence of TGR5, low-energy expenditure would be associated with less metabolic demand on the liver, result-

epithelial cells located all along the sites where BA is transported during its enterohepatic circuit, it is tempting to speculate that this BA receptor may have regulatory roles on BA transepithelial fluxes in the ileum, biliary tract and kidney, and thereby on BA pool composition. In normal conditions, most BA will cycle between the liver and the intestine through the enterohepatic cycle. GB bile, released into the duodenum upon feeding, primarily emulsifies dietary lipids. In the intestine, primary BA are transformed by the gut microbiota, resulting in the formation of toxic (more hydrophobic) secondary BA. In the ileum, most BA is reabsorbed and returned to the liver. Beside the enterohepatic cycle, a cholecystohepatic shunt has been described, by which BA from the GB are reabsorbed toward portal circulation, and return directly to the liver, bypassing the intestine [62]. Thus, the cholecystohepatic shunt restricts the amount of toxic secondary BA entering the liver. Overall, the enterohepatic cycle and cholecystohepatic shunt are essential for determining BA pool hydrophobicity. GB is both the tissue displaying the highest level of TGR5 expression [39, 50] and a crucial physiological site for the regulation of BA pool hydrophobicity through the cholecystohepatic shunt [62]. As one of the most remarkable features observed in TGR5-KO mice is the excessive hydrophobicity of the BA pool, we asked if an alteration in the cholecystohepatic shunt could be responsible for this phenotype. Unpublished experiments from our laboratory have suggested that GB filling was indeed controlled by TGR5, and that this control may result in regulation of the BA pool hydrophobicity.

Conclusion

Even though regeneration capacity is huge in the liver, tissue repair has to be tightly coupled with liver protection, otherwise liver injury and organ failure may develop. After PH or liver injury, the remnant liver faces BA overload and BA pool modifications that generate both protective and proliferative signaling pathways. Among these adaptive responses, FXR-dependent signaling is reported as being crucial for liver regeneration. We found that the other main BA receptor, TGR5, also protects the liver against BA overload after PH, thereby preserving its regeneration capacity. After PH, but also in other experimental models of BA overload (BDL, CA-enriched feeding), intrahepatic stasis of excessively hydrophobic bile may be a primary factor involved in liver injury observed in TGR5-KO mice. Preliminary data suggest that in the absence of TGR5, GB dysfunction may contribute to abnormal BA pool composition. Moreover, in the setting of BA overload, excessive inflammation, disturbed ionic composition of bile and impaired urinary BA efflux observed in the absence of TGR5 may worsen liver injury. Thus, when TGR5 is lacking, particularly noxious bile may be generated because of excessive hydrophobic BA and facilitated BA protonation, creating a highly unfavorable climate for liver cell functions and proliferation.

Disclosure Statement The authors have no conflict of interest to declare.

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