Long distance calling for liver regeneration: Identification of neuroendocrine signalling pathways activated after partial hepatectomy
Authors: Matías A. Avila
Journal: Journal of Hepatology (2010)

Immediate neuroendocrine signaling after partial hepatectomy through acute portal hyperpressure and cholestasisJournal of HepatologyVol. 54Issue 3PreviewEarly neuroendocrine pathways contribute to liver regeneration after partial hepatectomy (PH). We investigated one of these pathways involving acute cholestasis, immediate portal hyperpressure, and arginine vasopressin (AVP) secretion. Full-Text PDF Understanding the mechanisms that govern liver regeneration is a matter of paramount importance in the context of human liver disease. In the clinical setting this remarkable reaction takes place in a variety of situations including partial liver resection, organ transplantation, and toxic injury, and when it fails the consequences can be fatal [[1]Karp S.J. Clinical implications of advances in the basic science of liver repair and regeneration.Am J Transplant. 2009; 9: 1973-1980Crossref PubMed Scopus (38) Google Scholar]. Liver regeneration is a highly complex response, involving the whole organ with its different constituent cell types, and an intricate network of extracellular and intracellular signals and mediators [2Taub R. Liver regeneration: from myth to mechanism.Nat Rev Mol Cell Biol. 2004; 5: 836-847Crossref PubMed Scopus (1281) Google Scholar, 3Fausto N. Campbell J.S. Riehle K. Liver regeneration.Hepatology. 2006; 43: S45-S53Crossref PubMed Scopus (1283) Google Scholar, 4Michalopoulos G.K. Liver regeneration.J Cell Physiol. 2007; 213: 286-300Crossref PubMed Scopus (1174) Google Scholar]. Most of our current knowledge on the mechanisms of liver regeneration has been gathered in the experimental model of partial hepatectomy (PH) in rodents [[5]Higgins G.M. Anderson R.M. Experimental pathology of the liver: I. Restoration of the liver of the white rat following partial surgical removal.Arch Pathol. 1931; 12: 186-202Google Scholar]. Removal of 2/3 of the liver mass quickly triggers an orderly sequence of events in the remaining parenchyma, leading to hepatocyte proliferation and the restoration of normal liver weight 5–7 days after PH [5Higgins G.M. Anderson R.M. Experimental pathology of the liver: I. Restoration of the liver of the white rat following partial surgical removal.Arch Pathol. 1931; 12: 186-202Google Scholar, 6Michalopoulos G.K. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas.Am J Pathol. 2010; 176: 2-13Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar]. In this highly reproducible model the kinetics of the underlying proliferative events is well synchronized, allowing a fine molecular analysis of organ regeneration in vivo that has attracted the attention not only of hepatologists but of researchers from other fields of biology as well. The identification of the signals that trigger and terminate liver regeneration is an area of active investigation. Observations performed in the PH model over the past decades have put forward a number of intertwined signals and agents that when deficient or functionally blocked result in a defective regenerative response. These include a diversity of molecules, such as cytokines like tumour necrosis factor alpha and components of the innate immune system, growth factors like hepatocyte growth factor and different members of the epidermal growth factor (EGF) family, transforming growth factor beta, as well as hormones (insulin), neurotransmitters (norepinephrine), and metabolites (bile acids) [2Taub R. Liver regeneration: from myth to mechanism.Nat Rev Mol Cell Biol. 2004; 5: 836-847Crossref PubMed Scopus (1281) Google Scholar, 3Fausto N. Campbell J.S. Riehle K. Liver regeneration.Hepatology. 2006; 43: S45-S53Crossref PubMed Scopus (1283) Google Scholar, 4Michalopoulos G.K. Liver regeneration.J Cell Physiol. 2007; 213: 286-300Crossref PubMed Scopus (1174) Google Scholar, 6Michalopoulos G.K. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas.Am J Pathol. 2010; 176: 2-13Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar]. In spite of the wealth of information on the role of these factors in liver cell proliferation, knowledge on the mechanisms leading to their initial activation at the onset of liver regeneration is limited. Nonetheless, there are evidences pointing towards changes in portal vein hemodynamics, including increased portal vein pressure and liver tissue perfusion, as critical events in the initiation of the regenerative response in the remaining parenchyma [4Michalopoulos G.K. Liver regeneration.J Cell Physiol. 2007; 213: 286-300Crossref PubMed Scopus (1174) Google Scholar, 7Marubashi S. Sakon M. Nagano H. Gotoh K. Hashimoto K. Kubota M. et al.Effect of portal hemodynamics on liver regeneration studied in a novel portohepatic shunt rat model.Surgery. 2004; 136: 1028-1037Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar]. The circulating concentrations of most of the factors that participate in liver regeneration increase shortly after PH. Although many of these mediators are produced and accumulate within the regenerating liver, there are also evidences indicating the implication of other organs as sources of factors necessary for hepatic regeneration to proceed normally [[6]Michalopoulos G.K. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas.Am J Pathol. 2010; 176: 2-13Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar]. One such example is EGF, which is constitutively produced by the Brunner's glands of the duodenum and reaches the liver though the portal circulation at threefold higher concentrations per unit tissue after 2/3 PH [[6]Michalopoulos G.K. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas.Am J Pathol. 2010; 176: 2-13Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar]. Another endocrine factor involved in liver regeneration is arginine vasopressin [AVP]. AVP is a peptide produced by endocrine neurons in the supraoptic and paraventricular nuclei of the hypothalamus. Early reports pointed to its involvement in liver regeneration by demonstrating an impaired liver regeneration after PH in the AVP-deficient Brattleboro homozygote rats [[8]Russell W.E. Bucher N.L. Vasopressin modulates liver regeneration in the Brattleboro rat.Am J Physiol. 1983; 245: G321-G324PubMed Google Scholar], and by the fact that AVP could induce DNA synthesis in cultured rat hepatocytes [[9]Bhora F.Y. Kothary P.C. Imanishi H. Eckhauser F.E. Raper S.E. Vasopressin stimulates DNA synthesis in cultured rat hepatocytes.J Surg Res. 1994; 57: 706-710Abstract Full Text PDF PubMed Scopus (15) Google Scholar]. More recently the group of Tordjmann and co-workers demonstrated that plasma concentrations of AVP rise sharply after PH, peaking at 1 h after surgery, and provided pharmacological evidence showing that antagonism with AVP action significantly reduced liver regeneration in normal hepatectomized rats [[10]Nicou A. Serrière V. Prigent S. Boucherie S. Combettes L. Guillon G. et al.Hypothalamic vasopressin release and hepatocyte Ca2+ signalling during liver regeneration: an interplay stimulating liver growth and bile flow.FASEB J. 2003; 17: 1901-1903Crossref PubMed Google Scholar]. As occurs for other mediators of liver regeneration, the signals that stimulated AVP-secreting neurons in the hypothalamic nuclei upon PH were not known. Their identification was the aim of the current report by Doignon et al. in this issue of the Journal [[11]Doignon I. Julien B. Serrière-Lanneau V. Garcin I. Alonso G. Nicou A. et al.Immediate neuroendocrine signalling after partial hepatectomy through acute portal hyperpressure and cholestasis.J Hepatol. 2011; 54: 481-488Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. The search for signals able to stimulate AVP release during PH was guided by previous observations demonstrating the secretion of AVP in independent physio-pathological situations that to a certain extent also occur after liver resection. Two possible pathways were considered, one involved the recognition that portal hypertension was known to induce AVP release [12Song D. Liu H. Sharkley K.A. Hyperdynamic circulation in portal-hypertensive rats is dependent on central c-fos gene expression.Hepatology. 2002; 35: 159-166Crossref PubMed Scopus (44) Google Scholar, 13Anderson R.J. Cronin R.E. McDonald K.M. Schrier R.W. Mechanisms of portal hypertension-induced alterations in renal hemodynamics, renal water excretion, and renin secretion.J Clin Invest. 1976; 58: 964-970Crossref PubMed Scopus (61) Google Scholar], and the other was based on the observation that AVP secretion is stimulated during chronic cholestasis after bile duct ligation (BDL) in rats [[14]Swain M.G. Patchev V. Vergalla J. Chrousos G. Jones E.A. Suppression of hypothalamic–pituitary–adrenal axis responsiveness to stress in a rat model of acute cholestasis.J Clin Invest. 1993; 91: 1903-1908Crossref PubMed Scopus (79) Google Scholar]. In view of this, experiments were carefully designed to test the influence of portal hypertension and circulating bile acids on AVP production during liver regeneration after PH. Regarding the role of hemodynamic changes, the authors first showed that in the absence of liver resection an increase in portal vein pressure to levels equivalent to those observed after PH resulted in the activation of AVP-producing hypothalamic neurons, and in AVP secretion to the circulation. In order to directly assess the contribution of portal hyperpressure to AVP release after PH, liver resection was performed in rats with porto-caval anastomosis (PCA), a surgical modification that prevents extrahepatic portal vein pressure increase after hepatectomy. The finding that AVP-producing hypothalamic nuclei were still activated by PH under these conditions led the authors to suggest that intrahepatic hyperpressure, which is preserved in PCA rats, could be sufficient to promote AVP release. Nevertheless, the implication of a neural pathway in the rapid secretion of AVP after PH was substantiated by showing that release of this peptide was impaired in rats with chemical (capsaicin) or surgical (spinal cord lesions) afferent denervation. These findings add on the previously recognized role of the peripheral nervous system in liver regeneration after PH [[6]Michalopoulos G.K. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas.Am J Pathol. 2010; 176: 2-13Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar], and define a regulatory control loop in which signals triggered by baroreceptors in the liver travel to the hypothalamus eliciting AVP secretion. As discussed by the authors, given the ability of AVP to reduce portal blood flow, the released AVP could not only contribute to liver regeneration, but also to lower portal vein pressure. The second pathway potentially responsible for AVP production during liver regeneration considered in this study was related to the elevation of plasma bile acids observed after PH. Increased circulating levels of bile acids during liver regeneration had been previously reported [15Huang W. Ma K. Qatanani M. Cuvillier J. Liu J. Dong B. et al.Nuclear receptor-dependent bile acid signalling is required for normal liver regeneration.Science. 2006; 312: 233-236Crossref PubMed Scopus (537) Google Scholar, 16Csanaky I.L. Aleksunes L.M. Tanaka Y. Klaassen C.D. Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice.Am J Physiol Gastrointest Liver Physiol. 2009; 297: G419-G433Crossref PubMed Scopus (50) Google Scholar]. This was confirmed now by Doignon et al., who also demonstrated the accumulation of these molecules in the rat hypothalamus after PH and BDL [[11]Doignon I. Julien B. Serrière-Lanneau V. Garcin I. Alonso G. Nicou A. et al.Immediate neuroendocrine signalling after partial hepatectomy through acute portal hyperpressure and cholestasis.J Hepatol. 2011; 54: 481-488Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. Bile acids are emerging as potent regulatory molecules, with biological roles that exceed their traditional function in lipid digestion [[17]Keitel V. Kubitz R. Häussinger D. Endocrine and paracrine role of bile acids.World J Gastroenterol. 2008; 14: 5620-5629Crossref PubMed Scopus (103) Google Scholar]. These molecules have been directly involved in the regulation of liver regeneration through their interaction with the nuclear receptor FXR [[15]Huang W. Ma K. Qatanani M. Cuvillier J. Liu J. Dong B. et al.Nuclear receptor-dependent bile acid signalling is required for normal liver regeneration.Science. 2006; 312: 233-236Crossref PubMed Scopus (537) Google Scholar]. However, bile acids can bind and activate another receptor known as GPBAR1 or TGR5, a G protein coupled receptor present at the plasma membrane that conveys important regulatory intracellular signals in a variety of cells [17Keitel V. Kubitz R. Häussinger D. Endocrine and paracrine role of bile acids.World J Gastroenterol. 2008; 14: 5620-5629Crossref PubMed Scopus (103) Google Scholar, 18Fiorucci S. Mencarelli A. Palladino G. Cipriani S. Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders.Trends Pharmacol Sci. 2009; 30: 570-580Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar]. Expression of TGR5 was also detected in the rat and mouse hypothalamus by Doignon et al. [[11]Doignon I. Julien B. Serrière-Lanneau V. Garcin I. Alonso G. Nicou A. et al.Immediate neuroendocrine signalling after partial hepatectomy through acute portal hyperpressure and cholestasis.J Hepatol. 2011; 54: 481-488Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar], and the availability of TGR5 knockout mice (TGR5-KO) allowed testing the implication of this receptor in AVP release. Intriguingly, while AVP secretion upon BDL was attenuated in TGR5-KO mice compared to wild type animals, plasma AVP levels were similar in both genotypes after PH [[11]Doignon I. Julien B. Serrière-Lanneau V. Garcin I. Alonso G. Nicou A. et al.Immediate neuroendocrine signalling after partial hepatectomy through acute portal hyperpressure and cholestasis.J Hepatol. 2011; 54: 481-488Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. The authors speculate that additional stimuli, independent of TGR5, may be involved in AVP release after PH, and invoke the plasticity of the hepatic regenerative response characterized by the existence of multiple compensatory pathways [[6]Michalopoulos G.K. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas.Am J Pathol. 2010; 176: 2-13Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar]. However, we cannot overlook the fact that TGR5 is also expressed in two liver cell populations, Kupffer cells and sinusoidal endothelial cells, in which bile acids regulate cytokine production and NO synthesis [[18]Fiorucci S. Mencarelli A. Palladino G. Cipriani S. Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders.Trends Pharmacol Sci. 2009; 30: 570-580Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar], important players in the regulation of liver regeneration and intrahepatic microcirculation. This situation, together with the fact that TGR5-KO mice have a ∼20% decrease in bile acid pool size [[19]Maruyama T. Tanaka K. Suzuki J. Harada N. Nakamura T. Miyamoto Y. et al.Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice.J Endocrinol. 2006; 191: 197-205Crossref PubMed Scopus (233) Google Scholar], may complicate the interpretation of data regarding TGR5-mediated regulation of AVP in these animals. In view of this, it would be interesting to test AVP secretion during liver regeneration in tissue-specific TGR5-KO mice, ideally with targeted deletion of this receptor in AVP-producing cells. Finally, the authors also provide valuable observations on AVP levels in human liver donors for transplantation after right lobe hepatectomy, and in recipients after graft reperfusion [[11]Doignon I. Julien B. Serrière-Lanneau V. Garcin I. Alonso G. Nicou A. et al.Immediate neuroendocrine signalling after partial hepatectomy through acute portal hyperpressure and cholestasis.J Hepatol. 2011; 54: 481-488Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. Consistent with the experimental findings they show for the first time that circulating AVP levels rise shortly after PH in human donors. This response was accompanied by an increase in portal vein pressure and in plasma bile acid concentrations in hepatectomized patients. Interestingly, AVP levels were not modified in the plasma of liver graft recipients after reperfusion. Even though plasma bile acid concentrations were not measured in these patients, the fact that the grafted liver lacks innervation together with the normal secretion of AVP in TGR5-KO mice after PH, may suggest a preponderance of the neural pathway over the bile acid-mediated endocrine route for AVP regulation in liver regeneration. Furthermore, such predominant role of the nervous route may be more prominent in humans than in rodents, given the more profuse hepatic innervation found in primates [[20]Delalande J.M. Milla P.J. Burns A.J. Hepatic nervous system development.Anat Rec A Discov Mol Cell Evol Biol. 2004; 280: 848-853Crossref PubMed Scopus (17) Google Scholar]. Therefore, the precise elucidation of the nerve routes involved deserves further studies. In summary, this work provides novel and relevant information on the regulation of AVP production after PH, both experimental and clinical. Moreover, it nicely illustrates and contributes to define the complex interactions between the liver and other tissues during the extraordinary regenerative response of the liver. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.