B. Julien

Immediate neuroendocrine signaling after partial hepatectomy through acute portal hyperpressure and cholestasis

BACKGROUND & AIMSnEarly 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.nnnMETHODSnSurgical procedure (PH, Portal vein stenosis (PVS), bile duct ligation (BDL), spinal cord lesion (SCL)) and treatments (capsaicin, bile acids (BA), oleanolic acid (OA)) were performed on rats and/or wild type or TGR5 (GPBAR1) knock-out mice. In these models, the activation of AVP-secreting supraoptic nuclei (SON) was analyzed, as well as plasma BA, AVP, and portal vein pressure (PVP). Plasma BA, AVP, and PVP were also determined in human living donors for liver transplantation.nnnRESULTSnAcute cholestasis (mimicked by BDL or BA injection) as well as portal hyperpressure (mimicked by PVS) independently activated SON and AVP secretion. BA accumulated in the brain after PH or BDL, and TGR5 was expressed in SON. SON activation was mimicked by the TGR5 agonist OA and inhibited in TGR5 KO mice after BDL. An afferent nerve pathway also contributed to post-PH AVP secretion, as capsaicin treatment or SCL resulted in a weaker SON activation after PH.nnnCONCLUSIONSnAfter PH in rodents, acute cholestasis and portal hypertension, via the nervous and endocrine routes, stimulate the secretion of AVP that may protect the liver against shear stress and bile acids overload. Data in living donors suggest that this pathway may also operate in humans.

The four and a half LIM-only protein 2 regulates liver homeostasis and contributes to carcinogenesis.

BACKGROUND & AIMSnThe four and a half LIM-only protein 2 (FHL2) is upregulated in diverse pathological conditions. Here, we analyzed the effects of FHL2 overexpression in the liver of FHL2 transgenic mice (Apo-FHL2).nnnMETHODSnWe first examined cell proliferation and apoptosis in Apo-FHL2 livers and performed partial hepatectomy to investigate high FHL2 expression in liver regeneration. Expression of FHL2 was then analyzed by real time PCR in human hepatocellular carcinoma and adjacent non-tumorous livers. Finally, the role of FHL2 in hepatocarcinogenesis was assessed using Apo-FHL2;Apc(lox/lox) mice.nnnRESULTSnSix-fold increase in cell proliferation in transgenic livers was associated with concomitant apoptosis, resulting in normal liver mass. In Apo-FHL2 livers, both cyclin D1 and p53 were markedly increased. Evidence supporting a p53-dependent cell death mechanism was provided by the findings that FHL2 bound to and activated the p53 promoter, and that a dominant negative p53 mutant compromised FHL2-induced apoptosis in hepatic cells. Following partial hepatectomy in Apo-FHL2 mice, hepatocytes displayed advanced G1 phase entry and DNA synthesis leading to accelerated liver weight restoration. Interestingly, FHL2 upregulation in human liver specimens showed significant association with increasing inflammation score and cirrhosis. Finally, while Apo-FHL2 mice developed no tumors, the FHL2 transgene enhanced hepatocarcinogenesis induced by liver-specific deletion of the adenomatous polyposis coli gene and aberrant Wnt/β-catenin signaling in Apc(lox/lox) animals.nnnCONCLUSIONSnOur results implicate FHL2 in the regulation of signaling pathways that couple proliferation and cell death machineries, and underscore the important role of FHL2 in liver homeostasis and carcinogenesis.

Innate immunity, purinergic system, and liver regeneration: A trip in complexity†‡

L iver regeneration is a highly integrated process involving a wide array of cellular interactions occurring between the different liver cell types, but also between the liver and the extrahepatic environment. Besides the main growth factors and cytokines acting in a paracrine way, diverse endocrine and neuroendocrine interactions, as well as the recruitment of blood cells, affect liver regeneration. This entire network acts in concert to achieve a fine-tuning of proliferative and hepatoprotective cascades, ultimately leading to liver mass restoration after injury or resection. A study published in this issue of HEPATOLOGY, sheds new light on the complex interactions between immune cells and liver regeneration processes, with the purinergic system as one possible regulator. Among modulators of liver regeneration, the innate immune system constitutes a complex network of interacting cells and cytokines, of which the resulting effect on liver regeneration is not entirely understood. Surprisingly, the complement system as well as cytotoxic cytokines, like tumor necrosis factor alpha, are reported as positive regulators for hepatocyte regeneration. The role of Kupffer cells, the hepatic resident macrophages, is still controversial, because these cells secrete numerous cytokines, stimulating or inhibiting hepatocyte proliferation, after liver injury. As to natural killer (NK) and natural killer T (NKT) cells, the main lymphoid population in human and mouse liver, although the majority of studies reported on their negative effect on liver regeneration, their role still remains controversial. NK cells would inhibit regeneration, in particular through the secretion of interferon-gamma (IFN-c), whereas NKT cells would play a minor role in the normal liver after partial hepatectomy (PH). However, NK and NKT cells may have a positive effect on oval cell-dependent regeneration after acute liver injury when hepatocytes cannot replicate. The study by Graubardt et al. revisited the controversy on NK cells during liver regeneration by introducing a new parameter: the purinergic system, currently recognized as a major component of the inflammatory response after injury. Signaling by extracellular adenosine triphosphate (ATP) acting on plasma membrane purinergic receptors, that is, P2Y1,2,4,6,11-14 (G-protein-coupled receptors) and P2X1-7 (ATP-gated channels with high Ca 2þ permeability), is vital not only in excitable, but also in nonexcitable cells and tissues. Vascular shear stress, organ distension, or cellular injury are known to trigger ATP release from endothelial, epithelial, and other cell types. Once in the extracellular medium, ATP is degraded by the powerful ecto-ATPases expressed on cell surfaces to avoid excessive activation (and desensitization) of purinergic receptors. Adenosine, the breakdown product of ATP, can bind P1 purinergic receptors, with specific downstream biological responses. Thus, in a given tissue, the final purinergic input will be determined by the complex combination of numerous parameters, including mainly mechanisms of ATP release, purinergic receptors expression and distribution, and ecto-ATPases expression. In the liver, each cell type expresses its own repertoire of purinoceptors and ecto-ATPases, and evidence for a crucial effect of purinergic signaling in liver physiology is growing, including modulation of bile secretion and ischemia protection. In vitro studies suggested that extracellular ATP had a positive effect on proliferation of primary rat hepatocytes. Recently, we showed that an extracellular ATP release from the liver occurred immediately after PH, contributing to liver regeneration in the rat. We also observed an immediate ATP release from the liver after PH for living donor transplantation, suggesting that purinergic signaling may be also involved during human liver regeneration. However, the purinoceptors and precise mechanisms involved in ATP-mediated effect on liver regeneration still remain to be defined. The authors of the present study previously reported on a coordinating role of the ectonucleotidase CD39Abbreviations:: ATP, adenosine triphosphate; IFN-c, interferon-gamma; NK, natural killer cells; NKT, natural killer T cells; PH, partial hepatectomy. Address reprint requests to: Thierry Tordjmann, M.D., Ph.D, INSERM U. 757, Universit e Paris Sud, Bât. 443, 91405 Orsay, France. E-mail: thierry.tordjmann@u-psud.fr; fax: (33) 1 69155893. Copyright VC 2013 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26312 Potential conflict of interest: Nothing to report.