Reply to: “Arginase 1: a potential marker of a common pattern of liver steatosis in HCV and NAFLD children”
Authors: Eric Assenat, Leila Akkari, Marie Moreau, Urszula Hibner
Journal: Journal of Hepatology (2015)

Arginase 1: A potential marker of a common pattern of liver steatosis in HCV and NAFLD childrenJournal of HepatologyVol. 62Issue 5PreviewWe read with great interest a recent article published in this Journal by Moreau et al. [1] on the effect of hepatitis C virus (HCV) proteins in metabolic liver zonation and steatosis in previously established FL-N/35 transgenic mice [2]. In these mice with a quasi-pure C57BL/6 genetic background liver steatosis is mainly localized around the central vein of the hepatic lobule, while only a subset of hepatocytes seem to be involved in the activation of steatogenic enzymes with a prevalent periportal zonation, as well as the HCV proteins [3]. Full-Text PDF Open AccessHepatitis C viral proteins perturb metabolic liver zonationJournal of HepatologyVol. 62Issue 2PreviewHepatic lobule, the basic unit of the liver architecture, is organised into spatially distinct areas along the porto-centrilobular axis, known as metabolic zones [1]. As a consequence, metabolic liver functions involved in lipid, carbohydrate and ammonia metabolism, as well as detoxifying activities, are carried out by distinct sets of hepatocytes, whose metabolic identity in a healthy liver is determined by their position within the lobule. Full-Text PDF We thank Alisi and colleagues for their comments [[1]Alisi A. Comparcola D. De Stefanis C. Nobili V. Arginase 1: a potential marker of a common pattern of liver steatosis in HCV and NAFLD children.J Hepatol. 2015; 62: 1207-1208Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar] on our recent report characterizing the effects of the hepatitis C virus (HCV) proteins on metabolic liver zonation and steatosis [[2]Moreau M. Riviere B. Vegna S. Aoun M. Gard C. Ramos J. et al.Hepatitis C viral proteins perturb metabolic liver zonation.J Hepatol. 2015; 62: 278-285Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. In a transgenic mouse model with hepato-specific expression of the full complement of HCV proteins we found that fatty acid synthase, a major lipogenic enzyme, was redistributed to the midzone of the lobule, coinciding with zonated accumulation of lipids. Based on these and additional results, we hypothesized that low levels of viral proteins are sufficient to drive striking alterations of hepatic metabolic zonation. However, not all genes that display zonated expression in the liver were altered in the animal model studied. Notably, we found no change in the pattern of expression of E-cadherin or arginase 1. In contrast to the results reported by Alisi et al. we did not study the global level of expression of the latter. Alisi et al. compared arginase 1 expression in liver tissues from children with no hepatic pathologies or suffering from non-alcoholic fatty liver disease (NAFLD) or hepatitis C [[1]Alisi A. Comparcola D. De Stefanis C. Nobili V. Arginase 1: a potential marker of a common pattern of liver steatosis in HCV and NAFLD children.J Hepatol. 2015; 62: 1207-1208Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. The quantification of the immunhistochemical staining showed identical mean intensity of arginase 1 in healthy livers and in HCV-positive patients without steatosis. This is consistent with our results showing no difference of arginase 1 expression in hepatocytes from control and HCV-transgenic mice [[2]Moreau M. Riviere B. Vegna S. Aoun M. Gard C. Ramos J. et al.Hepatitis C viral proteins perturb metabolic liver zonation.J Hepatol. 2015; 62: 278-285Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. In our work, appearance of steatosis did not alter arginase distribution. In contrast, Alisi et al. observed increased arginase 1 expression in HCV patients with steatosis and in NAFLD. Their results highlight the link between lipid accumulation and arginase expression, as well as the effect of HCV infection on arginase 1 accumulation. Noteworthy, Alisi et al. give no information on the HCV genotype, while our study focused solely on genotype 1. It would be of interest to determine whether the reported observations are genotype specific or more generalizable. As Alisi and colleagues correctly pointed out, the role of arginase 1 in steatosis is not well understood and possibly underestimated. Interestingly, its increased expression has been described in HCV infection and it was suggested that it might participate in promoting cell growth and proliferation [[3]Cao W. Sun B. Feitelson M.A. Wu T. Tur-Kaspa R. Fan Q. Hepatitis C virus targets over-expression of arginase I in hepatocarcinogenesis.Int J Cancer. 2009; 124: 2886-2892Crossref PubMed Scopus (25) Google Scholar]. Indeed, arginase 1 converts arginine to ornithine, which is further metabolized to polyamines that promote cellular proliferation. Thus, elevated arginase 1 expression may be hepatoprotective during chronic infection by promoting survival and proliferation of HCV-infected hepatocytes. In consequence, the inflammatory immune response that contributes to liver damage would be inefficient in eliminating virus-infected cells. Elevated arginase 1 expression is associated with many tumor types [[4]Rodriguez P.C. Ochoa A.C. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives.Immunol Rev. 2008; 222: 180-191Crossref PubMed Scopus (496) Google Scholar] and therapeutic strategies aiming at inhibiting this metabolic pathway are being tested in the clinic. Interestingly, in HCC, the predominant peri-tumoral distribution of arginase 1 expression is in agreement with proteomic analyses of samples from HCV infected HCC and non-tumoral liver [3Cao W. Sun B. Feitelson M.A. Wu T. Tur-Kaspa R. Fan Q. Hepatitis C virus targets over-expression of arginase I in hepatocarcinogenesis.Int J Cancer. 2009; 124: 2886-2892Crossref PubMed Scopus (25) Google Scholar, 5Kuramitsu Y. Nakamura K. Current progress in proteomic study of hepatitis C virus-related human hepatocellular carcinoma.Expert Rev Proteomics. 2005; 2: 589-601Crossref PubMed Scopus (51) Google Scholar]. Recent evidence indicates that interactions between tumor cells and the host microenvironment have a major role in driving cancer progression and metastasis [6Hao N.B. Lu M.H. Fan Y.H. Cao Y.L. Zhang Z.R. Yang S.M. Macrophages in tumor microenvironments and the progression of tumors.Clin Dev Immunol. 2012; 2012: 948098Crossref PubMed Scopus (651) Google Scholar, 7Quail D.F. Joyce J.A. Microenvironmental regulation of tumor progression and metastasis.Nat Med. 2013; 19: 1423-1437Crossref PubMed Scopus (4291) Google Scholar]. The abundance of macrophages, pivotal members of tumor stroma, strongly correlates with poor prognosis in different types of solid tumors, including HCC [[8]Zhu W. Guo L. Zhang B. Lou L. Lin Z. Zhu X. et al.Combination of osteopontin with peritumoral infiltrating macrophages is associated with poor prognosis of early-stage hepatocellular carcinoma after curative resection.Ann Surg Oncol. 2014; 21: 1304-1313Crossref PubMed Scopus (20) Google Scholar]. It has been proposed that tumor-associated macrophages (M2-polarized) play an important role in generating overall immunosuppressive milieu within the tumor microenvironment that suppresses anti-tumor immunity and promotes tumor progression [[6]Hao N.B. Lu M.H. Fan Y.H. Cao Y.L. Zhang Z.R. Yang S.M. Macrophages in tumor microenvironments and the progression of tumors.Clin Dev Immunol. 2012; 2012: 948098Crossref PubMed Scopus (651) Google Scholar]. Interestingly, the differential metabolism of l-arginine provides a means of distinguishing the two macrophage activation states. M1, or classically activated macrophages, upregulate iNOS to catabolize l-arginine to nitric oxide and citrulline, while M2, or alternatively activated macrophages, induce arginase 1, the enzyme upstream of polyamines production, and thus increase collagen synthesis and cellular proliferation [[9]Rath M. Muller I. Kropf P. Closs E.I. Munder M. Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages.Front Immunol. 2014; 5: 532Crossref PubMed Scopus (615) Google Scholar]. In HCC, high numbers of peri-tumoral M2-polarized TAMs are associated with poor patient prognosis, and while no analyses of arginase 1 expression have yet been conducted in this context, it is likely that they express high levels of this enzyme along with the other M2 genes described. In this context, TAM-derived arginase 1 might promote tumorigenesis in a non-cell autonomous manner. Furthermore, several TAM-derived factors, such as TGF-β, IL-10, and arginase 1, make a significant contribution to tumoral immunosuppression [[7]Quail D.F. Joyce J.A. Microenvironmental regulation of tumor progression and metastasis.Nat Med. 2013; 19: 1423-1437Crossref PubMed Scopus (4291) Google Scholar]. Hepatic damage, including metabolic disorders, is linked to activation of Kupffer cells (the tissue resident macrophages in the liver) and other stromal cells, which sustain inflammatory cytokine secretion [[10]Bieghs V. Trautwein C. The innate immune response during liver inflammation and metabolic disease.Trends Immunol. 2013; 34: 446-452Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. These resident cells are also responsive to inflammatory factors and adipokines secreted by adipocytes. Thus, synergic events can perpetuate a vicious cycle that amplifies inflammatory processes, which will sustain both steatosis and inflammation while maintaining macrophage activation and the associated expression of arginase-1. Altogether, these events might favour disease progression, worsen hepatic damage and increase the risk of tumorigenesis. In this context, we fully agree that a better understanding of cell autonomous and non-autonomous effects of arginase 1 and/or macrophage polarization could open new therapeutic horizons for liver diseases, particularly in the setting of NAFLD and HCC. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.