Arginase 1: A potential marker of a common pattern of liver steatosis in HCV and NAFLD children
Authors: Anna Alisi, Donatella Comparcola, Cristiano De Stefanis, Valerio Nobili
Journal: Journal of Hepatology (2015)

We read with great interest a recent article published in this Journal by Moreau et al. [[1]Moreau M. Rivière B. Vegna S. Aoun M. Gard C. Ramos J. et al.Hepatitis C viral proteins perturb metabolic liver zonation.J Hepatol. 2014; 62: 278-285Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] on the effect of hepatitis C virus (HCV) proteins in metabolic liver zonation and steatosis in previously established FL-N/35 transgenic mice [[2]Lerat H. Kammoun H.L. Hainault I. Merour E. Higgs M.R. Callens C. et al.Hepatitis C virus proteins induce lipogenesis and defective triglyceride secretion in transgenic mice.J Biol Chem. 2009; 284: 33466-33474Crossref PubMed Scopus (79) Google Scholar]. 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]Nasheri N. Joyce M. Rouleau Y. Yang P. Yao S. Tyrrell D.L. et al.Modulation of fatty acid synthase enzyme activity and expression during hepatitis C virus replication.Chem Biol. 2013; 20: 570-582Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. Interestingly, the authors found that fatty acid synthase, was redistributed from its normal periportal expression into the midzone of the lobule, matching with lipid accumulation. This lipogenic enzyme activation and redistribution in humans with HCV infection may precede the manifestation of a steatotic phenotype. However, some markers of metabolic zonation, such as arginase 1, was not influenced by HCV protein expression. Arginase 1 is one of the two enzymes that competes with nitric oxide synthase for arginine, and it is mainly expressed in hepatocytes. The fact that arginases 1 and 2 are crucial to maintain liver lipid homeostasis has also emerged in a recent article by Navarro et al. which reported an increased expression of lipogenic genes and a consequent increased steatosis in Arg2−/− mice compared to wild-type, generating a model that resembled human NAFLD [[4]Navarro L.A. Wree A. Povero D. Berk M.P. Eguchi A. Ghosh S. et al.Arginase 2 deficiency results in spontaneous steatohepatitis: a novel link between innate immune activation and hepatic de novo lipogenesis.J Hepatol. 2014; 62 (pii: S0168-8278(14)00669-2): 412-420Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar]. However, in both cases the role of arginase 1 is underestimated. In this regard, we have analyzed the expression of arginase 1 in liver tissue from four healthy children without any sign of steatosis, four children with HCV infection but no steatosis, four children with HCV and steatosis and seven children with NAFLD. As shown in Fig. 1A, the quantification of the immunohistochemistry by MetaMorph Software demonstrated that mean intensity of arginase 1 was increased in HCV patients with steatosis and in NAFLD subjects compared to healthy livers and HCV that displayed the same average intensity. Furthermore, as confirmed by Western blot analysis (Fig. 1B) arginase 1 protein expression was higher in HCV patients with steatosis than in NAFLD. Data presented by both Moreau et al. [[1]Moreau M. Rivière B. Vegna S. Aoun M. Gard C. Ramos J. et al.Hepatitis C viral proteins perturb metabolic liver zonation.J Hepatol. 2014; 62: 278-285Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] and us highlight that arginase 1 increase may represent a marker of common patterns of steatosis in HCV and NAFLD when the derangement of lipid metabolism has already occurred. The arginase 1 in inflammatory response is clearly demonstrated by the fact that the murine enzyme is inducible by lipopolysaccharide or oxidized and acetylated lipoproteins suggesting its role in diseases characterized by altered lipid metabolism and a pro-inflammatory pattern [5Munder M. Arginase: an emerging key player in the mammalian immune system.Br J Pharmacol. 2009; 158: 638-651Crossref PubMed Scopus (467) Google Scholar, 6Gallardo-Soler A. Gomez-Nieto C. Campo M.L. Marathe C. Tontonoz P. Castrillo A. et al.Arginase I induction by modified lipoproteins in macrophages: a peroxisome proliferator activated receptor-gamma/delta-mediated effect that links lipid metabolism and immunity.Mol Endocrinol. 2008; 22: 1394-1402Crossref PubMed Scopus (108) Google Scholar]. Further experimental data could be useful to confirm this hypothesis and to fully depict the molecular mechanisms that could link intra-hepatic lipid accumulation and consequent arginase 1 increase in HCV and NAFLD. Finally, these findings might open new therapeutic horizons for liver disease progression, especially as it has been reported that the inhibition of arginase 1 by silencing or by a specific Nω-hydroxy-nor-L-arginine could reduce growth rate of HCV-infected hepatocarcinoma cells and obesity-induced hepatic lipid abnormalities in mice with NAFLD, respectively [7Cao 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, 8Moon J. Do H.J. Cho Y. Shin M.J. Arginase inhibition ameliorates hepatic metabolic abnormalities in obese mice.PLoS One. 2014; 9: e103048Crossref PubMed Scopus (18) Google Scholar]. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. This work was supported by grants from AIRC ( MFAG12936 ) to Anna Alisi. Hepatitis 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 Reply to: "Arginase 1: a potential marker of a common pattern of liver steatosis in HCV and NAFLD children"Journal of HepatologyVol. 62Issue 5PreviewWe thank Alisi and colleagues for their comments [1] on our recent report characterizing the effects of the hepatitis C virus (HCV) proteins on metabolic liver zonation and steatosis [2]. 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. Full-Text PDF Open Access