Targeting heme oxygenase/adiponectin axis for chronic hepatitis C treatment
Authors: Federico Salamone, Giovanni Li Volti
Journal: Hepatology (2010)

We read with great interest the article by Lehmann et al. in which the authors demonstrate that heme oxygenase-1 (HO-1) induction by cobalt protoporphyrin (CoPP) markedly inhibits the replication of hepatitis C virus (HCV) by increasing interferon response in vitro.1 The heme oxygenase system plays a key role in the antioxidant defenses of many tissues and organs,2 and a number of evidence suggests that HO-1 induction could exert therapeutic effects in a variety of liver conditions, including viral hepatitis and nonalcholic steatohepatitis.3 The study by Lehmann et al. is consistent with previous reports showing the potent anti-HCV activity of HO-1 and further proposes HO-1 as a promising tool for the treatment of chronic hepatitis C. Nonetheless, there are some issues that we would like to point out in order to better underline the putative in vivo HO-1 activity against HCV through the modulation of interferon response. These issues regard the HO-1/adiponectin axis. Adiponectin is an adipose tissue cytokine exerting potent anti-inflammatory effects in the liver, and has been demonstrated to play a key role in various liver diseases.4 In particular, adiponectin is decreased in patients with obesity and insulin resistance,5 which are strongly associated with a negative sustained virological response (SVR) following antiviral treatments.6 Of note, it has been clearly demonstrated that HO-1 induction may favorably affect insulin sensitivity by increasing adiponectin levels.7, 8 L'Abbate et al. first showed that induction of HO-1 by CoPP increases serum adiponectin levels in mice with experimental diabetes.7 Successively, the same group confirmed the potent insulin-sensitizing action of CoPP in ob/ob mice through the increase of adiponectin and its downstream target adenosine monophosphate kinase.8 Therefore, it is conceivable that in vivo HO-1 induction could also be important not only for its classical antioxidant activity but also for the insulin-sensitizing action, which could be exploited to achieve more SVR in patients with chronic hepatitis C. Furthermore, far from the strict metabolic action of the adiponectin system, it has been also demonstrated that adiponectin displays a direct role in immune response against HCV. Palmer et al. elegantly showed that administration of adiponectin to ex vivo peripheral blood mononuclear cells from patients with chronic hepatitis C enhances interferon γ production.9 Thus, in our opinion, the existence of an HO/adiponectin axis should be taken into account when considering the potent modulation of interferon response by HO-1 induction. In conclusion, besides the classical antioxidant action of HO-1, we think that the brilliant results of Lehmann et al. should be further extended to the contribution of adiponectin on in vivo response to interferon in patients with chronic hepatitis C, and, in particular, in those patients presenting with insulin resistance. We do agree with the authors' conclusions, which further confirm HO-1 as a key element in the liver antioxidant defenses and as a therapeutical target to develop future hepatoprotective strategies.10 Federico Salamone M.D.*, Giovanni Li Volti M.D., Ph.D. , * Department of Internal Medicine, University of Catania, Catania, Italy, Department of Biological Chemistry, University of Catania, Catania, Italy.