The Multiple Functions of Heme Oxygenase-1 in the Liver

Abstract

Heme oxygenases (HO) are essential enzymes which degrade heme into carbon monoxide (CO), biliverdin and free iron. Due to its anti-inflammatory, anti-apoptotic and, as recently described, anti-viral properties the inducible HO isoform HO-1 is an important molecule which could find its way into therapy of gastrointestinal diseases. Acute and chronic liver injuries including acute liver failure, alcoholic or viral hepatitis, chronic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma are life threatening diseases and as a consequence might result in the necessity of liver transplantation. HO-1 as well as its reaction products of heme degradation has been linked to cytoprotection. HO-1 induction in rodent models of acute and chronic hepatic inflammation resulted in improvement of liver damage and down-regulation of pro-inflammatory cytokine levels. Furthermore HO-1 induction interfered with fibrosis progression in mice and partially resolved existing fibrosis. Likewise, HO-1 induction interfered with replication of hepatitis viruses B and C, which frequently are the reason for chronic hepatitis and subsequent tumor growth. Liver transplantation is limited by ischemia/reperfusion (I/R) injury, which is characterized by hypoxia and nutrient deficiency resulting in oxidative stress, apoptosis and immune activation. Induction of HO-1 and application predominantly of CO have been shown to interfere with I/R liver injury and to improve recipient and graft survival. On the other hand HO-1 has been shown to be over-expressed in various tumors, including hepatocellular carcinoma (HCC). Due to its anti-apoptotic properties this bears the risk to promote tumor growth. Anti-apoptotic effects are predominantly mediated by CO. This review aims to summarize beneficial as well as detrimental effects of HO-1 and its products within the liver.

Zusammenfassung

Hämoxygenasen (HO) sind essenzielle Enzyme, die Häm zu Kohlenmonoxid, Biliverdin und freiem Eisen abbauen. Aufgrund der antientzündlichen, antiapoptotischen und der erst kürzlich beschriebenen antiviralen Eigenschaften der einzigen induzierbaren Hämoxygenase-Isoform, der HO-1, birgt dieses Molekül ein großes therapeutisches Potenzial in Bezug auf gastrointestinale Erkrankungen in sich. Akute und chronische Lebererkrankungen, wie bspw. akutes Leberversagen, alkoholische oder virale Hepatitis, eine mögliche hieraus resultierende chronische Entzündung, Fibrose, Zirrhose und hepatozelluläres Karzinom stellen lebensbedrohliche Erkrankungen dar, in deren Folge eine Lebertransplantation unumgänglich sein kann. HO-1, aber auch deren Abbauprodukte wurden als hepatoprotektiv beschrieben. So führte die Induktion der HO-1 in Mausmodellen zu einer Hemmung akuter Leberentzündungen verbunden mit einer Reduktion proinflammatorischer Zytokine. Im Modell einer chronischen Leberentzündung wirkte HO-1-Induktion antifibrotisch. Hepatitis B und C Virus Infektionen führen oft zu chronischer Leberentzündung und können die Entstehung des hepatozellulären Karzinoms begünstigen. Interessanterweise hemmen HO-1 sowie deren Produkt Biliverdin die Replikation dieser Viren. Der Erfolg einer Lebertransplantation ist durch Ischämie/Reperfusionsschäden limitiert, die durch oxidativen Stress, Entzündung und hepatozelluläre Apoptose charakterisiert sind. Die Induktion von HO-1 sowie die Applikation von Kohlenmonoxid konnten Ischämie/Reperfusionsschäden verringern und das Überleben des Transplantats und des Transplantatempfängers selbst verlängern. Andererseits konnte gezeigt werden, dass HO-1 in verschiedenen Tumoren, inklusive Lebertumoren, häufig überexprimiert vorliegt. Die hauptsächlich durch Kohlenmonoxid vermittelte antiapoptotische Funktion der HO-1 könnte in diesem Fall das Tumorwachstum unterstützen. Dieser Review-Artikel soll einen Überblick über positive sowie negative Eigenschaften der HO-1 und ihrer Produkte in der Leber geben.

Key words

viral hepatitis - liver fibrosis - hepatocellular carcinoma

Schlüsselwörter

Virushepatitis - Leberfibrose - hepatozelluläres Karzinom

• References

• 1 Maines MD, Trakshel GM, Kutty RK. Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible. J Biol Chem 1986; 261: 411-419
• 2 Maines MD. Heme oxygenase: multifunction, multiplicity, regulatory mechanisms and clinical application. FASEB J 1988; 2: 2557-2568
• 3 McCoubrey Jr WK, Huang TJ, Maines MD. Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. Eur J Biochem 1997; 247: 725-732
• 4 Elbirt KK, Bonkovsky HL. Heme oxygenase: recent advances in understanding its regulation and role. Proc Assoc Am Physicians 1999; 111: 438-447 [Review]
• 5 Shan Y, Pepe J, Lu TH et al. Induction of heme oxygenase-1 gene by metalloporphyrins. Arch Biochem Biophys 2000; 380: 219-227
• 6 Sun J, Hoshino H, Takaku K et al. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J 2002; 21: 5216-5224
• 7 Ogawa K, Sun J, Taketani S et al. Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1. EMBO J 2001; 20: 2835-2843
• 8 Sun J, Brand M, Zenke Y et al. Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network. Proc Natl Acad Sci USA 2004; 101: 1461-1466
• 9 Shan Y, Lambrecht RW, Ghaziani T et al. Role of Bach-1 in regulation of heme oxygenase-1 in human liver cells: insights from studies with small interfering RNAS. J Biol Chem 2004; 279: 51769-5174
• 10 Sass G, Seyfried S, Soares MP et al. Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury. Hepatology 2004; 40: 1128-1135
• 11 Sass G, Soares MP, Yamashita K et al. Heme oxygenase-1 and its reaction product carbon monoxide prevent inflammation related apoptotic liver damage in mice. Hepatology 2003; 38: 909-918
• 12 Barikbin R, Neureiter D, Wirth J et al. Induction of heme oxygenase 1 prevents progression of liver fibrosis in Mdr2 knockout mice. Hepatology 2011; doi: 10.1002/hep.24711. [Epub ahead of print]
• 13 Protzer U, Seyfried S, Quasdorff M et al. Antiviral activity and hepatoprotection by heme oxygenase-1 in hepatitis B virus infection. Gastroenterology 2007; 133: 1156-1165
• 14 Shan Y, Zheng J, Lambrecht RW et al. Reciprocal effects of micro-RNA-122 on expression of heme oxygenase-1 and hepatitis C virus genes in human hepatocytes. Gastroenterology 2007; 133: 1166-1174
• 15 Zhu Z, Wilson AT, Mathahs MM et al. Heme oxygenase-1 suppresses hepatitis C virus replication and increases resistance of hepatocytes to oxidant injury. Hepatology 2008; 48: 1430-1439
• 16 Lehmann E, El-Tantawy WH, Ocker M et al. The heme oxygenase 1 product biliverdin interferes with HCV replication by increasing anti-viral interferon response. Hepatology 2010; 51: 398-404
• 17 Amersi F, Buelow R, Kato H et al. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest 1999; 104: 1631-1639
• 18 Rensing H, Bauer I, Datene V et al. Differential expression pattern of heme oxygenase-1/heat shock protein 32 and nitric oxide synthase-II and their impact on liver injury in a rat model of hemorrhage and resuscitation. Crit Care Med 1999; 27: 2766-2775
• 19 Lee J, Lee SK, Lee BU et al. Upregulation of heme oxygenase-1 in oral epithelial dysplasias. Int J Oral Maxillofac Surg 2008; 37: 287-292
• 20 Nuhn P, Künzli BM, Hennig R et al. Heme oxygenase-1 and its metabolites affect pancreatic tumor growth in vivo. Mol Cancer 2009; 8: 37
• 21 Sass G, Leukel P, Schmitz V et al. Inhibition of heme oxygenase 1 expression by small interfering RNA decreases orthotopic tumor growth in livers of mice. Int J Cancer 2008; 123: 1269-1277
• 22 Yachie A, Niida Y, Wada T et al. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 1999; 103: 129-135
• 23 Kawashima A, Oda Y, Yachie A et al. Heme oxygenase-1 deficiency: the first autopsy case. Hum Pathol 2002; 33: 125-130
• 24 Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA 1997; 94: 10919-10924
• 25 Tsoyi K, Lee TY, Lee YS et al. Heme-oxygenase-1 induction and carbon monoxide-releasing molecule inhibit lipopolysaccharide (LPS)-induced high-mobility group box 1 release in vitro and improve survival of mice in LPS- and cecal ligation and puncture-induced sepsis model in vivo. Mol Pharmacol 2009; 76: 173-182
• 26 Chung SW, Liu X, Macias AA et al. Heme oxygenase-1-derived carbon monoxide enhances the host defense response to microbial sepsis in mice. J Clin Invest 2008; 118: 239-247
• 27 Yu JB, Yao SL. Effect of heme oxygenase – endogenous carbon monoxide on mortality during septic shock in rats. Ir J Med Sci 2009; 178: 491-496
• 28 Otterbein LE, Soares MP, Yamashita K et al. Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol 2003; 24: 449-455
• 29 Lee BS, Heo JH, Kim YM et al. Carbon monoxide mediates heme oxygenase-1 induction via Nrf2 activation in hepatoma cells. Biochem Biophys Res Comm 2006; 343: 965-972
• 30 Stocker R, Yamamoto Y, McDonagh AF et al. Bilirubin is an antioxidant of possible physiological importance. Science 1987; 235: 1043-1046
• 31 Sima P, Mala J, Miler I et al. The suppressive effect of continuous infusion of bilirubin on the immune response in mice. Folia Microbiol (Praha) 1980; 25: 483-490
• 32 Immenschuh S, Baumgart-Vogt E, Mueller S. Heme oxygenase-1 and iron in liver inflammation: a complex alliance. Curr Drug Targets 2010; 11: 1541-1550 [Review]
• 33 Schaer DJ, Schaer CA, Schoedon G et al. Hemophagocytic macrophages constitute a major compartment of heme oxygenase expression in sepsis. Eur J Haematol 2006; 77: 432-436
• 34 Li QF, Zhu YS, Jiang H et al. Heme oxygenase-1 mediates the anti-inflammatory effect of isoflurane preconditioning in LPS-stimulated macrophages. Acta Pharmacol Sin 2009; 30: 228-234
• 35 She H, Xiong S, Lin M et al. Iron activates NF-kappaB in Kupffer cells. Am J Physiol Gastrointest Liver Physiol 2002; 283: G719-726
• 36 Tsukamoto H, Lin M, Ohata M et al. Iron primes hepatic macrophages for NF-kappaB activation in alcoholic liver injury. Am J Physiol Gastrointest Liver Physiol 1999; 277: G1240-G1250
• 37 Mandal P, Park PH, McMullen MR et al. The anti-inflammatory effects of adiponectin are mediated via a heme oxygenase-1-dependent pathway in rat Kupffer cells. Hepatology 2010; 51: 1420-1429
• 38 Mauad TH, van Nieuwkerk CM, Dingemans KP et al. Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Am J Pathol 1994; 145: 1237-1245
• 39 Tsui TY, Lau CK, Ma J et al. rAAV mediated stable expression of heme oxygenase-1 in stellate cells: a new approach to attenuate liver fibrosis in rats. Hepatology 2005; 42: 335-342
• 40 Li L, Grenard P, Nhieu JT et al. Heme oxygenase-1 is an antifibrogenic protein in human hepatic myofibroblasts. Gastroenterology 2003; 125: 460-469
• 41 Li L, Julien B, Grenard P et al. Molecular mechanisms regulating the antifibrogenic protein heme-oxygenase-1 in human hepatic myofibroblasts. J Hepatol 2004; 41: 407-413
• 42 Vashist YK, Uzungolu G, Kutup A et al. Heme oxygenase-1 germ line GTn promoter polymorphism is an independent prognosticator of tumor recurrence and survival in pancreatic cancer. J Surg Oncol 2011; 104: 305-311
• 43 Sawa T, Mounawar M, Tatemichi M et al. Increased risk of gastric cancer in Japanese subjects is associated with microsatellite polymorphisms in the heme oxygenase-1 and the inducible nitric oxide synthase gene promoters. Cancer Lett 2008; 269: 78-84
• 44 Lo SS, Lin SC, Wu CW et al. Heme oxygenase-1 gene promoter polymorphism is associated with risk of gastric adenocarcinoma and lymphovascular tumor invasion. Ann Surg Oncol 2007; 14: 2250-2256
• 45 Zhang W, Qiao T, Zha L. Inhibition of heme oxygenase-1 enhances the radiosensitivity in human nonsmall cell lung cancer A549 cells. Cancer Biother Radiopharm 27. Sep 2011 [Epub ahead of print]
• 46 Miyake M, Fujimoto K, Anai S et al. Inhibition of heme oxygenase-1 enhances the cytotoxic effect of gemcitabine in urothelial cancer cells. Anticancer Res 2010; 30: 2145-2152
• 47 Alaoui-Jamali MA, Bismar TA, Gupta A et al. A novel experimental heme oxygenase-1-targeted therapy for hormone-refractory prostate cancer. Cancer Res 2009; 69: 8017-8024
• 48 Conde de la Rosa L, Vrenken TE, Hannivoort RA et al. Carbon monoxide blocks oxidative stress-induced hepatocyte apoptosis via inhibition of the p54 JNK isoform. Free Radic Biol Med 2008; 44: 1323-1333
• 49 Berberat PO, Katori M, Kaczmarek E et al. Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury. FASEB J 2003; 17: 1724-1726
• 50 El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132: 2557-2576
• 51 Blonski W, Reddy KR. Hepatitis C virus infection and hepatocellular carcinoma. Clin Liver Dis 2008; 12: 661-674
• 52 Qiu L, Fan H, Jin W et al. miR-122-induced down-regulation of HO-1 negatively affects miR-122-mediated suppression of HBV. Biochem Biophys Res Commun 2010; 398: 771-777
• 53 Shan Y, Zheng J, Lambrecht RW et al. Reciprocal effects of micro-RNA-122 on expression of heme oxygenase-1 and hepatitis C virus genes in human hepatocytes. Gastroenterology 2007; 133: 1166-1174
• 54 Chang J, Nicolas E, Marks D et al. miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may down-regulate the high affinity cationic amino acid transporter CAT-1. RNA Biol 2004; 1: 106-113
• 55 Ghaziani T, Shan Y, Lambrecht RW et al. HCV proteins increase expression of heme oxygenase-1 (HO-1) and decrease expression of Bach1 in human hepatoma cells. J Hepatol 2006; 45: 5-12
• 56 Abdalla MY, Britigan BE, Wen F et al. Down-regulation of heme oxygenase-1 by hepatitis C virus infection in vivo and by the in vitro expression of hepatitis C core protein. J Infect Dis 2004; 190: 1109-1118
• 57 Wen F, Brown KE, Britigan BE et al. Hepatitis C core protein inhibits induction of heme oxygenase-1 and sensitizes hepatocytes to cytotoxicity. Cell Biol Toxicol 2008; 24: 175-188
• 58 Jopling CL, Yi M, Lancaster AM et al. Modulation of hepatitis C virus RNA abundance by a liver-specific micro-RNA. Science 2005; 309: 1577-1581
• 59 Hou W, Tian Q, Zheng J et al. MicroRNA-196 represses Bach1 protein and hepatitis C virus gene expression in human hepatoma cells expressing hepatitis C viral proteins. Hepatology 2010; 51: 1494-1504
• 60 Zhu Z, Wilson AT, Luxon BA et al. Biliverdin inhibits hepatitis C virus nonstructural 3/4A protease activity: mechanism for the antiviral effects of heme oxygenase?. Hepatology 2010; 52: 1897-1905
• 61 Lin C, Kwong AD, Perni RB. Discovery and development of VX-950, a novel, covalent, and reversible inhibitor of hepatitis C virus NS3.4A serine protease. Infect Disord Drug Targets 2006; 6: 3-16 [Review]
• 62 Öllinger R, Pratschke J. Role of heme oxygenase-1 in transplantation. Transpl Int 2010; 23: 1071-1081
• 63 Buis CI, van der Steege G, Visser DS et al. Heme oxygenase-1 genotype of the donor is associated with graft survival after liver transplantation. Am J Transplant 2008; 8: 377-385
• 64 Katori M, Buelow R, Ke B et al. Heme oxygenase-1 overexpression protects rat hearts from cold ischemia/reperfusion injury via an antiapoptotic pathway. Transplantation 2002; 73: 287-292
• 65 Kato H, Amersi F, Buelow R et al. Heme oxygenase-1 overexpression protects rat livers from ischemia/reperfusion injury with extended cold preservation. Am J Transplant 2001; 1: 121-128
• 66 Tullius SG, Nieminen-Kelhä M, Buelow R et al. Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1. Transplantation 2002; 74: 591-598
• 67 Amersi F, Buelow R, Kato H et al. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest 1999; 104: 1631-1639
• 68 Ollinger R, Wang H, Yamashita K et al. Therapeutic applications of bilirubin and biliverdin in transplantation. Antioxid Redox Signal 2007; 9: 2175-2185 [Review]
• 69 Ma J, Lau CK, Obed A et al. A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury. Gene Ther 2009; 16: 320-328
• 70 Amersi F, Shen XD, Anselmo D et al. Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway. Hepatology 2002; 35: 815-823
• 71 Clark JE, Naughton P, Shurey S et al. Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ Res 2003; 93: e2-8
• 72 Zwacka RM, Zhang Y, Halldorson J et al. CD4(+) T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver. J Clin Invest 1997; 100: 279-289
• 73 Haga Y, Tempero MA, Zetterman RK. Unconjugated bilirubin inhibits in vitro cytotoxic T lymphocyte activity of human lymphocytes. Biochim Biophys Acta 1996; 1317: 65-70
• 74 McDaid J, Yamashita K, Chora A et al. Heme oxygenase-1 modulates the allo-immune response by promoting activation-induced cell death of T cells. FASEB J 2005; 19: 458-460
• 75 Bader T, Fazili J, Madhoun M et al. Fluvastatin inhibits hepatitis C replication in humans. Am J Gastroenterol 2008; 103: 1383-1389
• 76 O’Leary JG, Chan JL, McMahon CM et al. Atorvastatin does not exhibit antiviral activity against HCV at conventional doses: a pilot clinical trial. Hepatology 2007; 45: 895-898
• 77 Milazzo L, Caramma I, Mazzali C et al. Fluvastatin as an adjuvant to pegylated interferon and ribavirin in HIV/hepatitis C virus genotype 1 co-infected patients: an open-label randomized controlled study. J Antimicrob Chemother 2010; 65: 735-740