- Email: [email protected]
The Bridge
Journal of Hepatology 40 (2004) 877 www.elsevier.com/locate/jhep
The Bridge – June 2004 Gender differences in hepatic expression of the iron regulator hepcidin (pages 891–896) Hepcidin evolves to be a key regulator of iron metabolism. Hepcidin is a 25-amino acid peptide with antimicrobial activity which is mainly expressed in the liver and is detected in blood and urine. Its expression is under control of the HFE protein and is stimulated in response to iron overload and inflammatory cytokines and suppressed by anemia and hypoxia. Hepcidin expression is impaired in patients with hereditary hemochromatosis who carry mutations in the HFE gene. In a mouse model of HFE hemochromatosis, expression of a hepcidin transgene protects against iron overload. Thus, stimulation of hepcidin synthesis might become a promising goal of future therapeutic strategies in HFE hemochromatosis. It is still unresolved why advanced stages of hereditary hemochromatosis are much more frequently observed in men than in women although the protective role of menses for women carrying HFE mutations has always been stressed. Krijt et al studied the genderand strain-dependent expression pattern of hepcidin 1 and 2 genes in mice – mice express two hepcidin isoforms with divergent functions whereas man expresses only one isoform – and found higher expression of hepcidin 2 mRNA in female than male mice in addition to species differences. This corresponds to another report of higher hepcidin 1 and 2 mRNA expression in female than male mice (Blood Cells Mol Dis 2004;32:283). Together, these reports allow to speculate that gender differences in hepcidin expression might explain at least in part the male preponderance in the clinical manifestation of hereditary hemochromatosis in man. Medical treatment of hepatocellular carcinoma: 1 1 1 . 2 ? (pages 952–956) Treatment of hepatocellular carcinoma (HCC) is a domain of surgical and interventional measures. Medical treatment has been disappointing so far and no single agent has proved to be effective in prolonging survival of patients with unresectable HCC when evaluated in meta-analyses of well-designed, randomized clinical trials (Hepatology 2003;37:429). Ganslmayer et al. tested the potential efficacy of combination treatment with two substances which had temporarily raised hope in the past as therapeutic options for HCC: tamoxifen and 9-cis retinoic acid. The authors did not present a clearcut rationale for the use of this particular combination of compounds on the basis of their potential mechanisms of action. However, both agents have in common to be quite well tolerable at therapeutic doses. Subsequent to previous work in vitro, the authors were able to demonstrate that a combination of tamoxifen and 9-cis retinoic acid was more effective than predicted from the effect of each single agent to reduce both primary tumor growth and metastasis in a rat model of HCC in vivo. Although the exact mechanisms of action remain elusive, the data suggest that these drugs which are regarded as ineffective for treatment of HCC when administered alone may have potential when combined with an adequate partner.
Ulrich Beuers [email protected]
Puzzling role of cyclooxygenase-2 in liver injury and repair (pages 926–933 and pages 963–970) Prometheus taught mankind in their early days the arts of life and for them stole fire from heaven. He was punished by Zeus by being chained to a rock on the Caucasus mountains. The daily visits of an eagle feasting upon Prometheus’ liver until he was rescued by Heracles generations later proved that liver is able to regenerate – although not always within a night (hidden hint to gender differences). Today, the molecular mechanisms by which liver regenerates are increasingly being unraveled. Zeini et al. and Ferna´ndez-Martı´nez et al. concentrated on the contribution of nitric oxide and prostaglandins, particularly PGE2, when they studied the role of nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) in liver regeneration after partial hepatectomy and toxic liver injury in mice, respectively. It has been shown that both, NOS-2 and COX-2, are upregulated in regenerating liver. While gene knockout of NOS-2 or pharmacological inhibition of COX-2 alone delays liver regeneration, simultaneous inhibition of NOS-2 and COX-2 led to animal death within days after partial hepatectomy due to an insufficient regenerative response and increased liver-cell apoptosis in the remaining liver. In contrast, inhibition of COX-2 alone or simultaneous inhibition of NOS-2 and COX-2 in thioacetamide-induced liver injury markedly decreased liver damage and did not cause animal death under these conditions. Even more confusing, COX-2 had been shown to be protective in acetaminophen-induced liver injury in mice in the past (Chem Res Toxicol 2001;14:1620). Thus, the different faces of COX-2 in liver injury and repair leave the observer puzzled at this state. Hepatitis C virus NS3 protein targeted by intracellular antibodies (pages 1000–1007) The HCV-NS3 protein is a serine protease and helicase which is essential for viral polyprotein processing and HCV replication. Inhibition of the protease function effciently and promptly decreases viral titers. Therefore, protease inhibitors are now in early clinical trials. NS3 also exerts cell transforming activity in vitro, although the relevance of this effect in vivo is unknown. Zemel et al. chose an elaborate approach to inhibit the NS3 associated transforming activity by coexpressing NS3-specific antibody fragments in cell lines. Additional sequences added to the antibody fragments targeted the antibody to different subcellular compartments, e.g. to the cytoplasm, the endoplasmatic reticulum, or the nucleus. Interestingly, antibodies targeting NS3 to the nucleus very efficiently inhibited the transforming capacity of NS3, whereas no effect was seen with antibodies targeting NS3 to other subcellular compartments, suggesting that mainly the removal of NS3 from the cytosol was effective. Indeed, the antibodies did not inhibit protease function in a protease inhibition assay. Helicase function was not addressed in this study. The model might be able to contribute to our understanding of transforming activity of NS3 (and ultimately hepatocarcinogenesis ?) in chronic hepatitis C.
0168-8278/$30.00 q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/S0 168-8278(04 )00 171-0
The Bridge – June 2004 Gender differences in hepatic expression of the iron regulator hepcidin (pages 891–896) Hepcidin evolves to be a key regulator of iron metabolism. Hepcidin is a 25-amino acid peptide with antimicrobial activity which is mainly expressed in the liver and is detected in blood and urine. Its expression is under control of the HFE protein and is stimulated in response to iron overload and inflammatory cytokines and suppressed by anemia and hypoxia. Hepcidin expression is impaired in patients with hereditary hemochromatosis who carry mutations in the HFE gene. In a mouse model of HFE hemochromatosis, expression of a hepcidin transgene protects against iron overload. Thus, stimulation of hepcidin synthesis might become a promising goal of future therapeutic strategies in HFE hemochromatosis. It is still unresolved why advanced stages of hereditary hemochromatosis are much more frequently observed in men than in women although the protective role of menses for women carrying HFE mutations has always been stressed. Krijt et al studied the genderand strain-dependent expression pattern of hepcidin 1 and 2 genes in mice – mice express two hepcidin isoforms with divergent functions whereas man expresses only one isoform – and found higher expression of hepcidin 2 mRNA in female than male mice in addition to species differences. This corresponds to another report of higher hepcidin 1 and 2 mRNA expression in female than male mice (Blood Cells Mol Dis 2004;32:283). Together, these reports allow to speculate that gender differences in hepcidin expression might explain at least in part the male preponderance in the clinical manifestation of hereditary hemochromatosis in man. Medical treatment of hepatocellular carcinoma: 1 1 1 . 2 ? (pages 952–956) Treatment of hepatocellular carcinoma (HCC) is a domain of surgical and interventional measures. Medical treatment has been disappointing so far and no single agent has proved to be effective in prolonging survival of patients with unresectable HCC when evaluated in meta-analyses of well-designed, randomized clinical trials (Hepatology 2003;37:429). Ganslmayer et al. tested the potential efficacy of combination treatment with two substances which had temporarily raised hope in the past as therapeutic options for HCC: tamoxifen and 9-cis retinoic acid. The authors did not present a clearcut rationale for the use of this particular combination of compounds on the basis of their potential mechanisms of action. However, both agents have in common to be quite well tolerable at therapeutic doses. Subsequent to previous work in vitro, the authors were able to demonstrate that a combination of tamoxifen and 9-cis retinoic acid was more effective than predicted from the effect of each single agent to reduce both primary tumor growth and metastasis in a rat model of HCC in vivo. Although the exact mechanisms of action remain elusive, the data suggest that these drugs which are regarded as ineffective for treatment of HCC when administered alone may have potential when combined with an adequate partner.
Ulrich Beuers [email protected]
Puzzling role of cyclooxygenase-2 in liver injury and repair (pages 926–933 and pages 963–970) Prometheus taught mankind in their early days the arts of life and for them stole fire from heaven. He was punished by Zeus by being chained to a rock on the Caucasus mountains. The daily visits of an eagle feasting upon Prometheus’ liver until he was rescued by Heracles generations later proved that liver is able to regenerate – although not always within a night (hidden hint to gender differences). Today, the molecular mechanisms by which liver regenerates are increasingly being unraveled. Zeini et al. and Ferna´ndez-Martı´nez et al. concentrated on the contribution of nitric oxide and prostaglandins, particularly PGE2, when they studied the role of nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) in liver regeneration after partial hepatectomy and toxic liver injury in mice, respectively. It has been shown that both, NOS-2 and COX-2, are upregulated in regenerating liver. While gene knockout of NOS-2 or pharmacological inhibition of COX-2 alone delays liver regeneration, simultaneous inhibition of NOS-2 and COX-2 led to animal death within days after partial hepatectomy due to an insufficient regenerative response and increased liver-cell apoptosis in the remaining liver. In contrast, inhibition of COX-2 alone or simultaneous inhibition of NOS-2 and COX-2 in thioacetamide-induced liver injury markedly decreased liver damage and did not cause animal death under these conditions. Even more confusing, COX-2 had been shown to be protective in acetaminophen-induced liver injury in mice in the past (Chem Res Toxicol 2001;14:1620). Thus, the different faces of COX-2 in liver injury and repair leave the observer puzzled at this state. Hepatitis C virus NS3 protein targeted by intracellular antibodies (pages 1000–1007) The HCV-NS3 protein is a serine protease and helicase which is essential for viral polyprotein processing and HCV replication. Inhibition of the protease function effciently and promptly decreases viral titers. Therefore, protease inhibitors are now in early clinical trials. NS3 also exerts cell transforming activity in vitro, although the relevance of this effect in vivo is unknown. Zemel et al. chose an elaborate approach to inhibit the NS3 associated transforming activity by coexpressing NS3-specific antibody fragments in cell lines. Additional sequences added to the antibody fragments targeted the antibody to different subcellular compartments, e.g. to the cytoplasm, the endoplasmatic reticulum, or the nucleus. Interestingly, antibodies targeting NS3 to the nucleus very efficiently inhibited the transforming capacity of NS3, whereas no effect was seen with antibodies targeting NS3 to other subcellular compartments, suggesting that mainly the removal of NS3 from the cytosol was effective. Indeed, the antibodies did not inhibit protease function in a protease inhibition assay. Helicase function was not addressed in this study. The model might be able to contribute to our understanding of transforming activity of NS3 (and ultimately hepatocarcinogenesis ?) in chronic hepatitis C.
0168-8278/$30.00 q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/S0 168-8278(04 )00 171-0