The Bridge – November 2002
Authors: Jürg Reichen
Journal: Journal of Hepatology (2002)

Effect of variations in bile salt flux on bile salt transporter expression (pages 556–563)Increasing bile salt concentrations as seen in cholestasis lead to down-regulation of bile salt uptake pumps – such as ntcp – and up-regulation of export pumps – such as bsep – thereby protecting the hepatocyte from toxic bile salt concentrations. Wolters and colleagues demonstrate that increasing bile salt flux by taurocholate feeding has similar but not very pronounced effects, while decreasing bile salt flux by cholestyramine feeding has no effects on transporter expression. The nuclear farnesoid receptor, which partially regulates bile salt transporter expression, was not affected by any of the experimental conditions. This paper is important for two reasons: it demonstrates that there must be an excess expression of bile salt transporters which can accommodate wide variations in bile salt flux; furthermore, the regulation of bile salt transporters is yet incompletely understood.Transit times determined by sonography – a measure of shunting? (pages 578–583)Sonography with contrast material is making its entry into radiology very fast; so far, it has proven useful in the characterization of nodules in the cirrhotic liver. Sugimoto and colleagues add a novel twist: they measure arrival times of the signal after intravenous administration of the bubbles in portal vein, hepatic artery and hepatic veins. The signal appeared earlier only in the hepatic vein in patients with cirrhosis while the appearance times were not different in portal vein and hepatic artery. The latter finding is surprising since one would expect earlier appearance times there also when there is marked hyperdynamic circulation. Only patients with Child Pugh score A or B were studied. It will be interesting to see such studies expanded to patients with more advanced liver disease. Also, correlation with hemodynamic changes are impatiently expected.Mechanism of action of pirfenidone, a potential antifibrotic agent (pages 584–591)Pirfenidone has shown the potential to inhibit fibrogenesis in different animal models; Di Sario and colleagues shed some light onto potential mechanisms of action. The agent inhibits stellate cell proliferation induced by platelet-derived growth factor (PDGF); interestingly, this was not achieved by interference with PDGF signaling but by preventing activation of Na+,H+-exchange. Na+,H+-exchange has been shown previously by this group to be important in stellate cell proliferation. As previously shown by others, pirfenidone also directly interfered with collagen synthesis. This study clearly established the stellate cell as a primary target of pirfenidone. In this, its antiproliferative activities appear of particular interest.Vascular endothelial growth factor (VEGF) in microcancers in mice – a very early event in carcinogenesis (pages 620–624)Microcancers are foci of well-differentiated hepatocytes invading vessels. Angiogenesis is important in cancer invasion, including that of hepatocellular carcinoma, and is over expressed in a sizeable percentage of such tumors. Turlin et al. used diethyl nitrosamine to induce tumors in mice; 8% of the tumors induced were microcancers. These expressed VEFG in a higher percentage and more intensely than adenomas or overt carcinomas. This was associated with a breakdown of adjacent vessel walls, a well-known effect of VEGF. This study demonstrates the importance of angiogenesis and permeabilization in early cancer; the place of microcancer in the multistep carcinogenesis as well as the trigger for VEGF over expression remain to be defined.Liver regeneration – does size matter? (pages 625–632)After the usual 60% hepatectomy in rodents, there is marked regenerative activity within days after surgery. In patients, it seems to take much longer for organ size to be restored. Therefore, Gaglio and colleagues explored whether the Rhesus macaque could serve as a model closer to the clinical situation. Indeed, in contradistinction to rodents, peak mitotic activity was observed only at days 21–30; also, the time course of different cytokines being involved in regeneration differed from those seen in rodents leading the authors to postulate the existence of signals other than those studied. The authors feel that this is a question of species and not size since dogs – with a similar body weight as the Rhesus macaque have peak regenerative activity at 72 h, much closer to rodents. Thus, species matters but not size. This model is a welcome tool, which will prove helpful in resolving questions related to liver regeneration in man, in particular with respect to living related donors.Gene therapy for hepatitis C (pages 660–668)In an elegant proof of principle study, Sullivan et al. constructed an adenovirus containing the gene for a single chain antibody fragment interfering with the helicase domain of the NS3 region of the hepatitis C virus. This vector efficiently reduced virus replication when introduced into HepG2 cells and into hepatocytes isolated from HCV-infected human livers. This is – as expected – achieved in part by inhibiting helicase activity but other factors might also play a role. Different such single-chain antibodies against different regions of the HCV virus have been described; the present report is the first to analyze the biological consequences in the real target, human hepatocytes. While there is a long road to go before this is seen in clinical practice, this study emphasizes the potential of therapeutic antibodies in the treatment of viral infections. Effect of variations in bile salt flux on bile salt transporter expression (pages 556–563) Increasing bile salt concentrations as seen in cholestasis lead to down-regulation of bile salt uptake pumps – such as ntcp – and up-regulation of export pumps – such as bsep – thereby protecting the hepatocyte from toxic bile salt concentrations. Wolters and colleagues demonstrate that increasing bile salt flux by taurocholate feeding has similar but not very pronounced effects, while decreasing bile salt flux by cholestyramine feeding has no effects on transporter expression. The nuclear farnesoid receptor, which partially regulates bile salt transporter expression, was not affected by any of the experimental conditions. This paper is important for two reasons: it demonstrates that there must be an excess expression of bile salt transporters which can accommodate wide variations in bile salt flux; furthermore, the regulation of bile salt transporters is yet incompletely understood. Transit times determined by sonography – a measure of shunting? (pages 578–583) Sonography with contrast material is making its entry into radiology very fast; so far, it has proven useful in the characterization of nodules in the cirrhotic liver. Sugimoto and colleagues add a novel twist: they measure arrival times of the signal after intravenous administration of the bubbles in portal vein, hepatic artery and hepatic veins. The signal appeared earlier only in the hepatic vein in patients with cirrhosis while the appearance times were not different in portal vein and hepatic artery. The latter finding is surprising since one would expect earlier appearance times there also when there is marked hyperdynamic circulation. Only patients with Child Pugh score A or B were studied. It will be interesting to see such studies expanded to patients with more advanced liver disease. Also, correlation with hemodynamic changes are impatiently expected. Mechanism of action of pirfenidone, a potential antifibrotic agent (pages 584–591) Pirfenidone has shown the potential to inhibit fibrogenesis in different animal models; Di Sario and colleagues shed some light onto potential mechanisms of action. The agent inhibits stellate cell proliferation induced by platelet-derived growth factor (PDGF); interestingly, this was not achieved by interference with PDGF signaling but by preventing activation of Na+,H+-exchange. Na+,H+-exchange has been shown previously by this group to be important in stellate cell proliferation. As previously shown by others, pirfenidone also directly interfered with collagen synthesis. This study clearly established the stellate cell as a primary target of pirfenidone. In this, its antiproliferative activities appear of particular interest. Vascular endothelial growth factor (VEGF) in microcancers in mice – a very early event in carcinogenesis (pages 620–624) Microcancers are foci of well-differentiated hepatocytes invading vessels. Angiogenesis is important in cancer invasion, including that of hepatocellular carcinoma, and is over expressed in a sizeable percentage of such tumors. Turlin et al. used diethyl nitrosamine to induce tumors in mice; 8% of the tumors induced were microcancers. These expressed VEFG in a higher percentage and more intensely than adenomas or overt carcinomas. This was associated with a breakdown of adjacent vessel walls, a well-known effect of VEGF. This study demonstrates the importance of angiogenesis and permeabilization in early cancer; the place of microcancer in the multistep carcinogenesis as well as the trigger for VEGF over expression remain to be defined. Liver regeneration – does size matter? (pages 625–632) After the usual 60% hepatectomy in rodents, there is marked regenerative activity within days after surgery. In patients, it seems to take much longer for organ size to be restored. Therefore, Gaglio and colleagues explored whether the Rhesus macaque could serve as a model closer to the clinical situation. Indeed, in contradistinction to rodents, peak mitotic activity was observed only at days 21–30; also, the time course of different cytokines being involved in regeneration differed from those seen in rodents leading the authors to postulate the existence of signals other than those studied. The authors feel that this is a question of species and not size since dogs – with a similar body weight as the Rhesus macaque have peak regenerative activity at 72 h, much closer to rodents. Thus, species matters but not size. This model is a welcome tool, which will prove helpful in resolving questions related to liver regeneration in man, in particular with respect to living related donors. Gene therapy for hepatitis C (pages 660–668) In an elegant proof of principle study, Sullivan et al. constructed an adenovirus containing the gene for a single chain antibody fragment interfering with the helicase domain of the NS3 region of the hepatitis C virus. This vector efficiently reduced virus replication when introduced into HepG2 cells and into hepatocytes isolated from HCV-infected human livers. This is – as expected – achieved in part by inhibiting helicase activity but other factors might also play a role. Different such single-chain antibodies against different regions of the HCV virus have been described; the present report is the first to analyze the biological consequences in the real target, human hepatocytes. While there is a long road to go before this is seen in clinical practice, this study emphasizes the potential of therapeutic antibodies in the treatment of viral infections.