- Email: [email protected]
Molecular pathogenesis of chronic cholestatic liver disease: Impact on novel therapeutic approaches
Molecular Aspects of Medicine 37 (2014) 1–2
Contents lists available at ScienceDirect
Molecular Aspects of Medicine journal homepage: www.elsevier.com/locate/mam
Editorial
Molecular pathogenesis of chronic cholestatic liver disease: Impact on novel therapeutic approaches Expressed already by its central anatomical position between the gastrointestinal tract and the systemic circulation the liver represents a pivotal organ in lipid-, glucose-, and protein metabolism and homeostasis as well as for the excretion of endo-, and xenobiotics. Bile formation with secretion of cholesterol, phospholipids, and bile salts together with the enterohepatic circulation of bile salts embodies a critical element of the body’s lipid and energy homeostasis. Cholestasis means stasis of bile flow. Consequently, a secretory failure of the liver at the level of hepatocytes or cholangiocytes is considered as the pathophysiological hallmark in cholestatic liver diseases. Such diseases are therefore characterized by the retention of cholephils such as bile salts and bilirubin in liver and systemic circulation with significant impact on different organs’ function and whole body homeostasis. Two prominent representatives of these frequently difficult to treat diseases are primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), which may ultimately develop into liver cirrhosis and end stage liver disease. Currently, the only therapy of endstage liver disease is liver transplantation. Mutations in the hepatobiliary transport systems involved in hepatocellular bile formation can also lead to chronic, progressive cholestasis. While the later are very rare, progress in the understanding of their molecular mechanisms and consequences has greatly enhanced our understanding of the physiology and pathophysiology of bile formation. It is therefore the aim of this issue of MAM to deliver a synopsis of the current knowledge on PBC and PSC representing two prototypic cholestatic liver diseases. In addition we aimed to embed this into a broad context of our current knowledge on physiology and pathophysiology of bile formation an it‘s potential therapeutic implications. The elucidation of the nature, localization, function, and transcriptional regulation of the major hepatic, intestinal, and renal transport proteins significantly increased our knowledge into the mechanisms of bile formation and the pathophysiology of specific cholestatic liver diseases. The first article of this MAM issue summarizes the current knowledge on the bile salt export pump BSEP, which constitutes the rate-limiting step for hepatocellular bile salt secretion. Since BSEP represents the rate limiting hepatocellular bile salt transport protein any impairment of BSEP function can potentially lead to cholestasis. This article also summarizes first attempts to correct for special mutations inherited malfunctioning of BSEP with a small molecule approach. The second article illustrates the power of modern approaches of population genetics to decipher molecular mechanisms of complex diseases involving multiple genes. It also highlights the potential of modern genetics to stratify therapeutic regimens for patients with chronic liver diseases. The third article summarizes the current understanding of the pathogenetic mechanism of chronic cholestatic liver diseases in humans. It also describes currently used animal models to study such diseases and critically evaluates currently available animal models for such diseases with respect to our knowledge on the respective human pathogenetic mechanisms. The forth article develops the topic of chronic cholestatic human liver diseases into innovative therapeutic approaches for such liver diseases. This article covers the central molecular mechanisms of the established therapy with ursodeoxycholic acid and gives insights into currently ongoing clinical trials with novel activators of gene expression of hepatocellular bile salts transporters raising considerable interest and make a strong point against therapeutic nihilism in this difficult to treat group of patients. As such, it demonstrates the power of animal models for the transformation for knowledge from bench to bedside. The fifth article deals with the central role of the liver in energy homeostasis. Also seemingly not directly relevant to chronic cholestatic liver diseases, it should be kept in mind that clinical experience well recognizes alterations in energy homeostasis and also in plasma cholesterol levels in chronic cholestatic liver diseases. Based on our increasing knowledge that bile salts do not only act as emulsifier molecules but act as central signaling molecules in maintaining the bodies energy homeostasis this research field raises progressively interest. We would like to thank all the authors for their willingness to spare time for contributing to this special issue. Our special thanks also go to the editor-in-chief, Dr. Angelo Azzi, for helping us to design the concept and commissioning the reviews
0098-2997/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mam.2013.11.001
2
Editorial / Molecular Aspects of Medicine 37 (2014) 1–2
and in addition to the technical staff, in particular to Arnold Justus Stanly, of the journal for its never ending support. In addition, we greatly appreciate the input of the reviewers who, by lending us their time and critical input were instrumental in assembling the articles for this special issue. We hope that the readers will enjoy what we think exciting updates on chronic cholestatic liver diseases at the bench and at the bedside and that these articles will foster novel ideas in basic research and in clinics. Peter Fickert 1 ⇑ Bruno Stieger University Hospital, Rämistrasse 100, 8091 Zürich, Switzerland ⇑ Corresponding author. Tel.: +41 44 634 3169; fax: +41 44 255 4411. E-mail address: [email protected] (B. Stieger) 1 Tel.: +43 316 385 81792; fax: +43 316 385 17108. Available online 25 November 2013
Contents lists available at ScienceDirect
Molecular Aspects of Medicine journal homepage: www.elsevier.com/locate/mam
Editorial
Molecular pathogenesis of chronic cholestatic liver disease: Impact on novel therapeutic approaches Expressed already by its central anatomical position between the gastrointestinal tract and the systemic circulation the liver represents a pivotal organ in lipid-, glucose-, and protein metabolism and homeostasis as well as for the excretion of endo-, and xenobiotics. Bile formation with secretion of cholesterol, phospholipids, and bile salts together with the enterohepatic circulation of bile salts embodies a critical element of the body’s lipid and energy homeostasis. Cholestasis means stasis of bile flow. Consequently, a secretory failure of the liver at the level of hepatocytes or cholangiocytes is considered as the pathophysiological hallmark in cholestatic liver diseases. Such diseases are therefore characterized by the retention of cholephils such as bile salts and bilirubin in liver and systemic circulation with significant impact on different organs’ function and whole body homeostasis. Two prominent representatives of these frequently difficult to treat diseases are primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), which may ultimately develop into liver cirrhosis and end stage liver disease. Currently, the only therapy of endstage liver disease is liver transplantation. Mutations in the hepatobiliary transport systems involved in hepatocellular bile formation can also lead to chronic, progressive cholestasis. While the later are very rare, progress in the understanding of their molecular mechanisms and consequences has greatly enhanced our understanding of the physiology and pathophysiology of bile formation. It is therefore the aim of this issue of MAM to deliver a synopsis of the current knowledge on PBC and PSC representing two prototypic cholestatic liver diseases. In addition we aimed to embed this into a broad context of our current knowledge on physiology and pathophysiology of bile formation an it‘s potential therapeutic implications. The elucidation of the nature, localization, function, and transcriptional regulation of the major hepatic, intestinal, and renal transport proteins significantly increased our knowledge into the mechanisms of bile formation and the pathophysiology of specific cholestatic liver diseases. The first article of this MAM issue summarizes the current knowledge on the bile salt export pump BSEP, which constitutes the rate-limiting step for hepatocellular bile salt secretion. Since BSEP represents the rate limiting hepatocellular bile salt transport protein any impairment of BSEP function can potentially lead to cholestasis. This article also summarizes first attempts to correct for special mutations inherited malfunctioning of BSEP with a small molecule approach. The second article illustrates the power of modern approaches of population genetics to decipher molecular mechanisms of complex diseases involving multiple genes. It also highlights the potential of modern genetics to stratify therapeutic regimens for patients with chronic liver diseases. The third article summarizes the current understanding of the pathogenetic mechanism of chronic cholestatic liver diseases in humans. It also describes currently used animal models to study such diseases and critically evaluates currently available animal models for such diseases with respect to our knowledge on the respective human pathogenetic mechanisms. The forth article develops the topic of chronic cholestatic human liver diseases into innovative therapeutic approaches for such liver diseases. This article covers the central molecular mechanisms of the established therapy with ursodeoxycholic acid and gives insights into currently ongoing clinical trials with novel activators of gene expression of hepatocellular bile salts transporters raising considerable interest and make a strong point against therapeutic nihilism in this difficult to treat group of patients. As such, it demonstrates the power of animal models for the transformation for knowledge from bench to bedside. The fifth article deals with the central role of the liver in energy homeostasis. Also seemingly not directly relevant to chronic cholestatic liver diseases, it should be kept in mind that clinical experience well recognizes alterations in energy homeostasis and also in plasma cholesterol levels in chronic cholestatic liver diseases. Based on our increasing knowledge that bile salts do not only act as emulsifier molecules but act as central signaling molecules in maintaining the bodies energy homeostasis this research field raises progressively interest. We would like to thank all the authors for their willingness to spare time for contributing to this special issue. Our special thanks also go to the editor-in-chief, Dr. Angelo Azzi, for helping us to design the concept and commissioning the reviews
0098-2997/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mam.2013.11.001
2
Editorial / Molecular Aspects of Medicine 37 (2014) 1–2
and in addition to the technical staff, in particular to Arnold Justus Stanly, of the journal for its never ending support. In addition, we greatly appreciate the input of the reviewers who, by lending us their time and critical input were instrumental in assembling the articles for this special issue. We hope that the readers will enjoy what we think exciting updates on chronic cholestatic liver diseases at the bench and at the bedside and that these articles will foster novel ideas in basic research and in clinics. Peter Fickert 1 ⇑ Bruno Stieger University Hospital, Rämistrasse 100, 8091 Zürich, Switzerland ⇑ Corresponding author. Tel.: +41 44 634 3169; fax: +41 44 255 4411. E-mail address: [email protected] (B. Stieger) 1 Tel.: +43 316 385 81792; fax: +43 316 385 17108. Available online 25 November 2013