miRNA in Liver Pathobiology, Diagnosis, and Therapy

It is with great excitement and enthusiasm that I present this issue of Seminars in Liver Disease dedicated to the role of microRNA (miRNA) biology in liver pathobiology, diagnosis, and therapy. Several lifetimes ago when I was a young investigator, I was taught that a great deal of the human genome was nonfunctional in that it did not code for proteins. We now realize that this DNA results in the generation of noncoding RNAs that have powerful effects on biology and disease. We have undergone a fundamental revolution in our understanding of mammalian biology, especially as it relates to human diseases, making it both timely and topical for Seminars to publish this issue on liver miRNA biology. Conceptually, this issue is divided into three sections regarding the role of miRNA: liver pathobiology, diagnosis, and therapy.

In regards to liver pathobiology, we have four outstanding contributions focused on miRNA biology. The first is an overview of miRNA biology. We then focus on the topics of fatty liver disease, biliary tract disease, and alcoholic liver disease. The first of these articles is written by Drs. Ashley Mohr and Justin Mott at the University of Nebraska. They discuss RNA biology, reviewing how miRNAs decrease expression of their target mRNAs, how they function within a cellular context, and how their expression is regulated. Sobolewski, Calo, Portius, and Foti address the role of miRNAs in fatty liver disease. Obviously, fatty liver disease is an extremely complicated process and the regulation of lipid metabolism is tightly controlled by several checkpoints. In an exhaustive, thoughtful, and reflective overview, Sobolewski et al detail the potential role of a wide variety of miRNAs in lipid metabolism relevant to hepatic steatosis. This contribution will be useful to all readers interested in hepatic lipid metabolism and fatty liver disease. The cholangiopathies represent a distinct type of liver disease involving altered biology and pathophysiology of cholangiocytes, the cells that line the ducts of the biliary tree. Dr. Gradilone and colleagues have assembled all the information relevant to miRNA regulation of cholangiocyte biology. In particular, they focus on the role of miRNAs in regulating cholangiocyte activation, secretion, and proliferation. Their pioneering work highlights the particular role of miRNAs in polycystic kidney and liver disease, and inflammatory states involving the biliary tract. Finally, Dr. Gyongyi Szabo and Abhishek Satishchandran examine the role of miRNAs in affecting alcohol metabolism, inflammation induced by alcohol, and potential therapeutic applications targeting miRNAs for amelioration of alcohol-associated liver injury. They have been international leaders in this scientific arena and their work is particularly informative in understanding not only alcohol-related liver disease, but also miRNA regulation of hepatic inflammation.

MicroRNAs are very interesting molecules in that they can be secreted by the cell into the extracellular fluid, circulation, and bile. Outside the cell, they can be sequestered by lipoproteins, secreted in exosomes or extracellular vesicles, or complexed to a protein called Argonaut. Thus, extracellular miRNA signatures in serum or bile have potential utility as biomarkers. The validation, pitfalls, and approaches to using miRNAs as biomarkers are superbly summarized by Drs. Marco Arrese, Akiko Eguchi, and Ariel Feldstein. This impressive contribution covers all the known information relating to the utility of miRNAs as biomarkers in liver disease. In concert with this article, are two articles by Drs. Klaus Piontek and Florin Selaru, and Drs. Joseph George and Tushar Patel. Drs. Piontek and Selaru assess the role of miRNA in the biology and diagnosis of cholangiocarcinoma. In a related study, they demonstrated a miRNA signature in bile present in exosomes that is highly diagnostic of cholangiocarcinoma. Drs. Patel and George highlight the role of noncoding RNAs in the biology and diagnosis of hepatocellular carcinoma. Although they focus heavily on the biology of miRNAs in hepatocellular carcinoma, they do also point out the potential use of miRNA biomarkers in screening high-risk populations for hepatocellular carcinoma or following response to therapy. They also emphasize that long noncoding RNAs, which are considerably larger in size than miRNAs, are also relevant to cancer biology, can be detected in the serum, and may be uniquely important as biomarkers.

In the final subsection of this issue of Seminars, the therapeutic role of modulating miRNAs is reviewed. Drs. Cecilia Sedano and Peter Sarnow highlight the role of miRNA-122 in the biology of hepatitis C virus (HCV). MicroRNA 122 is essential for hepatitis C replication as it stabilizes the HCV-related RNA for replication. Indeed, miRNAs can be targeted by antagomirs and their functions inhibited. An antagomir of miRNA-122 has been developed for human use. Several injections of this antagomir of miRNA-122 alone are sufficient to inhibit HCV replication. Thus, we now have proof of concept that modulating miRNA biology can be of great therapeutic importance. In their article, Drs. Xie, Burt, and Gao discuss a different approach to inhibit miRNA in a variety of models of human disease. They use adeno-associated virus approaches to express miRNA-binding partners for established miRNAs. These expressed RNA molecules act as “molecular sponges” to bind known miRNAs in a regulated or titratable manner. They also highlight other approaches to modulating miRNAs and the pros and cons of these various therapeutic concepts.

In summary, miRNAs play a critical role in virtually all biological processes and diseases. Their expression modulates disease activity; their signatures can be used as biomarkers for the diagnosis and monitoring of disease and the miRNAs can be therapeutically targeted for human benefit. Hopefully, in the future, there will be therapeutically modulating miRNAs for the treatment of human liver disease. I hope you will enjoy this issue of Seminars as much as I have enjoyed serving as its Guest Editor.