The Last Hurrah

This issue of Seminars in Liver Disease, devoted to gut microbiota and hepatic disease and guest edited by Professor Eamonn M. M. Quigley, is the journal's 144th regular quarterly issue since Seminars was launched in 1981. Its content deals with such currently hot topics as the nature and mechanisms of the ongoing conversation now known to occur between the gut and the liver, the implications of that conversation for liver and biliary tract disease, and experimental therapeutic innovations such as fecal microbiota transplants (FMTs), a subject probably considered too revolting to be included in polite conversation at the time of that first issue. Indeed, perusal of the tables of contents of Seminars' 144 issues provides an interesting summary of the focus of both the science and clinical practice of hepatology over the past 36 years. Although the titles of the issues confirm our discipline's continuing interest in the diagnosis, pathophysiology, and management of the most prevalent liver diseases—the various forms of viral hepatitis, alcoholic hepatitis, drug-related liver diseases, diseases of the biliary tract, and a selection of metabolic and genetic disorders—the titles of individual articles confirm the subtle, but progressive infiltration of more and more basic science: not only good old biochemistry and physiology, but also molecular biology, cell biology, immunology, virology, the pathobiology of fibrosis, and modern genetics, among others, into our content. This is as it should be, indeed as it must be, if hepatology as a discipline is to remain, in the service of our patients, at the cutting edge of clinical medicine.

The goal of Seminars from the very beginning, established by the original Editorial Board and strongly supported by our Publisher, Henry Stratton, and our subtle, low-key, behind-the-scenes advisor, Hans Popper, was to provide a platform for our readers that—over time—would keep them up-to-date with what was important in both the clinical practice and scientific underpinnings of contemporary hepatology. We believe that we have largely accomplished that goal, a belief supported by Seminars' Impact Factor, which has averaged 5.9 over the past 10 years, ranking 11th among 78 Gastroenterology and Hepatology journals for which such data are collected. The durable value of the reviews published in Seminars is suggested by its cumulative 5-year Impact Factor, as calculated by Journal Citation Reports. The latest (2015) value is 7.50, ranking 8th among the 78 GI/Liver competitors.

The next issue of Seminars will reflect the ideas of my successors, Drs. Gregory Gores and Jordi Bruix. Both are experienced members of Seminars' Editorial Board, and each has served—over the years—as Guest Editor of several high Impact Factor issues. They fully share my goals for Seminars and those of our founders, but will bring their own new ideas and a new energy to the enterprise, along with an explicit goal to further enhance its impact. It goes without saying that I wish them and the new Editorial Board every success.

Editing Seminars has been one of my major professional activities for more than three decades. However, simultaneously with the launching of Seminars, my professional identity and research interests were both evolving. I transformed from a Nathaniel Berlin- and Louis Wasserman-trained hematologist, interested in myeloproliferative diseases, hemolytic anemias, and the hematologic aspects of bilirubin metabolism, into a Sheila Sherlock-trained hepatologist, focused not just on general clinical hepatology, but more specifically, on hereditary hyperbilirubinemias, hepatic bilirubin disposition, and—in parallel—the hepatic disposition of other classes of organic anions, notably long- chain fatty acids (LCFAs). The latter led inexorably to an interest in fatty liver.

It was virtually dogma in the early 1980s that LCFA entered cells by passive diffusion. My colleagues and I were among the first to establish that LCFAs entered at least some cell types, notably adipocytes, hepatocytes, and cardiac myocytes, by regulatable, facilitated transport. These observations were not initially well received; for several years any reviewer of our manuscripts or grant applications had merely to state, in effect, that everyone knows that fatty acids enter cells solely by diffusion” to insure rejection of the manuscript or nonfunding of the grant. Nevertheless, publications about facilitated LCFA transport in relation to obesity and fatty liver increased almost exponentially from ≤ 200 a year worldwide in 1980 to almost 1,440 a year by 2014 when I stopped counting.

Over the years, increased facilitated LCFA uptake by adipocytes, hepatocytes, and cardiac myocytes has been shown to be a key part of the pathogenesis of obesity, hepatic steatosis, and obesity cardiomyopathy, respectively. Although both our earliest and now our latest efforts have focused on obesity, in the middle years—from roughly the late 1980s through 2015—the pathogenesis of fatty liver disease held center stage. Various steps along the way were duly summarized in reviews that appeared in Seminars in Liver Disease and elsewhere. After documenting the existence of facilitated LCFA uptake and identifying the plasma membrane LCFA-binding proteins with posited roles as LCFA transporters, we documented the upregulation of genes for several of these proteins in association with increased LCFA uptake in obese mice, and the exponential relationship between body mass index and increased LCFA uptake in human adipocytes. As our laboratory shifts its current focus from the pathophysiology of fatty liver to the therapeutic effects of a novel adipokine, spexin, on both obesity and type 2 diabetes mellitus, what may well be the last major endeavors in our fatty liver research program were presented at the 2015 Annual Meeting of American Association for the Study of Liver Diseases (AASLD) and at the 2016 Annual Meetings of AASLD and The Obesity Society this month. An article describing these findings more completely and summarizing our research on LCFA uptake in fatty liver disease can be found on pages 360–372 of this issue of Seminars.

Seminars, and research funded by the National Institutes of Health for approximately 40 years and reflected in more than 300 publications, have been the obvious hallmarks of my professional career, for which I owe thanks to several outstanding and gracious mentors, department chairs, editorial and faculty colleagues, students, laboratory technicians, and postdocs, collectively too numerous to identify and thank individually. I am particularly proud of—and also grateful to—the 15 postdocs who have gone on from the laboratory to become full professors, division chiefs, and department chairs in the United States and around the world. I undoubtedly learned more from them than they ever did from me.

Our new research directions and related new technologies are requiring me to master new disciplines and new techniques. Overall, the future has been designed to keep me engaged in science, off the streets, and out of mischief. However, as a hepatologist (and only as a hepatologist), this issue of Seminars may well represent my last hurrah.