Editor-in-Chief: Satdarshan (Paul) S. Monga Volume 21, 2021
ISSN: 1052-2166; E-ISSN: 1555-3884 Open Access 3 numbers per volume
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Gene Expression The Journal of Liver Researchwill publisharticles in all aspects of hepatology. Hepatology, as a research discipline, has seen unprecedented growth especially in the cellular and molecular mechanisms of hepatic health and disease, which continues to have a major impact on understanding liver development, stem cells, carcinogenesis, tissue engineering, injury, repair, regeneration, immunology, metabolism, fibrosis, and transplantation. Continued research and improved understanding in these areas will have a meaningful impact on liver disease prevention, diagnosis, and treatment. The existing journal Gene Expression has expanded its focus to become Gene Expression The Journal of Liver Research to meet this growing demand. In its revised and expanded scope, the journal will publish high-impact original articles, reviews, short but complete articles, and special articles (editorials, commentaries, opinions) on all aspects of hepatology, making it a unique and invaluable resource for readers interested in this field. The expanded team, led by an Editor-in-Chief who is uniquely qualified and a renowned expert, along with a dynamic and functional editorial board, is determined to make this a premier journal in the field of hepatology.
Supplementary Material: Please note that Gene Expression The Journal of Liver Research discourages and hence is unable to host supplementary material. If you wish to include supplementary material, then you will need to provide a link within the manuscript to a permanent hosting site of this material.
Europe – Frédéric Lemaigre, Université catholique de Louvain, Belgium Asia – Hua Wang, Institute for Liver Diseases of Anhui Medical University, China United States – Scott Friedman, Mount Sinai, USA
Associate Editors Bin Gao, NIAAA, NIH, USA Hongliang Li, Wuhan University, China Joseph Locker, University of Pittsburgh, USA George Michalopoulos, University of Pittsburgh, USA Atsushi Miyajima, University of Tokyo, Japan Tushar Patel, Mayo Clinic, USA Steve Weinman, The University of Kansas, USA Min You, Northeast Ohio Medical University, USA
Gianfranco Alpini, Indiana University, USA Frank Anania, Food and Drug Administration, USA Udayan Apte, The University of Kansas, USA Gavin Arteel, University of Pittsburgh, USA Jésus M. Bañales, Biodonostia Institute, San Sebastian, Spain Ramon Bataller, University of Pittsburgh, USA Timothy Billiar, University of Pittsburgh, USA John Chiang, Northeast Ohio Medical University, USA Amedeo Columbano, Universita di Cagliari, Italy Carlo Croce, The Ohio State University, USA Jonathan Dranoff, University of Arkansas for Medical Sciences, USA Deyu Fang, Northwestern University, USA Gen-Sheng Feng, University of California, San Diego, USA Kalpana Ghoshal, The Ohio State University, USA Sanjeev Gupta, Albert Einstein College of Medicine, USA Tsonwin Hai, The Ohio State University, USA Samson T. Jacob, Founding Editor, The Ohio State University, USA Hartmut Jaeschke, University of Kansas, USA Won-il Jeong, KAIST, Korea Xiaoni Kong, Shanghai Jiao Tong University, China Fouad Lafdi, Inserm, France Alex Lentsch, University of Cincinnati, USA Mark McNiven, Mayo Clinic- Rochester, Minnesota, USA Laura Nagy, Cleveland Clinic, USA Kari Nejak-Bowen, University of Pittsburgh, USA Wei Qui, Loyola University of Chicago, USA Ratna Ray, Saint Louis University, USA Janardhan Reddy, Northwestern University Medical School, USA Lewis Roberts, Mayo Clinic- Rochester, Minnesota, USA David Rudnick, Washington University in St. Louis, USA Arun Sanyal, Virginia Commonwealth University, USA Peter Sarnow, Stanford University School of Medicine, USA Hiroyuki Seimiya, Japanese Foundation for Cancer Research, Japan Ekihiro Seki, Cedars Sinai, USA Vijay Shah, Mayo Clinic- Rochester, Minnesota, USA David Shafritz, Albert Einstein College of Medicine, USA Donghun Shin, University of Pittsburgh, USA Ashwani Singal, University of Alabama Birmingham, USA Christian Trautwein, Aachen University, Germany Rebecca Wells, University of Pennsylvania, USA Mingjiang Xu, NIAAA, NIH, USA Yingzi Yang, Harvard University, USA George Yeoh, Harry Perkins Institute of Medical Research, Australia Jessica Zucman-Rossi, French Institute of Health and Medical Research, France
Peer review is the evaluation of scientific, academic, or professional work by others working in the same field to ensure only good scientific research is published.
In order to maintain these standards, Gene Expression The Journal of Liver Research utilizes a single blind review process whereby the identity of the reviewers is not known to the authors but the authors are shown on the article being reviewed.
The peer review process for Gene Expression The Journal of Liver Research is laid out below:
An article is first checked for formatting and required statements on animal and IRB approvals by the Editorial Manager after which it is forwarded to the Editor-in-Chief (EIC). The only exception would be if the article is being submitted from the EIC’s lab or institution, in which case the article is automatically assigned to one of the Senior Editors based on specific key words and article content.
The article is then assigned to one of the Associate Editors (AEs) based on expertise and verification of lack of any conflict.
The AE then selects between 2 and 5 reviewers for detailed peer review. The reviewers are always experts in their field and could be part of the Gene Expression The Journal of Liver Research editorial board. All reviewers would lack any conflict with the authors and are reviewers in good standing based on previous track record and history.
Comments from the reviewers (minimum 2 reviewers) are expected in 2 weeks or less and are delivered to the AEs who assess the merit of the manuscript based on these comments as well as on their own assessment of the article. Special attention is given to declaration of conflict of interest if any. If relevant, statements on use of appropriate animal protocol approved by institutional regulatory boards and inclusion of appropriate IRB approvals in cases of human studies are verified. Likewise, appropriate comments on use of appropriate statistical tests are ensured.
The recommendation is then relayed to the EIC or Senior Editors who look at all comments collectively and make the decision, which is then relayed to the authors. Authors receive detailed comments along with the final decision of: accept, accept with minor revision, accept with major revision, or rejection. The comments to authors are blinded. The identity of AEs and handling Senior Editor/EIC is revealed in the decision letter.
As a reviewer for Gene Expression The Journal of Liver Research you would have the benefit of reading and evaluating current research in your area of expertise at its early stage, thereby contributing to the integrity of scientific exploration. If you are interested in becoming a reviewer for Gene Expression The Journal of Liver Research, please contact the EIC Satdarshan (Paul) S. Monga, University of Pittsburgh, USA at firstname.lastname@example.org
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*Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA †Department of Medicine, University of Rome Tor Vergata, Rome, Italy ‡Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
Mast cells are key players in acute immune responses that are evidenced by degranulation leading to a heightened allergic response. Activation of mast cells can trigger a number of different pathways contributing to metabolic conditions and disease progression. Aging results in irreversible physiological changes affecting all organs, including the liver. The liver undergoes senescence, changes in protein expression, and cell signaling phenotypes during aging, which regulate disease progression. Cellular senescence contributes to the age-related changes. Unsurprisingly, mast cells also undergo age-related changes in number, localization, and activation throughout their lifetime, which adversely affects the etiology and progression of many physiological conditions including liver diseases. In this review, we discuss the role of mast cells during aging, including features of aging (e.g., senescence) in the context of biliary diseases such as primary biliary cholangitis and primary sclerosing cholangitis and nonalcoholic fatty liver disease.
Key words: Senescence; Senescence-associated secretory phenotype (SASP); Aging; Mast cells (MCs); Liver diseases; Inflammation; Fibrosis Downregulation of p16 Decreases Biliary Damage and Liver Fibrosis in the Mdr2−/− Mouse Model of Primary Sclerosing Cholangitis – 89 DOI: https://doi.org/10.3727/105221620X15889714507961
*Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA †Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, USA ‡Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, USA §Liver Unit, Department of Medicine, University of Rome “Tor Vergata,” Rome, Italy ¶Department of Nutrition, Texas A&M University, College Station, TX, USA
Biliary senescence and hepatic fibrosis are hallmarks of cholangiopathies including primary sclerosing cholangitis (PSC). Senescent cholangiocytes display senescence-associated secretory phenotypes [SASPs, e.g., transforming growth factor-β1 (TGF-β1)] that further increase biliary senescence (by an autocrine loop) and trigger liver fibrosis by paracrine mechanisms. The aim of this study was to determine the effect of p16 inhibition and role of the TGF-β1/microRNA (miR)-34a/sirtuin 1 (SIRT1) axis in biliary damage and liver fibrosis in the Mdr2−/− mouse model of PSC. We treated (i) in vivo male wild-type (WT) and Mdr2−/− mice with p16 Vivo-Morpholino or controls before measuring biliary mass [intrahepatic bile duct mass (IBDM)] and senescence, biliary SASP levels, and liver fibrosis, and (ii) in vitro intrahepatic murine cholangiocyte lines (IMCLs) with small interfering RNA against p16 before measuring the mRNA expression of proliferation, senescence, and fibrosis markers. p16 and miR-34a increased but SIRT1 decreased in Mdr2−/− mice and PSC human liver samples compared to controls. p16 immunoreactivity and biliary senescence and SASP levels increased in Mdr2−/− mice but decreased in Mdr2−/− mice treated with p16 Vivo-Morpholino. The increase in IBDM and hepatic fibrosis (observed in Mdr2−/−mice) returned to normal values in Mdr2−/− mice treated with p16 Vivo-Morpholino. TGF-β1 immunoreactivity and biliary SASPs levels were higher in Mdr2−/− compared to those of WT mice but returned to normal values in Mdr2−/− mice treated with p16 Vivo-Morpholino. The expression of fibrosis/senescence markers decreased in cholangiocytes from Mdr2−/− mice treated with p16 Vivo-Morpholino (compared to Mdr2−/− mice) and in IMCLs (after p16 silencing) compared to controls. Modulation of the TGF-β1/miR-34a/SIRT1 axis may be important in the management of PSC phenotypes.
*Laboratory of Neuroendocrinology, Fujian Key Laboratory of Developmental and Neuro Biology, School of Life Sciences, Fujian Normal University, Fuzhou, China †Clinical Medicine Research Institute, First Affiliated Hospital of Jinan University, Guangzhou, China ‡Division of Gastroenterology, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China §National Clinical Research Center for Infectious Diseases, Shenzhen Third People’s Hospital, The Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China ¶Department Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, China #Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan **Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China ††Department of Oncology, the First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, China
Globally, alcohol consumption contributes to more than 3 million deaths each year. While much of its ramifications is preventable, a coherent public health discourse on how to limit alcohol-related harm has been overdue. By synthesizing information from national and global databases, we show in this analysis that alcohol consumption level and alcohol-attributable burden of diseases, particularly alcoholic liver disease (ALD), are intimately linked to national income distribution, cultural norms, religion, sex, age, and health status. Prevalence and burden of ALD are positively associated with economic standing in most countries, which necessitate active governmental control via cost-effective policies, such as the “best buys” proposed by the World Health Organization. To date, a number of critical questions remain unanswered over the molecular mechanisms underlying ALD pathophysiology; the insights gained thereof should provide new opportunities for the advancement of novel diagnostic and management strategies. In comparison with other prevailing liver diseases (e.g., viral hepatitis and nonalcoholic fatty liver disease), governmental support to ALD investigation has been sluggish in most Western countries and China, resulting in a dearth of breakthroughs on both the basic and clinical research fronts in the past decades. Emerging foci of clinical trials for ALD therapy include empirical use of probiotics, antioxidants, growth factors, monoclonal antibodies against key inflammatory mediators, and technology-enhanced behavioral interventions. In this article, we seek to provide a comprehensive analysis on the progress and challenges in tackling ALD as a global health problem, with particular emphasis on global disease burden, socioeconomic influences, research trends, government roles, and future therapies.
Key words: Alcoholic liver disease (ALD); Public health policy; Global disease burden; Disease mechanisms; Alcohol abuse; Intervention Brief Review
The Conundrum of the Pericentral Hepatic Niche: WNT/β-Catenin Signaling, Metabolic Zonation, and Many Open Questions – 119 DOI: https://doi.org/10.3727/105221620X16007982788168
Jan S. Tchorz
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
WNT/β-catenin signaling promotes stemness, proliferation, and cell fate decisions in various tissue stem cell compartments, which maintain organs with a high turnover of cells (e.g., skin, stomach, and gut). Thus, the β-catenin target genes AXIN2 and LGR5 are widely considered as tissue stem cell markers. In contrast, AXIN2 and LGR5 are expressed in pericentral hepatocytes, which do not show overt proliferation during liver homeostasis. Given the low hepatocyte turnover, the liver does not require constant high rates of proliferation, whereas WNT/β-catenin signaling is critical for metabolic zonation. Yet, WNT/β-catenin pathway upregulation, including AXIN2 and LGR5 induction in hepatocytes throughout the liver, enables hepatocyte regeneration in response to various injuries. In this brief review, I discuss the role of WNT/β-catenin signaling in controlling metabolic zonation and the conundrum around pericentral hepatocytes that have been proposed as liver stem cells.
Acetaminophen Test Battery (ATB): A Comprehensive Method to Study Acetaminophen-Induced Acute Liver Injury – 125 DOI: https://doi.org/10.3727/105221620X15901763757677
Bharat Bhushan* and Udayan Apte†
*Department of Pathology and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA †Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
Acetaminophen (APAP) overdose is the major cause of acute liver failure (ALF) in the Western world. Extensive research is ongoing to identify the mechanisms of APAP-induced ALF. APAP-induced acute liver injury is also one of the most commonly studied drug-induced liver injury models in the field of hepatotoxicity. APAP toxicity is triphasic and includes three mechanistically interlinked but temporally distinct phases of initiation, progression, and recovery/regeneration. Despite how commonly it is studied, the methods to study APAP toxicity differ significantly, often leading to confusing and contradictory data. There are number of reviews on mechanisms of APAP toxicity, but a detailed mechanism-based comprehensive method and list of assays that covers all phases of APAP hepatotoxicity are missing. The goal of this review is to provide a standard protocol and guidelines to study APAP toxicity in mice including a “test battery” that can help investigators to comprehensively analyze APAP toxicity in the specific context of their hypothesis. Further, we will identify the major roadblocks and common technical problems that can significantly affect the results. This acetaminophen test battery (ATB) will be an excellent guide for scientists studying this most common and clinically relevant drug-induced liver injury and will also be helpful as a roadmap for hypothesis development to study novel mechanisms.
“Inside-Out” or “Outside-In”: Choosing the Right Model of Hepatocellular Cancer – 139 DOI: https://doi.org/10.3727/105221620X15913805462476
Satdarshan P. Monga
Division of Experimental Pathology, Department of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh, Pittsburgh, PA, USA Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center and University of Pittsburgh, Pittsburgh, PA, USA Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh, Pittsburgh, PA, USA
The incidence of hepatocellular cancer (HCC) is gradually rising. HCC occurs as a sequela to various chronic liver diseases and ensuing cirrhosis. There have been many therapies approved for unresectable HCC in the last 5 years, including immune checkpoint inhibitors, and the overall response rates have improved. However, there are many cases that do not respond, and personalized medicine is lacking, making HCC an unmet clinical need. Generation of appropriate animal models have been key to our understanding of HCC. Based on the overall concept of hepatocarcinogenesis, two major categories of animal models are discussed herein that can be useful to address specific questions. One category is described as the “outside-in” model of HCC and is based on the premise that it takes decades of hepatocyte injury, death, wound healing, and regeneration to eventually lead to DNA damage and mutations in a hepatocyte, which initiates tumorigenesis. Several animal models have been generated, which attempt to recapitulate this complex tissue damage and cellular interplay through genetics, diets, and toxins. The second category is the “inside-out” model of HCC, where clinically relevant genes can be coexpressed in a small subset of hepatocytes to yield a tumor, which matches HCC subsets in gene expression. This model has been made possible in part by the widely available molecular characterization of HCC, and in part by modalities like sleeping beauty transposon/transposase, Crispr/Cas9, and hydrodynamic tail vein injection. These two categories of HCC have distinct pros and cons, which are discussed in this Thinking Out Loud article.
Key words: Hepatocellular cancer (HCC); Animal models; “Outside-in” model; “Inside-out” model
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