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Aims & Scope
Gene Expression The Journal of Liver Research will publish articles 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.
Satdarshan (Paul) S. Monga, University of Pittsburgh, USA
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
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
The publishers and editorial board of Gene Expression The Journal of Liver Research have adopted the publication ethics and malpractice statements of the Committee on Publication Ethics (COPE) https://publicationethics.org/core-practices. These guidelines highlight what is expected of authors and what they can expect from the reviewers and editorial board in return. They also provide details of how problems will be handled. Briefly:
Author Responsibilities: Authors listed on a manuscript must have made a significant contribution to the study and/or writing of the manuscript. During revisions, authors cannot be removed without their permission and that of the other authors. All authors must also agree to the addition of new authors. It is the responsibility of the corresponding author to ensure that this occurs.
Financial support and conflicts of interest for all authors must be declared. Further information on this can be obtained from the International Committee for Medical Journal Editors (http://www.icmje.org/).
The reported research must be novel and authentic and the authors should confirm that the same data has not been and is not going to be submitted to another journal (unless already rejected). Statements made in the introduction and discussion should be supported by appropriate references and sufficient experimental detail should be provided to allow for repetition of the study by another group. Plagiarism of the text/data will not be tolerated and could result in retraction of an accepted article. Any text or figures reproduced from another source require the permission of the original copyright holders (normally the publishers).
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When humans, animals, or tissue derived from them have been used, then mention of the appropriate ethical approval must be included in the manuscript.
Reviewer Responsibilities: Reviewers are expected to not possess any conflicts of interest with the authors and research. They should review the science objectively and provide recommendations for improvements where necessary. When aware of relevant published work not being cited, the reviewers should recommend inclusion of these references. If the reviewer feels that they would be unable to repeat the study as described, then additional methodological details should be requested. Any unpublished information read by a reviewer should be treated as confidential.
Editorial Responsibilities: The editorial office is expected to select an appropriate number of reviewers for the manuscript so that they can make an informed decision about whether to reject/accept a manuscript. Their decision must be based only on the paper’s importance, originality, clarity, and whether it is suitable for the journal. They must not have a conflict of interest with the authors or work described. The anonymity of the reviewers must be maintained.
Should problems come to light after acceptance then the editors agree to promote the publication of corrections and/or retractions as deemed necessary.
NIH Public Access Policy: Cognizant Communication Corporation uploads published manuscripts on the authors’ behalf to PubMed Central so authors may remain in compliance with the NIH Public Access Policy.
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Table of Contents:
Volume 20, Number 3
Characterization of the Gene Expression Patterns in the Murine Liver Following Intramuscular Administration of Baculovirus – 89
Mitsuhiro Iyori,* Ryohei Ogawa,† Talha Bin Emran,* Shuta Tanbo,* and Shigeto Yoshida*
*Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kanazawa, Japan
†Department of Radiological Sciences, University of Toyama, Toyama, Japan
Intramuscular administration of wild-type baculovirus is able to both protect against Plasmodium sporozoite challenge and eliminate liver-stage parasites via a Toll-like receptor 9-independent pathway. To investigate its effector mechanism(s), the gene expression profile in the liver of baculovirus-administered mice was characterized by cDNA microarray analysis. The ingenuity pathway analysis gene ontology module revealed that the major gene subsets induced by baculovirus were immune-related signaling, such as interferon signaling. A total of 40 genes commonly upregulated in a Toll-like receptor 9-independent manner were included as possible candidates for parasite elimination. This gene subset consisted of NT5C3, LOC105246895, BTC, APOL9a/b, G3BP3, SLC6A6, USP25, TRIM14, and PSMB8 as the top 10 candidates according to the special unit. These findings provide new insight into effector molecules responsible for liver-stage parasite killing and, possibly, the development of a new baculovirus-mediated prophylactic and therapeutic biopharmaceutical for malaria.
Key words: Liver; Baculovirus; Plasmodium; Interferon signaling; cDNA microarray
Hepatocyte-Specific Hepatocyte Nuclear Factor 4 Alpha (HNF4α) Deletion Decreases Resting Energy Expenditure by Disrupting Lipid and Carbohydrate Homeostasis – 99
Ian Huck,* E. Matthew Morris,† John Thyfault,†‡ and Udayan Apte*
*Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
†Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA
‡Research Service, Kansas City VA Medical Center, Kansas City, KS, USA
Hepatocyte nuclear factor 4 alpha (HNF4α) is required for hepatocyte differentiation and regulates expression of genes involved in lipid and carbohydrate metabolism including those that control VLDL secretion and gluconeogenesis. Whereas previous studies have focused on specific genes regulated by HNF4α in metabolism, its overall role in whole-body energy utilization has not been studied. In this study, we used indirect calorimetry to determine the effect of hepatocyte-specific HNF4α deletion (HNF4α-KO) in mice on whole-body energy expenditure (EE) and substrate utilization in fed, fasted, and high-fat diet (HFD) conditions. HNF4α-KO had reduced resting EE during fed conditions and higher rates of carbohydrate oxidation with fasting. HNF4α-KO mice exhibited decreased body mass caused by fat mass depletion despite no change in energy intake and evidence of positive energy balance. HNF4α-KO mice were able to upregulate lipid oxidation during HFD, suggesting that their metabolic flexibility was intact. However, only hepatocyte-specific HNF4α-KO mice exhibited significant reduction in basal metabolic rate and spontaneous activity during HFD. Consistent with previous studies, hepatic gene expression in HNF4α-KO supports decreased gluconeogenesis and decreased VLDL export and hepatic b-oxidation in HNF4α-KO livers across all feeding conditions. Together, our data suggest that deletion of hepatic HNF4α increases dependence on dietary carbohydrates and endogenous lipids for energy during fed and fasted conditions by inhibiting hepatic gluconeogenesis, hepatic lipid export, and intestinal lipid absorption resulting in decreased whole-body energy expenditure. These data clarify the role of hepatic HNF4α on systemic metabolism and energy homeostasis.
Key words: Metabolism; Indirect calorimetry; High-fat diet; Fasting; Liver
Ferroptosis and Acetaminophen Hepatotoxicity: Are We Going Down Another Rabbit Hole? – 111
Hartmut Jaeschke, Olamide B. Adelusi, and Anup Ramachandran
Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure in the US. The mechanisms of APAP-induced liver injury have been under extensive investigations for decades, and many key events of this necrotic cell death are known today. Initially, two opposing hypotheses for cell death were proposed: reactive metabolite and protein adduct formation versus reactive oxygen and lipid peroxidation (LPO). In the end, both mechanisms were reconciled, and it is now generally accepted that the toxicity starts with formation of reactive metabolites that, after glutathione depletion, bind to cellular proteins, especially on mitochondria. This results in a mitochondrial oxidant stress, which requires amplification through a mitogen-activated protein kinase cascade, leading ultimately to enough reactive oxygen and peroxynitrite formation to trigger the mitochondrial membrane permeability transition and cell death. However, the earlier rejected LPO hypothesis seems to make a comeback recently under a different name: ferroptosis. Therefore, the objective of this review was to critically evaluate the available information about intracellular signaling mechanisms of APAP-induced cell death and those of ferroptosis. Under pathophysiologically relevant conditions, there is no evidence for quantitatively enough LPO to cause cell death, and thus APAP hepatotoxicity is not caused by ferroptosis. However, the role of mitochondria-localized minor LPO remains to be further investigated.
Key words: Acetaminophen hepatotoxicity; Oncotic necrosis; Apoptosis; Ferroptosis; Lipid peroxidation; Fenton reaction; Glutathione peroxidase 4
Role of Noncoding RNAs in Acetaminophen-Induced Liver Injury – 121
Vivek Chowdhary,*† Pipasha Biswas,† and Kalpana Ghoshal*†
*Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA
†Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, USA
Genomic and transcriptomic analyses have well established that the major fraction of the mammalian genome is transcribed into different classes of RNAs ranging in size from a few nucleotides to hundreds of thousands of nucleotides, which do not encode any protein. Some of these noncoding RNAs (ncRNAs) are directly or indirectly linked to the regulation of expression or functions of ~25,000 proteins coded by <2% of the human genome. Among these regulatory RNAs, microRNAs are small (21–25 nucleotides) RNAs that are processed from precursor RNAs that have stem–loop structure, whereas noncoding RNAs >200 nucleotides are termed long noncoding RNAs (lncRNAs). Circular RNAs (circRNAs) are newly identified lncRNA members that are generated by back-splicing of primary transcripts. The functions of ncRNAs in modulating liver toxicity of xenobiotics are emerging only recently. Acetaminophen (N-acetyl-para-aminophenol, paracetamol or APAP) is a safe analgesic and antipyretic drug at the therapeutic dose. However, it can cause severe liver toxicity that may lead to liver failure if overdosed or combined with alcohol, herbs, or other xenobiotics. This review discusses the role of ncRNAs in acetaminophen metabolism, toxicity, and liver regeneration after APAP-induced liver injury (AILI).
Key words: Noncoding RNAs; Acetaminophen metabolism; Acetaminophen-induced liver injury (AILI); Toxicity; Liver regeneration
Wnt/β-Catenin Signaling and Liver Regeneration: Circuit, Biology, and Opportunities – 131
Shikai Hu*† and Satdarshan P. Monga†‡§
*School of Medicine, Tsinghua University, Beijing, China
†Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
‡Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
§Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
The liver is uniquely bestowed with an ability to regenerate following a surgical or toxicant insult. One of the most researched models to demonstrate the regenerative potential of this organ is the partial hepatectomy model, where two thirds of the liver is surgically resected. The remnant liver replenishes the lost mass within 10–14 days in mice. The distinctive ability of the liver to regenerate has allowed living donor and split liver transplantation. One signaling pathway shown to be activated during the process of regeneration to contribute toward the mass and functional recovery of the liver is the Wnt/β-catenin pathway. Very early after any insult to the liver, the cell–molecule circuitry of the Wnt/β-catenin pathway is set into motion with the release of specific Wnt ligands from sinusoidal endothelial cells and macrophages, which, in a paracrine manner, engage Frizzled and LDL-related protein-5/6 coreceptors on hepatocytes to stabilize β-catenin inducing its nuclear translocation. Nuclear β-catenin interacts with T-cell factor family of transcription factors to induce target genes including cyclin D1 for proliferation, and others for regulating hepatocyte function. Working in collaboration with other signaling pathways, Wnt/β-catenin signaling contributes to the restoration process without any compromise of function at any stage. Also, stimulation of this pathway through innovative means induces liver regeneration when this process is exhausted or compromised and thus has applications in the treatment of end-stage liver disease and in the field of liver transplantation. Thus, Wnt/β-catenin signaling pathway is highly relevant in the discipline of hepatic regenerative medicine.
Key words: Liver regeneration; Wnt; β-Catenin; Cyclin D1; Proliferation; Metabolism; Endothelial cells; Hepatocytes; Macrophages
Integrin Linked Kinase (ILK) and its Role in Liver Pathobiology – 143
Nicole Martucci, George K. Michalopoulos, and Wendy M. Mars
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Integrin linked kinase (ILK) is a vital signaling protein ubiquitously expressed throughout the body. It binds to intracellular integrins to help promote signaling related to cell adhesion, apoptosis, proliferation, migration, and a plethora of other common cellular functions. In this review, ILK’s role in the liver is detailed. Studies have shown ILK to be a major participant in hepatic ECM organization, liver regeneration, insulin resistance, and hepatocellular carcinoma.
Key words: Partial hepatectomy; Hepatocyte proliferation; Termination of liver regeneration; Hepatocellular carcinoma; Glucose/carbohydrate metabolism
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