Hepatic Cell News Volume 3.22 | Jun 21 2019

TOP STORY

Nqo1 Ablation Inhibits Activation of the PI3K/Akt and MAPK/ERK Pathways and Blocks Metabolic Adaptation in Hepatocellular Carcinoma

Nqo1 ablation triggered simultaneous inhibition of the PI3K/Akt and MAPK/ERK pathways, suppressed the expression of glycolysis and glutaminolysis genes and blocked metabolic adaptation in liver cancer cells. Conversely, Nqo1 overexpression caused hyper-activation of the PI3K/Akt and MAPK/ERK pathways and promoted metabolic adaptation. [Hepatology] Abstract

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Analysis of Host Responses to Hepatitis B and Delta Viral Infections in a Micro-Scalable Hepatic Co-Culture System

Scientists established hepatitis B virus (HBV) and HBV/HDV co- and super-infections in self-assembling co-cultured primary human hepatocytes (SACC-PHHs) for up to 28 days in a 384 well format and highlighted the suitability of this platform for high-throughput drug testing. They demonstrated that hepatocytes in SACC-PHHs maintain a mature hepatic phenotype over time regardless of infection condition. [Hepatology] Abstract | Press Release

Inherited IL-18BP Deficiency in Human Fulminant Viral Hepatitis

Researchers showed that human IL-18 and IL-18 binding protein (IL-18BP) were both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive natural killer cell activation by IL-18 resulted in uncontrolled killing of human hepatocytes in vitro. [J Exp Med] Full Article | Graphical Abstract

Epigenetic Compensation Promotes Liver Regeneration

The authors identified the epigenetic regulator ubiquitin-like with PHD and ring finger domains 1 (UHRF1), which is essential for DNA methylation, as dynamically expressed during liver regeneration in mice. UHRF1 deletion in hepatocytes caused genome-wide DNA hypomethylation but, surprisingly, had no measurable effect on gene or transposon expression or liver homeostasis. [Dev Cell] Full Article

Gamma-Secretase Complex-Dependent Intramembrane Proteolysis of CD147 Regulates the Notch1 Signaling Pathway in Hepatocellular Carcinoma

Investigators demonstrated that CD147 underwent an intramembranous cleavage by the γ-secretase at lysine 231 to release its intracellular domains (ICDs). The nuclear translocation of the CD147ICD regulated Notch1 expression by directly binding to the Notch1 promoter and promoted the activation of the Notch signaling pathway. Simultaneously, overexpression of CD147ICD promoted cancer cell proliferation via Notch1 signaling. [J Pathol] Abstract

Isovitexin Reduces Carcinogenicity and Stemness in Hepatic Carcinoma Stem-Like Cells by Modulating MnSOD and FoxM1

Forkhead box M1 (FoxM1) upregulation by manganese superoxide dismutase (MnSOD) contributed to carcinogenicity and stemness, with increased sphere- and colony-formation capabilities, upregulated stemness-associated markers and CD133⁺ subpopulation as well as elevated oncogenicity in vivo in hepatic carcinoma stem-like cells compared with hepatic carcinoma cells. [J Exp Clin Cancer Res] Full Article

Gasdermin D Protects against Noninfectious Liver Injury by Regulating Apoptosis and Necroptosis

Scientists examined the contribution of gasdermin D (GsdmD) using WT and GsdmD^-/- mice in two models of noninfectious liver injury: hemorrhagic shock with resuscitation and acetaminophen overdose. [Cell Death Dis] Full Article

Caveolin-1 Promotes Invasion and Metastasis by Upregulating Pofut1 Expression in Mouse Hepatocellular Carcinoma

Mouse Hepa1-6 hepatocellular carcinoma (HCC) cells lacking caveolin-1 (Cav-1) expression exhibited low transcription levels of Pofut1, whereas strong Pofut1 expression was found in high-metastasis-potential Hca-F cells with high levels of Cav-1. Cav-1 activated MAPK signaling and promoted phosphorylation of the transcription factors CREB, Sp1, HNF4A and c-Myc, which bound to the Pofut1 promoter region to induce its transcription. [Cell Death Dis] Full Article

Phenotype-Based Screens with Conformation-Specific Inhibitors Reveal p38 Gamma and Delta as Targets for HCC Polypharmacology

Researchers identified a multi-kinase inhibitor—AD80—with anti-tumoral activity across a variety of hepatocellular carcinoma (HCC) preclinical models, including mouse xenografts. They found a number of kinases as putative targets for AD80, including several receptor and cytoplasmic protein kinases. Among these, they found p38 gamma and delta as direct targets of AD80. [Mol Cancer Ther] Abstract

MicroRNA-301b-3p Contributes to Tumor Growth of Human Hepatocellular Carcinoma by Repressing Vestigial Like Family Member 4

Mechanistically, miR-301b-3p directly bound to the 3′UTR of vestigial like family member 4 (VGLL4) and negatively regulated its expression. VGLL4 knockdown markedly repressed cell proliferation, resulted in G2/M phase arrest and promoted apoptosis of hepatocellular carcinoma (HCC) cells. Accordingly, VGLL4 silencing rescued miR-301b-3p knockdown attenuated HCC cell proliferation, cell cycle progression and apoptosis resistance. [J Cell Mol Med] Full Article

Identification of Keratin 23 as a Hepatitis C Virus-Induced Host Factor in the Human Liver

Scientists investigated keratin 23 (KRT23) mRNA levels in datasets from liver biopsies of chronic hepatitis C patients and in primary human hepatocytes experimentally infected with hepatitis C virus (HCV), in addition to hepatoma cells. They observed an HCV-dependent increase of mRNA levels. Importantly, KRT23 protein levels in patient plasma decreased upon viral clearance. [Cells] Full Article

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Application of Nintedanib and Other Potential Anti-Fibrotic Agents in Fibrotic Diseases

The authors summarize the mechanisms and efficacy of nintedanib in the treatment of fibrotic diseases in animal models and clinical trials, provide an update on recent advances in the development of other novel antifibrotic agents in preclinical and clinical study, and offer perspective about the possible clinical application of these agents in fibrotic diseases. [Clin Sci (Lond)] Abstract

Humanized Mouse Models for the Study of Hepatitis C and Host Interactions

Investigators focus on humanized mice in hepatitis C virus (HCV) research. Humanized mice are defined as animal models that encompass either only human hepatocytes or both human liver and immune cells. Aspects related to immunopathogenesis, anti-viral interventions, drug testing and perspectives of these models for future HCV research are discussed. [Cells] Full Article

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Alnylam Completes Enrollment for ILLUMINATE-A Phase III Study of Lumasiran in Patients with Primary Hyperoxaluria Type 1 (PH1)

Alnylam Pharmaceuticals, Inc. announced that it has achieved full patient enrollment in its ILLUMINATE-A Phase III study of lumasiran, an investigational RNAi therapeutic targeting glycolate oxidase for the treatment of adults and children with PH1. [Alnylam Pharmaceuticals, Inc.] Press Release

DURECT Announces Completion of the 90 Mg Severe Cohort and Dose Escalation Committee Approval to Commence 150 Mg Dosing in Patients with Severe Alcoholic Hepatitis (AH) in Its Ongoing DUR-928 Phase IIa AH Trial

DURECT Corporation announced that it has completed dosing the 90 mg cohort of severe AH patients in its ongoing DUR-928 Phase IIa clinical trial, and that after reviewing safety and pharmacokinetic data from the completed cohorts, the Dose Escalation Committee has approved commencement of dosing at the 150 mg level in severe AH patients. [DURECT Corporation] Press Release

Zydus Announces Completion of Enrolment in EVIDENCES IV Phase II Clinical Trial of Saroglitazar Magnesium in NASH

Zydus Cadila announced that it has completed enrolment of 104 patients with non-alcoholic fatty liver disease, including non-alcoholic steatoHepatitis (NASH) across 20 clinical sites in the United States of America. The trial will evaluate the percentage change from baseline in serum ALT levels in patients treated with saroglitazar magnesium as compared to placebo as the primary endpoint. [Zydus Cadila (PR Newswire Association LLC.)] Press Release

Dicerna™ Presents Additional Data from PHYOX™1 Study of DCR-PHXC in Patients with Primary Hyperoxaluria Type 1 (PH1) and Type 2 (PH2)

Dicerna^™Pharmaceuticals, Inc. announced updated data from its ongoing PHYOX™1 Phase I clinical trial evaluating DCR-PHXC, the company’s lead GalXC^™ product candidate. PH is a family of severe, rare, genetic liver disorders characterized by overproduction of oxalate, a natural chemical in the body that is normally eliminated as waste through the kidneys. [Dicerna Pharmaceuticals, Inc.] Press Release

CymaBay Therapeutics Announces IND to Commence a Clinical Study of Seladelpar to Treat Primary Sclerosing Cholangitis

CymaBay Therapeutics, Inc. announced FDA clearance of the company’s Investigational New Drug Application (IND) for seladelpar to treat primary sclerosing cholangitis (PSC). The company intends to initiate a Phase II study to evaluate the safety, tolerability, and efficacy of seladelpar in patients with PSC in the third quarter. [CymaBay Therapeutics, Inc.] Press Release

ContraVir Pharmaceuticals Receives Positive FDA Response to CRV431 Pre-IND Package for NASH

ContraVir Pharmaceuticals, Inc. announced positive feedback from the FDA in response to ContraVir’s pre-Investigational New Drug (IND) meeting with respect to the development of CRV431 in non-alcoholic steatohepatitis (NASH). [ContraVir Pharmaceuticals, Inc.] Press Release

University Distinguished Professor X.J. Meng Awarded Nearly $2 Million NIH Grant Renewal

With a new, five-year National Institutes of Health (NIH) RO1 grant totaling nearly $2 million — X.J. Meng’s third successful competing renewal — the molecular virologist and his team in the Department of Biomedical Sciences and Pathobiology are aiming to strengthen their life-altering research on hepatitis E virus. [Virginia Polytechnic Institute and State University] Press Release

Theratechnologies Confirms Decision to Pursue Development of Tesamorelin for NASH in HIV

Theratechnologies Inc. announced that it will pursue the development of tesamorelin for the treatment of non-alcoholic steatohepatitis (NASH) in people living with HIV. The development of tesamorelin in NASH-HIV will be made using a new formulation which is patent protected until 2033 in the United States and in key European countries until 2034. [Theratechnologies Inc.] Press Release

Dr. Caroline Lindemans explains her work on intestinal repair following injury in graft versus host disease. Listen Now

UK’s Leading Mouse Genetics Center Faces Closure

Britain’s leading center for mouse genetics is facing closure in a move that critics say will undermine crucial research on serious diseases and threaten the standing of UK science. The Medical Research Council has told staff at its Harwell Institute in Oxfordshire that an internal strategy board recommended the closure of all academic work at the site, threatening research on diabetes, neurodegenerative disease, child deafness and other conditions. [The Guardian] Editorial

House Panel Clarifies How Universities Would Report Sexual Harassment Cases to US Funders

New rules from the National Science Foundation (NSF) on reporting sexual harassment by someone with an NSF grant raise questions about due process, university administrators say. A key congressional panel took those concerns to heart by modifying language in a bill that would require the administration to write guidelines applying to half a dozen major federal research agencies. [ScienceInsider] Editorial

NEW Gordon Research Seminar (GRS): Epigenomics of Diabetes and Other Metabolic Diseases
May 23-24, 2020
Hong Kong, China

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NEW Research Lab Specialist – Tumor Microenvironment & Cell Behavior (University of Southern California)

NEW PhD Position – Cytokine-Induced Metabolic Rewiring of the Liver (Research Center for Molecular Medicine of the Austrian Academy of Sciences)

Postdoctoral Position – Clinical Proteomics & Liver Metabolism (University of Copenhagen)

Postdoctoral Scientist – Epigenetic Mechanisms of NAFLD (Institute of Hepatology, Foundation for Liver Research)

Postdoctoral Position – Liver Disease (University of Illinois at Chicago)

Research Assistant – Liver Immunology (Maynooth University)

Postdoctoral Research Scientists – Hepatitis Virus Research (Ohio State University)

Faculty Position/Director – Cancer Research (Lewis Katz School of Medicine at Temple University)

Research Assistant – Liver Damage Research (University of Colorado Denver)

Tier I CIHR Canada Research Chair – Mechanisms of Health & Disease (Brock University)

Postdoctoral Fellow – Profiling Single Exosomes & Liver Metastasis Research (McGill University)

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