Hepatic Cell News Volume 3.44 | Nov 21 2019

TOP STORY

Neutralization of Oxidized Phospholipids Ameliorates Non-Alcoholic Steatohepatitis

Targeting oxidized phospholipids (OxPLs) in hyperlipidemic Ldlr^−/− mice improved multiple aspects of non-alcoholic steatohepatitis, including steatosis, inflammation, fibrosis, hepatocyte death, and progression to hepatocellular carcinoma. Mechanistically, researchers found that OxPLs promote ROS accumulation to induce mitochondrial dysfunction in hepatocytes. [Cell Metab] Abstract | Graphical Abstract

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Intestinal IL-17R Signaling Constrains IL-18-Driven Liver Inflammation by the Regulation of Microbiome-Derived Products

Upon disease induction, absence of enteric interleukin (IL)-17RA signaling exacerbated hepatitis and hepatocyte cell death. IL-18 was necessary for disease exacerbation and is associated with increased activated hepatic lymphocytes based on Ifng and Fasl expression. [Cell Rep] Abstract | Graphical Abstract

TGF-β1 Accelerates the Hepatitis B Virus X-Induced Malignant Transformation of Hepatic Progenitor Cells by Upregulating miR-199a-3p

Investigators provided evidence linking the coexistence of hepatitis B virus X protein (HBx) and transforming growth factor beta 1 (TGF-β1) with miR-199a-3p in the malignant transformation of hepatic progenitor cell. The examination of liver cancer specimens demonstrated that HBx and TGF-β1 expression was positively correlated with epithelial cell adhesion molecule and cluster of differentiation 90. [Oncogene] Full Article

Upregulation of Histamine Receptor H1 Promotes Tumor Progression and Contributes to Poor Prognosis in Hepatocellular Carcinoma

The authors found that H1 histamine receptor (H1HR) was frequently unregulated in hepatocellular carcinoma (HCC), which is significantly associated with both recurrence-free survival and overall survival in HCC patients. Functional experiments revealed that H1HR promoted both the growth and metastasis of HCC cells by inducing cell cycle progression, formation of lamellipodia, production of matrix metalloproteinase 2, and suppression of cell apoptosis. [Oncogene] Full Article

Kinesin Family Member 15 Promotes Cancer Stem Cell Phenotype and Malignancy via Reactive Oxygen Species Imbalance in Hepatocellular Carcinoma

Kinesin family member 15 (KIF15) expression was shown to be over-expressed in hepatocellular carcinoma (HCC) tissues, cell lines, and cancer stem cells. Patients with HCC with high KIF15 expression had shortened overall survival and high recurrence probability. Downregulation of KIF15 in vitro as well as in HCC organoids resulted in a significant reduction in sphere formation and expression of stemness-related genes. [Cancer Lett] Full Article

In Vitro Human Liver Model of Nonalcoholic Steatohepatitis by Coculturing Hepatocytes, Endothelial Cells, and Kupffer Cells

An in vitro human liver model of NAFLD by co-culturing human hepatocytes, umbilical vein endothelial cells (HUVECs), and Kupffer cells (KCs) into spheroids is presented. Analysis of indirect cross-talk using conditioned media between steatotic spheroids-composed of hepatocellular carcinoma-derived cells and HUVECs-and mouse KCs revealed that the latter could be activated showing increased cell area, elevated production of reactive oxygen species, and proinflammatory cytokines. [Adv Healthc Mater] Abstract

Silencing of Long Noncoding RNA HOXA11-AS Inhibits the Wnt Signaling Pathway via the Upregulation of HOXA11 and Thereby Inhibits the Proliferation, Invasion, and Self-Renewal of Hepatocellular Carcinoma Stem Cells

Initially, the expression patterns of homeobox A11 antisense (HOXA11-AS) and HOXA11 in hepatocellular carcinoma (HCC) tissues, cells, and stem cells were determined. HCC stem cells, successfully sorted from Hep3B and Huh7 cells, were transfected with short hairpin or overexpression plasmids for HOXA11-AS or HOXA11 overexpression and depletion, with an aim to study the influences of these mediators on the self-renewal, proliferation, migration, and tumorigenicity of HCC stem cells in vivo. [Exp Mol Med] Full Article

Celastrol Exerts Anti-Inflammatory Effect in Liver Fibrosis via Activation of AMPK-SIRT3 Signaling

Scientists investigated the anti-inflammatory effect of celastrol in liver fibrosis and to further reveal mechanisms of celastrol-induced anti-inflammatory effects with a focus on AMPK-SIRT3 signalling. Celastrol showed potent ameliorative effects on liver fibrosis both in activated hepatic stellate cells and in fibrotic liver. [J Cell Mol Med] Full Article

P7TP3 Inhibits Tumor Development, Migration, Invasion and Adhesion of Liver Cancer via Wnt/β-Catenin Signal Pathway

Overexpression of p7 trans-regulated protein 3 (P7TP3) in HepG2 cells has significantly repressed the growth of hepatocellular carcinoma (HCC) xenografts in nude mice. Furthermore, wound-healing tests, transwell assays, matrigel transwell assays, adhesion assays, CCK‐8 assays, flow cytometry and western blotting analysis revealed that P7TP3 protein expression inhibited migration, invasion, adhesion, proliferation and cell cycle progression in HCC cell lines. [Cancer Sci] Abstract

TCF19 Promotes Cell Proliferation Through Binding to the Histone H3K4me3 Mark

Researchers showed that TCF19 mediated the hepatocellular carcinoma HepG2 cell proliferation through its Plant Homeodomain (PHD) finger that recognizes trimethylated lysine 4 of Histone 3 (H3K4me3). W316 of the PHD finger of TCF19 was one of the critical residues eliciting this function. Whole genome microarray analysis and orthogonal cell-based assays identified a large subset of genes involved in cell survival and proliferation that depend on TCF19. [Drug Metab Dispos] Abstract

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Western Diet and the Immune System: An Inflammatory Connection

A better understanding of how modern lifestyle and Western diet activate immune cells is essential for the development of efficient preventive and therapeutic strategies for common non-communicable diseases. The authors review the current mechanistic understanding of how the Western lifestyle can induce metaflammation, and they discuss how this knowledge can be translated to protect the public from the health burden associated with their selected lifestyle. [Immunity] Abstract

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Dicerna and Novo Nordisk Enter Agreement to Discover and Develop RNAi Therapies for Liver-Related Cardio-Metabolic Diseases

Dicerna™ Pharmaceuticals, Inc. and Novo Nordisk A/S announced an agreement to discover and develop novel therapies for the treatment of liver-related cardio-metabolic diseases using Dicerna’s proprietary GalXC™ RNAi platform technology. The collaboration plans to explore more than 30 liver cell targets and may deliver multiple clinical candidates for disorders including chronic liver disease, non-alcoholic steatohepatitis, type 2 diabetes, obesity, and rare diseases. [Dicerna Pharmaceuticals, Inc.] Press Release

CytoDyn Reports Strong Positive Preclinical Data to Demonstrate Potential of Leronlimab in Treating Nonalcoholic Fatty Liver Disease (NAFLD) in Humanized Mouse Model

CytoDyn Inc. announced strong positive pre-clinical data highlighting the potential of leronlimab in treating NAFLD, a common precursor to nonalcoholic steatohepatitis (NASH). These data, along with previous findings showing that leronlimab inhibits liver fibrosis, demonstrates the potential of leronlimab to control both the early and late stages of NASH. [CytoDyn, Inc.] Press Release

Alnylam Announces Approval of GIVLAARI™ (Givosiran) by the U.S. Food and Drug Administration (FDA)

Alnylam Pharmaceuticals, Inc. announced that the FDA approved GIVLAARI™ injection for subcutaneous use for the treatment of adults with acute hepatic porphyria (AHP). AHP is a family of ultra-rare, genetic diseases characterized by debilitating, potentially life-threatening attacks and, for some patients, chronic manifestations that negatively impact daily functioning and quality of life. [Alnylam Pharmaceuticals, Inc.] Press Release

European Data Law Is Impeding Studies on Diabetes and Alzheimer’s, Researchers Warn

Finland’s National Institute for Health and Welfare has sent 32,000 DNA samples to the laboratory of Francis Collins, director the US National Institutes of Health. But in May 2018, when European privacy law called the General Data Protection Regulationcame into force, the Finnish institute stopped all data sharing on the project, because NIH could not provide guarantees that would satisfy the institute’s interpretations of the law’s requirements. [ScienceInsider] Editorial

Science Funders Gamble on Grant Lotteries

Albert Einstein famously insisted that God does not play dice. But the Health Research Council of New Zealand does. The agency is one of a growing number of funders that award grants partly through random selection. Earlier this year, for example, David Ackerley, a biologist at Victoria University of Wellington, received NZ$150,000 (US$96,000) to develop new ways to eliminate cells – after his number came up in the council’s annual lottery. [Nature News] Editorial

NEW Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies
January 9-12, 2020
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NEW Postdoctoral Researcher – High Throughput Microfluidic Drug Screening (National University of Ireland Galway)

Postdoctoral Researcher – Oncogenic Pathways (University of Liège)

Faculty Member – Pathogen-Associated Malignancies (Fred Hutchinson Cancer Research Center)

Postdoctoral Fellow – Drug-Induced Liver Injury (Johnson & Johnson)

Postdoctoral Researcher – Liver Disease Treatment (University of Southern Denmark)

Postdoctoral Researcher – Personalized Medicine (Mayo Clinic Center for Individualized Medicine)

Postdoctoral Researcher – Liver Plasticity (University of Southern Denmark)

Postdoctoral Scientist – RAS Cancer Biology (Genetech, Inc.)

Assistant Professor – Liver Research (The University of Hong Kong)

Research Scientist – Fibrosis (Gilead Sciences, Inc.)

Principal Researcher – Systems Disease Biology (Boehringer Ingelheim)

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