Hepatic Cell News Volume 3.29 | Aug 9 2019

TOP STORY

Generation of Human Fatty Livers Using Custom-Engineered Induced Pluripotent Stem Cells with Modifiable SIRT1 Metabolism

To model human fatty livers, researchers repopulated decellularized rat livers with human mesenchymal cells, fibroblasts, macrophages, and human SIRT1 knockdown induced pluripotent stem cell (iPSC)-derived hepatocytes and found that the human iPSC-derived liver tissue developed macrosteatosis, acquired proinflammatory phenotype, and shared a similar lipid and metabolic profiling to human fatty livers. [Cell Metab] Abstract | Graphical Abstract

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Highly Diversified Shrew Hepatitis B Viruses Corroborate Ancient Origins and Divergent Infection Patterns of Mammalian Hepadnaviruses

Shrew hepatitis B viruses (HBVs) infection patterns showed important similarities with human HBV, and shrews might be susceptible to human HBV. In contrast, shrew HBVs could neither infect human cells nor use the canonical HBV receptor molecule for cellular entry. [Proc Natl Acad Sci USA] Abstract | Press Release

HBx Regulates Transcription Factor PAX8 Stabilization to Promote the Progression of Hepatocellular Carcinoma

The authors showed that PAX8 silencing inhibited the proliferation and clonogenicity of hepatoma cells and its growth in vivo. The HBV X protein (HBx) did not directly interact, but stabilized PAX8 by inhibiting proteasome-dependent ubiquitination and degradation. [Oncogene] Full Article

Deacetylation of β-Catenin by SIRT1 Regulates Self-Renewal and Oncogenesis of Liver Cancer Stem Cells

Mechanistically, researchers showed that nuclear accumulation of β-catenin resulted from deacetylation mediated by SIRT1. Further, nuclear β-catenin promoted the transcription of Nanog to help maintain self-renewal of liver cancer stem cells. [Cancer Lett] Abstract

The Kinase PKD3 Provides Negative Feedback on Cholesterol and Triglyceride Synthesis by Suppressing Insulin Signaling

Investigators showed that protein kinase D (PKD)3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2. [Sci Signal] Full Article

O-GlcNAcylated C-Jun Antagonizes Ferroptosis via Inhibiting GSH Synthesis in Liver Cancer

Scientists observed that erastin suppressed the malignant phenotypes of liver cancer cells by inhibiting O-GlcNAcylation of c-Jun and further inhibited protein expression, transcription activity and nuclear accumulation of c-Jun. Overexpression of c-Jun-WT with simultaneous PuGNAc treatment conversely inhibited erastin-induced ferroptosis, whereas overexpression of c-Jun-WT alone or overexpression of c-Jun-S73A with PuGNAc treatment did not exert a similar effect. [Cell Signal] Abstract

Hydrogen Peroxide Inducible Clone-5 Sustains NADPH Oxidase-Dependent Reactive Oxygen Species-C-Jun N-Terminal Kinase Signaling in Hepatocellular Carcinoma

Researchers addressed this issue in a comprehensive manner. By RNA interference and ectopic hydrogen peroxide inducible clone-5 (Hic-5) expression, they demonstrated that Hic-5 was essential for activation of NADPH oxidase and reactive oxygen species generation leading to activation of downstream JNK and c-jun transcription factor. [Oncogenesis] Full Article

Gene Manipulation in Liver Ductal Organoids by Optimized Recombinant Adeno-Associated Virus Vectors

Investigators developed the adeno-associated virus (AAV) vector AAV-DJ as a powerful tool to transduce mouse and human liver ductal organoids. Via AAV-DJ-mediated up- or down-regulation of target genes, they successfully manipulated the cholangiocyte-to-hepatocyte differentiation: specifically, they induced differentiation by overexpressing the hepatocyte-specifying regulator hepatocyte nuclear factor 4α and blocked differentiation by stimulating Notch signaling or interfering Smads signaling. [J Biol Chem] Abstract

The Involvement of Lipid Raft Pathway in Suppression of TGFβ-Mediated Metastasis by Tolfenamic Acid in Hepatocellular Carcinoma Cells

The authors investigated the effect of tolfenamic acid (TA) on TGFβ-mediated pro-metastatic activity and the underlying mechanisms in hepatocellular carcinoma (HCC). TA suppressed TGFβ-induced migration and glycolysis in HCC cells, which was accompanied with reduced Smad phosphorylation and subsequent nuclear transcription activity. [Toxicol Appl Pharmacol] Abstract | Full Article

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Reversal of NASH Fibrosis with Pharmacotherapy

Worldwide, NAFLD has become one of the most common liver diseases and it has also become one of the leading indications for liver transplantation. The understanding of the NAFLD epidemiology, pathogenesis and its progression to cirrhosis has improved over the last two decades. [Hepatol Int] Abstract

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Galectin Therapeutics Submits Phase III NASH-RX Protocol in Nash Cirrhosis to FDA

Galectin Therapeutics Inc. announced it has submitted for assessment the Phase III protocol for using belapectin for the treatment of compensated non-alcoholic steatohepatitis (NASH) cirrhosis without esophageal varices. [Galectin Therapeutics Inc.] Press Release

Transgene Provides Update on PHOCUS Study of Pexa-Vec in Liver Cancer following Planned Interim Futility Analysis

Transgene announced that the Independent Data Monitoring Committee (IDMC) of the PHOCUS study of Pexa-Vec in liver cancer has completed a planned interim futility analysis. Sillajen has informed Transgene of the IDMC’s recommendation to stop enrolment in the study, as the study is unlikely to meet its primary objective by the time of the final analysis. [Transgene] Press Release

Akcea and Ionis Report Top-Line Results from the BROADEN Study with WAYLIVRA^® (Volanesorsen) in Patients with Familial Partial Lipodystrophy

Akcea Therapeutics, Inc. announced topline results from the BROADEN study in patients with familial partial lipodystrophy (FPL). The study met its primary endpoint demonstrating a statistically significant reduction in triglyceride levels in patients with FPL treated with WAYLIVRA compared to placebo-treated patients. [Akcea Therapeutics, Inc.] Press Release

Arrowhead Pharmaceuticals Doses First Patient in SEQUOIA Phase II/III Study of ARO-AAT for Treatment of Alpha-1 Liver Disease

Arrowhead Pharmaceuticals Inc. announced that it has dosed the first patient in SEQUOIA, a potentially pivotal Phase II/III clinical study of ARO-AAT, the company’s second generation subcutaneously administered RNA. [Arrowhead Pharmaceuticals] Press Release

Eureka Therapeutics Announces Initiation of Phase I/II Clinical Trial of ET140202 ARTEMIS™ T-Cell Therapy in Liver Cancer

Eureka Therapeutics, Inc. announced initiation of Phase I/II clinical trial of ET140202 ARTEMIS™ T-Cell therapy in liver cancer at City of Hope. [Eureka Therapeutics, Inc.] Press Release

UK Announces Fast-Track Visa to Recruit Top Scientists

British Prime Minister Boris Johnson has announced a new fast-track visa to attract elite scientists to live and work in the UK, in light of the nation leaving the European Union later this year. “I want the UK to continue to be a global science superpower, and when we leave the EU we will support science and research and ensure that, far from losing out, the scientific community has a huge opportunity to develop and export our innovation around the world,” Johnson said in a statement. [The Scientist] Editorial

UC Faculty Protest Elsevier by Suspending Work for Cell Press

Faculty members at a number University of California (UC) schools have stopped serving on the editorial boards of journals published by Cell Press in protest of its parent company, Elsevier, not having reached a deal with UC for access to its publications. The 31 signatories of a letter to Elsevier, posted August 7^th online, write that unless Elsevier and UC can agree upon a new contract, they will not serve on the boards of Cell, Neuron, Immunity, Current Biology, and others. [The Scientist] Editorial

Mexican Science Suffers under Debilitating Budget Cuts

Austerity measures recently enacted by Mexico’s president are pushing the country’s scientific efforts — chronically underfunded for years — to a breaking point, according to researchers. [Nature News] Editorial

Novartis CEO: ‘We Tried to Do the Right Things’ in FDA Data Scandal

Novartis CEO Vas Narasimhan defended his company’s decision to wait three months to tell authorities about falsified data submitted to the FDA, saying the company “tried to do the right things” in the process. He also said Novartiswas now “in the process of exiting” a small number of scientists at AveXis, Novartis’s gene therapy business, who were “involved in these data inaccuracies.” [STAT News] Editorial

NEW European Cancer (ECCO) Summit 2019
September 12-14, 2019
Brussels, Belgium

Visit our events page to see a complete list of events in the community.

NEW Postdoctoral Fellow – Multi-Omics Data in the Gut-Liver Axis (Mayo Clinic Health System)

Scientific Communications Coordinator (STEMCELL Technologies Inc.)

Postdoctoral Researcher – Liver Pathogenesis (Washington University)

Associate Scientist – In Vitro ADME Research (Gilead Sciences)

Researcher – Cell Biologist and Bioengineer (3D BioLabs, LLC)

Postdoctoral Fellow – Hepatitis C Virus (The Research Institute at Nationwide Children’s Hospital)

Postdoctoral Fellow – Inflammatory Liver Disease (The University of Kansas Medical Center)

Project Leader – Chronic Liver Disease Drug Discovery (Inserm Institute for Viral and Liver Disease)

Postdoctoral Position – Human Liver Microphysiology Systems (University of Pittsburgh Drug Discover Institute)

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

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