Hepatic Cell News Volume 1.13 | Apr 28 2017

TOP STORY

SIRT3 Acts As a Negative Regulator of Autophagy Dictating Hepatocyte Susceptibility to Lipotoxicity

Using cultured HepG2 and AML-12 hepatocytes, the authors demonstrated that unlike monounsaturated fatty acids (FAs), saturated FAs upregulate SIRT3 expression/activity. SIRT3 overexpression rendered both the liver and hepatocytes susceptible to palmitate-induced cell death, which could be alleviated by SIRT3 siRNA transfection. [Hepatology] Abstract

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Protein Disulfide Isomerase Inhibition Synergistically Enhances the Efficacy of Sorafenib for Hepatocellular Carcinoma

Scientists employed a systems approach by combining transcriptome analysis of the mRNA changes in hepatocellular carcinoma cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene list functional enrichment analysis and gene set enrichment analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. [Hepatology] Abstract

A Postprandial FGF19-SHP-LSD1 Regulatory Axis Mediates Epigenetic Repression of Hepatic Autophagy

Researchers showed that small heterodimer partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed-state hormone hFGF19, mFGF15 (FGF19). FGF19 treatment or feeding inhibited macroautophagy, including lipophagy, but the effects were blunted in SHP-null mice or LSD1-depleted mice. [EMBO J] Abstract | Graphical Abstract

Hepatic Tm6sf2 Overexpression Affects Cellular ApoB-Trafficking, Plasma Lipid Levels, Hepatic Steatosis and Atherosclerosis

The authors investigated the role of Tm6sf2 in metabolic homeostasis. They generated mice with elevated expression using adeno-associated virus-mediated gene delivery. Hepatic overexpression of mouse Tm6sf2 resulted in phenotypes previously observed in Tm6sf2-deficient mice including reduced plasma lipid levels, diminished hepatic TG secretion and increased hepatosteatosis. [Hum Mol Genet] Abstract

Keratin 8/18 Regulation of Insulin Receptor Signaling and Trafficking in Hepatocytes through a Concerted Phosphoinositide-Dependent Akt and Rab5 Modulation

Scientists investigated the role of keratin (K)8/K18 intermediate filaments in the regulation of insulin receptor (IR) signaling and trafficking in hepatocytes. They found that the IR substrate 1/PI3K/Akt signaling cascade—downstream of IR—display prolonged activation in K8-null compared with wild-type hepatocytes. [FASEB J] Abstract

A Systematic Evaluation of MicroRNAs in Regulating Human Hepatic CYP2E1

Investigators applied in silico, in vivo, and in vitro approaches to investigate microRNAs (miRs) involved in the regulation of cytochrome P450 2E1 (CYP2E1). In a HepG2-derived CYP2E1 over-expression cell model, hsa-miR-214-3p exhibited strong suppression of CYP2E1 expression by targeting the coding region of its mRNA transcript, but hsa-miR-942-5p did not inhibit CYP2E1 levels. [Biochem Pharmacol] Abstract | Graphical Abstract

Effects of Selenium on Apoptosis and Abnormal Amino Acid Metabolism Induced by Excess Fatty Acid in Isolated Rat Hepatocytes

Scientists investigated the effect of selenium (Se) on apoptosis and abnormal amino acid metabolism initiated by excess free fatty acid (FFA) in isolated rat hepatocytes. Although Se had the capability of preventing the apoptosis initiated by ROS, insulin resistance and abnormal amino acid failed to be reversed in hepatocytes exposed to FFA. [Mol Nutr Food Res] Abstract

Specific Hepatic Stellate Cell-Penetrating Peptide Targeted Delivery of a KLA Peptide Reduces Collagen Accumulation by Inducing Apoptosis

The authors report that a specific hepatic stellate cell (HSC)-penetrating peptide reduced collagen accumulation by inducing the apoptosis of HSC-T6 cells. A chimeric peptide termed HSC-targeted cell-penetrating peptide (HTP)K25 was consequently generated by coupling HTP with the antimicrobial peptide KLA, which is capable of initiating cell apoptosis in mammalian cells. HTPK25 entered cells in a dose-dependent manner, reduced the cell viability and induced apoptosis via the caspase 3 pathway in HSC-T6 cells. [J Drug Target] Abstract

MiR-221 Regulates CD44 in Hepatocellular Carcinoma through the PI3K-AKT-mTOR Pathway

To discover miRNAs that may be involved in the miR-221 regulation of CD44, the authors performed miRNA profiling in SNU-449 cells treated with anti-miR-221. Several miRNAs were increased with miR-221 inhibition including miR-708-5p, a miRNA that targets CD44. [Biochem Biophys Res Commun] Abstract

Non-Coding RNA in Hepatocellular Carcinoma: Mechanisms, Biomarkers and Therapeutic Targets

The authors review examples of the functions of non-coding RNAs in liver cancer and their potential use for the detection of liver cancer as well as for the treatment of liver cancer. [J Hepatol] Abstract | Graphical Abstract

Visit our reviews page to see a complete list of reviews in the hepatic cell research field.

NGM Bio Announces NGM282 Dramatically Reduced Liver Fat and Other Biomarkers Associated with Nonalcoholic Steatohepatitis (NASH) in Phase II Trial

NGM Bio announced that its lead product candidate, NGM282, met the primary endpoint and key secondary endpoints in a Phase II trial of patients with nonalcoholic steatohepatitis. [Press release from NGM Bio discussing research presented at The International Liver Congress™ (ILC) 2017, Amsterdam] Press Release

DURECT Announces Presentation of Data from a Phase Ib Study of DUR-928 in Nonalcoholic Steatohepatitis (NASH)

DURECT Corporation announced that clinical data on DUR-928 were presented. DUR-928 was well tolerated in this study and plasma exposure of the molecule was not significantly increased in NASH patients compared to matched control subjects with normal liver function. [Press release from DURECT Corporation discussing research presented at The International Liver Congress™ (ILC) 2017, Amsterdam] Press Release

Bristol-Myers Squibb’s BMS-986036 (Pegylated FGF21) Shows Consistent Improvement in Liver Fat, Liver Injury and Fibrosis in Patients with Nonalcoholic Steatohepatitis (NASH) in Phase II Trial

Bristol-Myers Squibb Company announced data from a Phase II study of BMS-986036, an investigational pegylated analogue of human fibroblast growth factor 21, in patients with biopsy-confirmed NASH. The study achieved its primary endpoint of significant reduction in liver fat versus placebo. [Press release from Bristol-Myers Squibb Company discussing research presented at The International Liver Congress™ (ILC) 2017, Amsterdam] Press Release

PhaseRx to Present Data

PhaseRx, Inc. announced a presentation discussing its Hybrid mRNA Technology™ as well as its lead product candidate, PRX-OTC. [Press release from PhaseRx, Inc. discussing research to be presented at the TIDES Oligonucleotide and Peptide Technology and Product Development Conference, San Diego] Press Release

Sangamo Therapeutics Announces Presentations

Sangamo Therapeutics, Inc. announced that data from the company’s therapeutic and research programs will be presented. [Press release from Sangamo Therapeutics, Inc. discussing research to be presented at the 20^th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT), Washington, D.C.] Press Release

Cellular Dynamics International Signs Distribution Deal with STEMCELL Technologies

Cellular Dynamics International (CDI) announced it has signed a distribution agreement with STEMCELL Technologies. Under the terms of the agreement, STEMCELL Technologies will distribute CDI’s iCell^® catalog of products in North America, Europe, and Singapore, with other countries under consideration. [STEMCELL Technologies Inc.] Press Release

SillaJen and Transgene Announce the Enrollment of the First European Patient in Multinational Phase III Trial for Pexa-Vec in Advanced Liver Cancer

SillaJen, Inc. and Transgene have enrolled the first European patient in the ongoing multinational randomized Phase III open-label study of Pexa-Vec, in patients with advanced liver cancer, also known as hepatocellular carcinoma. [SillaJen, Inc.] Press Release

Tiziana Life Sciences Announces Approval of a Phase II Clinical Trial Protocol for Milciclib in Patients with Hepatocellular Carcinoma

Tiziana Life Sciences plc announces the approval in Israel of a Phase II clinical trial protocol for testing milciclib, a novel inhibitor of cell cycle dependent kinases, in patients with refractory hepatocellular carcinoma. [Tiziana Life Sciences plc.] Press Release

Bayer Receives FDA Approval for Stivarga^® (Regorafenib) for the Second-Line Systemic Treatment of Liver Cancer

Bayer announced that the U.S. Food and Drug Administration (FDA) approved Stivarga^® tablets for the second-line treatment of patients with hepatocellular carcinoma who have been previously treated with Nexavar^®. [Bayer] Press Release | Press Release 2

PhaseRx Receives Positive Opinion for Orphan Drug Designation for PRX-OTC from European Medicines Agency

PhaseRx, Inc. announced that the European Medicines Agency’s Committee for Orphan Medicinal Products has issued a positive opinion recommending orphan medicinal product designation for PRX-OTC for the treatment of ornithine transcarbamylase deficiency. [PhaseRx, Inc.] Press Release

$10 Million Settlement over Alleged Misconduct in Boston Heart Stem Cell Lab

A research misconduct investigation of a prominent stem cell lab by the Harvard University-affiliated Brigham and Women’s Hospital in Boston has led to a massive settlement with the U.S. government over allegations of fraudulently obtained federal grants. [ScienceInsider] Editorial

Controversial UK Research Reform Crosses Finish Line

A controversial and wide-ranging shake-up of the United Kingdom’s research and higher-education landscape has been completed, amid a huge rush by the country’s parliament to push through legislation. [Nature News] Editorial

Marine Le Pen Is a ‘Terrible Danger,’ French Research Leaders Say

The French science and higher education community appears virtually united in its opposition against Marine Le Pen, the far-right candidate who could become France’s next president during the second round of elections on 7 May. In an unprecedented letter, the directors of nine major public research institutes describe Le Pen’s candidacy as a “terrible danger” and call on voters not to support her. [ScienceInsider] Editorial

NEW Worldwide Innovative Networking in Personalized Cancer Medicine (WIN) 2017
June 26-27, 2017
Paris, France

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

NEW Postdoctoral Fellow – Nonalcoholic Fatty Liver Disease Research (University of Groningen)

NEW Scientist – Hepatic Nuclear Receptor Biology (Moderna Therapeutics)

Postdoctoral Fellow – Non-Alcoholic Fatty Liver Disease Research (University of Groningen)

Research Lead – Liver Discovery (Spark Therapeutics)

Research Technician II – Translational Liver Cancer (Fred Hutchinson Cancer Research Center)

Faculty Member – GI/Liver Pathology (Merritt Hawkins)

Postdoctoral Researchers – Hepatology and Liver Transplantation (Instituto Maimónides de Investigación Biomédica de Córdoba/University of Cordoba)

Academic Surgical Pathologist – Liver/Gastrointestinal (Brigham and Women’s Hospital)

Academic Pathologist – Liver/GI (University of Texas Southwestern Medical Center)

Associate or Full Professor – Gastroenterology (University of Washington)

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