Hepatic Cell News Volume 3.20 | Jun 7 2019

TOP STORY

Aryl Hydrocarbon Receptor Signaling Prevents Activation of Hepatic Stellate Cells and Liver Fibrogenesis in Mice

Aryl hydrocarbon receptor (AHR) was expressed at high levels in quiescent hepatic stellate cells (HSCs), but the expression decreased with HSC activation. Activation of HSCs from AHR-knockout mice was accelerated, compared to HSCs from wild-type mice. In contrast, TCDD or ITE inhibited spontaneous and transforming growth factor beta-induced activation of HSCs. [Gastroenterology] Abstract

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APOBEC3B Interaction with PRC2 Modulates Microenvironment to Promote HCC Progression

APOBEC3B (A3B) promoter luciferase reporter and other techniques were applied to elucidate mechanisms of A3B upregulation in hepatocellular carcinoma (HCC). A3B overexpression and knockdown cell models, immunocompetent and immune-deficient mouse HCC model were conducted to investigate the influence of A3B on HCC progression. [Gut] Abstract

Glial Cell Line-Derived Neurotrophic Factor (GDNF) Mediates Hepatic Stellate Cell Activation via ALK5/Smad Signaling

GDNF was confined mainly to hepatic stellate cells (HSCs) and contributed to HSC activation through activin receptor-like kinase 5 (ALK5) at His³⁹ and Asp⁷⁶ and through downstream signaling via Smad2/3, but not through GDNF family receptor alpha-1. GDNF, ALK5 and α-smooth muscle actin colocalized in human and mouse HSCs, as demonstrated by confocal microscopy. [Gut] Full Article

CHML Promotes Liver Cancer Metastasis by Facilitating Rab14 Recycle

Investigators report that expression of choroideremia-like (CHML) was increased in hepatocellular carcinoma (HCC), associated with poor survival, early recurrence and more satellite nodules in HCC patients. CHML promoted migration, invasion and metastasis of HCC cells, in a Rab14-dependent manner. They revealed that CHML facilitated constant recycling of Rab14 by escorting Rab14 to the membrane. [Nat Commun] Full Article

TRAF6 Promotes Hepatocarcinogenesis by Interacting with HDAC3 to Enhance c-Myc Gene Expression and Protein Stability

Scientists report that c-Myc was significantly upregulated by TRAF6, an E3 ubiquitin ligase, in hepatocarcinogenesis. Mechanistically, TRAF6 interacted with and ubiquitinated histone deacetylase 3 (HDAC3) with K63-linked ubiquitin chains, which led to the dissociation of HDAC3 from the c-Myc promoter and subsequent acetylation of histone H3 at K9, thereby epigenetically enhancing the mRNA expression of c-Myc. [Hepatology] Abstract

Liver ASK1 Protects from Non-Alcoholic Fatty Liver Disease and Fibrosis

Researchers identified apoptosis signal-regulating kinase 1 (ASK1) as a suppressor of non-alcoholic steatohepatitis and fibrosis formation. High-fat diet-fed and aged chow-fed liver-specific ASK1-knockout mice developed a higher degree of hepatic steatosis, inflammation, and fibrosis compared to controls. [EMBO Mol Med] Full Article | Graphical Abstract

Circular RNA CircTRIM33-12 Acts as the Sponge of MicroRNA-191 to Suppress Hepatocellular Carcinoma Progression

Reduced expression of circular tripartite motif containing 33-12 (circTRIM33-12) in hepatocellular carcinoma (HCC) cells increased tumor proliferation, migration, invasion and immune evasion. Mechanistically, the authors demonstrated that circTRIM33-12 upregulated TET1 expression by sponging miR-191, resulting in significantly reduced 5-hydroxymethylcytosine levels in HCC cells. [Mol Cancer] Full Article

CREB Mediates Glucagon Action to Upregulate Hepatic MPC1: Inhibitory Effect of Ginsenoside Rb1 on Hepatic Gluconeogenesis

The correlation between hepatic glucagon response and mitochondrial pyruvate carrier 1 (MPC1) induction was investigated in fasted mice and primary hepatocytes. The effects of ginsenoside Rb1 on MPC1 function were observed. Glucagon challenge raised blood glucose with hepatic MPC1 induction and inhibition of MPC induction coincided with a reduced rise in blood glucose. [Br J Pharmacol] Abstract

p53-Dependent Upregulation of miR-16-2 by Sanguinarine Induces Cell Cycle Arrest and Apoptosis in Hepatocellular Carcinoma

Sanguinarine (SG) significantly inhibited hepatocellular carcinoma cell proliferation in a p53-dependent manner by inducing cell cycle arrest and reactive oxygen species-associated apoptosis. Silencing miR-16 by treatment with anti-miR16 miRNA inhibitors rescued the cell viability repression effect caused by SG. [Cancer Lett] Abstract

Down-Regulated LncRNA DLX6-AS1 Inhibits Tumorigenesis through STAT3 Signaling Pathway by Suppressing CADM1 Promoter Methylation in Liver Cancer Stem Cells

Long non-coding RNA (lncRNA) distal-less homeobox 6 antisense 1 (DLX6-AS1) was upregulated in hepatocellular carcinoma. The silencing of lncRNA DLX6-AS1 was shown to reduce and inhibit spheroid formation, colony formation, proliferation, and tumor formation abilities, as well as attenuated CD133, CD13, OCT-4, SOX2, and Nanog expression in liver cancer stem cells. [J Exp Clin Cancer Res] Full Article

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Pathobiology of Inherited Biliary Diseases: A Roadmap to Understand Acquired Liver Diseases

New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. The authors focus on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases and cystic fibrosis-related liver disease. [Nat Rev Gastroenterol Hepatol] Abstract

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Bristol-Myers Squibb Announces First Presentation of Results for Opdivo (nivolumab) plus Yervoy (ipilimumab) Combination in Advanced Hepatocellular Carcinoma

Bristol-Myers Squibb Company announced first results from the opdivo plus yervoy cohort of the Phase I/II CheckMate-040 study, evaluating the immuno-oncology combination in patients with advanced hepatocellular carcinoma previously treated with sorafenib. [Press release from Bristol-Myers Squibb Company discussing research presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago] Press Release

Interim Data on Cirius Therapeutics’ MSDC-0602K to Be Presented

Cirius Therapeutics announced that results from an interim analysis of exploratory endpoints from its Phase IIb EMMINENCE trial of MSDC-0602K will be presented. [Press release from Cirius Therapeutics (PR Newswire Association LLC.) discussing research to be presented at the American Diabetes Association (ADA) 79^th Scientific Sessions, San Francisco] Press Release

Get to know Dr. Meritxell Huch and her approach to studying liver disease with hepatic organoids. Read the Full Profile

GENFIT Launches a Phase II Trial Evaluating Elafibranor on Hepatic Lipid Composition for NAFL

GENFIT announced the launch of a Phase II clinical trial evaluating elafibranor’s activity on liver fat quantity and – most importantly – fat composition in nonalcoholic fatty liver (NAFL) disease patients. The Phase II is a randomized, placebo-controlled, double-blind, cross-over study in sixteen patients with NAFL as identified with magnetic resonance spectroscopy. [GENFIT] Press Release

CStone Received Approval to Initiate Clinical Development in China of CS1001 and BLU-554 (CS3008) in Combination Therapy for HCC

CStone Pharmaceuticals announced that it has received approval to initiate clinical development in China of CS1001 in combination with BLU-554 in patients with locally advanced or metastatic hepatocellular carcinoma (HCC). The trial is a multi-center, open-label, and multi-dose Phase Ib/II study that aims to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor efficacy of the combination in advanced HCC. [CStone Pharmaceuticals (PR Newswire Association LLC.)] Press Release

ContraVir Pharmaceuticals Sets the Stage for CRV431 Development in NASH with Positive Results from Second Model of Liver Fibrosis

ContraVir Pharmaceuticals, Inc. announced findings from a preclinical study where CRV431, a novel cyclophilin inhibitor, significantly decreased the extent of fibrosis in a second animal model of liver fibrosis. [ContraVir Pharmaceuticals, Inc.] Press Release

Alnylam Completes Rolling Submission of New Drug Application to US Food and Drug Administration (FDA) for Givosiran for the Treatment of Acute Hepatic Porphyria

Alnylam Pharmaceuticals, Inc. announced the completion of the rolling submission of a New Drug Application to the FDA for givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 in development for the treatment of acute hepatic porphyria. [Alnylam Pharmaceuticals, Inc.] Press Release

Powerful US Senator Calls for Vetting NIH Grantees at Hearing on Foreign Influences

Research typically enjoys bipartisan support in the US Congress. But when it comes to the increasingly contentious topic of academic espionage by foreign governments, politics is never far from the surface. At a hearing of the Senate Committee on Finance, Chairman Chuck Grassley urged federal agencies to do more to thwart “real, aggressive, and ongoing” attempts by foreign entities to steal the fruits of US-funded research. [ScienceInsider] Editorial

Hungarians Protest against Proposed Government Takeover of Science

Thousands of scientists and their supporters marched through the streets of Budapest on 2 June to protest against a proposed law that would give the Hungarian government direct control of the country’s top research institutes. [Nature News] Editorial

Brexit ‘May Bar UK Scientists from €100bn EU Research Fund’

The Horizon Europe program will fund €100bn in research projects, making it one of the largest science funds in the world. British researchers will be locked out unless the government negotiates an access deal in the coming months. [The Guardian] Editorial

NEW Advances in Metabolic Communication
October 15-18, 2019
Rio de Janeiro, Brazil

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NEW 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)

Research Scientist – Head of the Human Liver Cell Isolation Lab (University of California, San Diego)

Postdoctoral Researcher – Liver Mutagenesis (IRSET)

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