Hepatic Cell News Volume 2.18 | May 18 2018

TOP STORY

Liver Regeneration Requires Yap1-TGFβ-Dependent Epithelial-Mesenchymal Transition in Hepatocytes

TGF-β expression and hepatocyte nuclear accumulation of pSmad2 and Yap1 increased in parallel with hepatocyte proliferative activity after partial hepatectomy. Proliferative hepatocytes also upregulated Snai1, a pSmad2 target gene that promotes epithelial-to-mesenchymal transition, suppressed epithelial genes, induced myofibroblast markers, and produced collagen 1α1. [J Hepatol] Abstract | Graphical Abstract

(Ranked by impact factor of the journal)

Genetic Inactivation of Nrf2 Prevents Clonal Expansion of Initiated Cells in a Nutritional Model of Rat Hepatocarcinogenesis

Researchers examined whether Nrf2 activation occurs at early steps of rat hepatocarcinogenesis, to assess critical contributions of Nrf2 to the onset of hepatocellular carcinoma. Nrf2 knockout rats were used to directly investigate whether Nrf2 is critical for initiation and/or clonal expansion of diethylnitrosamine-damaged hepatocytes. [J Hepatol] Abstract

IRE1α Prevents Hepatic Steatosis by Processing and Promoting the Degradation of Select MicroRNAs

Scientists found that inositol-requiring enzyme 1α (IRE1α) was critical to maintaining lipid homeostasis in the liver by repressing the biogenesis of microRNAs that regulate lipid mobilization. [Sci Signal] Full Article

HBV Suppresses ZHX2 Expression to Promote Proliferation of HCC through miR-155 Activation

The authors investigated whether the oncogenic properties of hepatitis B virus (HBV) and, more specifically, HBV X (HBx) protein, involved zinc fingers and homeoboxes 2 silencing. In vitro and in vivo studies confirmed that HBV‐encoded proteins, particularly HBx, inhibits both the expression and tumor suppression properties of ZHX2. [Int J Cancer] Abstract

Hypoxia-Induced MicroRNA-191 Contributes to Hepatic Ischemia/Reperfusion Injury through the ZONAB/Cyclin D1 Axis

Investigators demonstrated that miR-191 is significantly upregulated in a cultured cell line during hypoxia/reperfusion and in liver tissue during hepatic ischemia/reperfusion injury in mice. Upon induction by hypoxia or ischemia, miR-191 suppresses expression of ZO-1-associated Y-box factor (ZONAB) and its downstream factor Cyclin D1, consequently resulting in cell death and tissue injury. [Cell Death Differ] Abstract

Long Non-Coding RNA NEAT1-Modulated Abnormal Lipolysis via ATGL Drives Hepatocellular Carcinoma Proliferation

The lncRNA-NEAT1 was found to modulate adipose triglyceride lipase (ATGL) expression and disrupt lipolysis in hepatocellular carcinoma (HCC) cells via ATGL. ATGL and its products, diacylglycerol and free fatty acid, were shown to be responsible for NEAT1-mediated HCC cell growth. [Mol Cancer] Full Article

Caspase-3 Suppresses Diethylnitrosamine-Induced Hepatocyte Death, Compensatory Proliferation and Hepatocarcinogenesis through Inhibiting p38 Activation

Researchers demonstrated that TNFα and IL1α stimulated increased activation of p38 in Caspase-3 KO hepatocytes compared with wild-type hepatocytes. They found that inhibition of p38 by SB202190 abrogated enhanced hepatocyte death, compensatory proliferation and hepatocellular carcinoma induced by diethylnitrosamine in Caspase-3-deficient mice. [Cell Death Dis] Full Article

The Extent of Liver Injury Determines Hepatocyte Fate toward Senescence or Cancer

Severe acute liver injury lead to hepatocyte senescence along with activating immune surveillance and a low incidence of hepatocellular carcinoma (HCC), whereas chronic moderate injury allowed hepatocytes to proliferate rather than to enter into senescence, and correlated with a high incidence of HCC. [Cell Death Dis] Full Article

Bone Morphogenetic Protein 9 as a Key Regulator of Liver Progenitor Cells in DDC-Induced Cholestatic Liver Injury

Absence of bone morphogenetic protein 9 (BMP9) resulted in overactivation of PI3K/AKT, ERK‐MAPKs and c‐Met signaling pathways, which together with an enhanced ductular reaction and oval cell expansion evidence an improved regenerative response and decreased damage in response to 3,5 diethoxicarbonyl‐1,4 dihydrocollidine (DDC) feeding. BMP9 directly targeted oval cells, it activated SMAD1,5,8, decreased cell growth and promoted apoptosis, effects that are mediated by activin receptor‐like kinase 2 type I receptor. [Liver Int] Abstract

Hepatic Stellate Cells Secrete CCL5 to Induce Hepatocyte Steatosis

Scientists developed an ex vivo assay that cocultures primary hepatic stellate cells (HSCs) from mouse models of liver disease with healthy hepatocytes to study their interaction. Their data indicated that chemokine CCL5 is one of the HSC-secreted mediators in early non-alcoholic steatohepatitis in humans and in mice fed with choline-deficient, L-amino acid defined, high fat diet. [Sci Rep] Full Article

De Novo Macrocyclic Peptide Inhibitors of Hepatitis B Virus Cellular Entry

Scientists applied random non-standard peptide integrated discovery screening to identify small macrocyclic peptide inhibitors of hepatitis B virus (HBV) entry that target the cell-surface receptor for HBV, sodium taurocholate cotransporting polypeptide. These molecules inhibited cellular entry by the related hepatitis D virus, and were active against diverse strains of HBV. [Cell Chem Biol] Abstract | Graphical Abstract

Immortalized Common Marmoset (Callithrix jacchus) Hepatic Progenitor Cells Possess Bipotentiality In Vitro and In Vivo

Marmoset hepatic progenitor cells proliferated indefinitely in vitro without chromosomal alteration and telomere shortening. These cells possessed hepatic progenitor cell-specific gene expression profiles with the potential to differentiate into both hepatocytic and cholangiocytic lineages in vitro and in vivo and also could be genetically modified. [Cell Discov] Full Article

Aryl Hydrocarbon Receptor Promotes Liver Polyploidization and Inhibits PI3K, ERK and Wnt/β-Catenin Signaling

The authors report that aryl hydrocarbon receptor (AhR) regulated polyploidization during the preweaning-to-adult mouse liver maturation. Preweaning AhR-null (AhR^-/-) livers had smaller hepatocytes, hypercellularity, altered cell cycle regulation and enhanced proliferation. [iScience] Abstract

Novel and Emerging Therapies for Cholestatic Liver Diseases

The authors summarize our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, present the rationale for already approved medical therapies, and discuss novel pharmacologic therapies under investigation. [Liver Int] Abstract

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

Galectin Therapeutics Proceeds to Phase III Development of GR-MD-02 for NASH Cirrhosis following FDA Meeting

Galectin Therapeutics Inc. announced it is proceeding with plans for a Phase III clinical trial program with its galectin-3 inhibitor GR-MD-02 in non-alcoholic steatohepatitis (NASH) cirrhosis, incorporating advice and guidance obtained in a meeting with the FDA. [Galectin Therapeutics Inc.] Press Release

HistoIndex and CymaBay Therapeutics Team Up to Advance NASH Drug Development

Histoindex Pte. Ltd. is collaborating with CymaBay Therapeutics, Inc. to evaluate the efficacy of seladelpar in a randomized, double-blind, placebo-controlled, multi-center Phase IIb study of 175 subjects with biopsy-confirmed nonalcoholic steatohepatitis (NASH). [Histoindex Pte Ltd.] Press Release

Arrowhead Doses First Hepatitis B Patients in Multiple Dose Portion of Phase I/II Study of ARO-HBV

Arrowhead Pharmaceuticals Inc. announced that it has dosed the first three hepatitis B virus (HBV) patients in the multiple-ascending dose portion of its ongoing Phase I/II study of ARO-HBV, the company’s third generation subcutaneously administered RNA interference therapeutic being developed as a potentially curative therapy for patients with chronic HBV infection. [Arrowhead Pharmaceuticals Inc.] Press Release

Dr. Meritxell Huch reviews organoid culture and applications for intestinal, hepatic, and pancreatic tissues. Watch Now

UK’s Powerful Funding Body Takes Shape

The United Kingdom’s newly minted unified funding agency has released the first outline of its strategy. The long-awaited document gives the nation’s researchers an insight into how the mega-funding agency — which will command a budget of £6 billion (US$8 billion) — will work. [Nature News] Editorial

Chief Academic Officer Accused in Ongoing Research Scandal at UCL

Prominent geneticist David Latchman, the chief academic and administrative officer of Birkbeck, University of London, has been accused of “recklessness” for his role in an ongoing research scandal, according to a report described by The Telegraph. [The Scientist] Editorial

Europe’s Open-Access Drive Escalates As University Stand-Offs Spread

Bold efforts to push academic publishing towards an open-access model are gaining steam. Negotiators from libraries and university consortia across Europe are sharing tactics on how to broker new kinds of contracts that could see more articles appear outside paywalls. [Nature News] Editorial

Huge Gender Disparity in Cancer Research Funding in U.K.

The analysis examined data on both public and philanthropic grants given to support cancer research in the U.K. Male PIs were awarded 69 percent of the grants, and their grants were on average 1.3 times as large as those given to women, so that they received 78 percent of the total money allocated. [The Scientist] Editorial

NEW 8^th Meeting of the European Club for Liver Cell Biology (ECLCB-8)
October 4-6, 2018
Bonn, Germany

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

NEW Postdoctoral Scholar – Cancer Biology (Penn State College of Medicine)

Research Technologist – Liver Biology (STEMCELL Technologies Inc.)

Postdoctoral Fellow – Liver Injury, Hepatocellular Carcinoma and Metabolic Liver Diseases (University of Rhode Island)

Postdoctoral Position – Necroptosis in Liver Diseases (Inserm)

EBPOD Fellowship – NAFLD/NASH (European Molecular Biology Laboratory)

Academic Position – Cancer Research (Cedars-Sinai Medical Center)

Postdoctoral Research Fellow – Liver Cancer Pathogenesis and Immunobiology (Fred Hutchinson Cancer Research Center)

Tenure-Track Faculty Position – Cancer Research (University of Ottawa)

Postdoctoral Research Associate – Liver Disease and Injury (University of Pittsburgh)

PhD Student – Hepatology and Cancer Biology (German Cancer Research Center)

Research Fellow – Liver Tumorigenesis (Harvard School of Dental Medicine)

Postdoctoral Fellow – Alcoholic Liver Disease (University of North Carolina at Greensboro)

Postdoctoral Position – Inflammation and Metabolism (Sanford Burnham Prebys Medical Discovery Institute)

Postdoctoral Position – Cancer, Immunotherapy, and Fibrosis (University of Alabama at Birmingham)

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