Hepatic Cell News Volume 3.13 | Apr 12 2019

TOP STORY

Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS

Researchers showed that insulin-driven phosphatidylinositol-3-kinase (PI3K)-AKT signaling depended on redundant PI3Kα and PI3Kβ activities, whereas PI3Kδ and PI3Kγ were largely dispensable. They have also found that RAS activity promoted AKT phosphorylation in insulin-stimulated hepatocytes and that promotion of insulin-driven AKT phosphorylation by RAS depended on PI3Kα. [Cell Metab] Abstract | Graphical Abstract

(Ranked by impact factor of the journal)

Hepatocyte-Specific Loss of GPS2 in Mice Reduces Non-Alcoholic Steatohepatitis via Activation of PPARα

Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes. The authors demonstrated that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor and histone deacetylase 3 complex, has a central role in these alterations and accelerated the progression of NAFLD towards non-alcoholic steatohepatitis. [Nat Commun] Full Article

Hepatic Arginase 2 (Arg2) Is Sufficient to Convey the Therapeutic Metabolic Effects of Fasting

Arg2 was upregulated in fasting conditions and upon treatment with the hepatocyte glucose transporter inhibitor trehalose. Hepatocyte-specific Arg2 overexpression enhanced basal thermogenesis, and protected from weight gain, insulin resistance, glucose intolerance, hepatic steatosis and hepatic inflammation in diabetic mouse models. [Nat Commun] Full Article

MicroRNA-223 Ameliorates Nonalcoholic Steatohepatitis and Cancer by Targeting Multiple Inflammatory and Oncogenic Genes in Hepatocytes

To understand how simple steatosis progresses to nonalcoholic steatohepatitis (NASH), scientists examined hepatic expression of anti-inflammatory miR-223 and found that this miRNA was highly elevated in hepatocytes in high-fed diet-fed mice and in human NASH samples. [Hepatology] Abstract

CD73 Promotes Hepatocellular Carcinoma Progression and Metastasis via Activating PI3K/AKT Signaling by Inducing Rap1-Mediated Membrane Localization of P110β and Predicts Poor Prognosis

Mechanistically, adenosine produced by CD73 bound to adenosine A2A receptor (A2AR) and activated Rap1, which recruited P110β to the plasma membrane and triggered PIP3 production, thereby promoting AKT phosphorylation in hepatocellular carcinoma (HCC) cells. A combination of anti-CD73 and anti-A2AR achieved synergistic depression effects on HCC growth and metastasis than single agent alone. [J Hematol Oncol] Full Article

Transketolase (TKT) Activity and Nuclear Localization Promote Hepatocellular Carcinoma in a Metabolic and a Non-Metabolic Manner

Researchers showed that TKT increased the proliferation and migration of hepatocellular carcinoma (HCC) cells, as well as the viability under oxidative stress in vitro and accelerated the growth and metastasis of HCC cells in vivo. They found as a key enzyme of the pentose phosphate pathway, TKT could promote the proliferation, cell cycle, migration and viability by regulating the metabolic flux. [J Exp Clin Cancer Res] Full Article

Long Noncoding RNA EPB41L4A-AS2 Inhibits Hepatocellular Carcinoma Development by Sponging miR-301a-5p and Targeting FOXL1

Forkhead box L1 (FOXL1) and miR-301a-5p showed opposite biological effects in cell proliferation and migration. Moreover, miR-301a-5p overexpression rescued the EPB41L4A-AS2 upregulation induced depression in proliferation, migration and invasion of hepatocellular carcinoma cells, as well as promotion effect on FOXL1 expression. [J Exp Clin Cancer Res] Full Article

Monomethyltransferase SET8 Facilitates Hepatocellular Carcinoma Growth by Enhancing Aerobic Glycolysis

Both in vitro and in vivo studies revealed that SET8 deficiency conferred an impaired glucose metabolism phenotype and thus inhibited the progression of hepatocellular carcinoma tumors. By contrast, SET8 overexpression aggravated glycolytic alterations and tumor progression. [Cell Death Dis] Full Article

Exosomes from Activated Hepatic Stellate Cells Contain GLUT1 and PKM2: A Role for Exosomes in Metabolic Switch of Liver Nonparenchymal Cells

Exosomes released from hepatic stellate cells (HSCs) were associated with the activation and glucose uptake of HSCs. Delivery of exosomes from activated HSCs induced glycolysis of quiescent HSCs, Kupffer cells, and liver sinusoidal endothelial cells. Disruption of hypoxia-inducible factor 1 expression suppressed the glycolysis effect delivered by exosomes. [FASEB J] Abstract

Targeting AMP-Activated Kinase Impacts Hepatocellular Cancer Stem Cells Induced by Long-Term Treatment with Sorafenib

Scientists report that sorafenib-resistant cells had lower levels of total and phosphorylated AMP-activated kinase (AMPK) as well as its downstream substrate, ACC, compared with the parental cells. Interestingly, AMPK knockdown with siRNA or inhibition with dorsomorphin increased the expression of stem cell markers in parental cells and blocked sorafenib-induced cell death. [Mol Oncol] Abstract | Full Article

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Recent Insight into the Role of Fibrosis in Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma

In the near future, knowledge of fibrosis-dependent carcinogenic mechanisms will help optimize antifibrotic therapies as an approach to prevent and treat hepatocellular carcinoma in patients with non-alcoholic steatohepatitis and advanced fibrosis. [Int J Mol Sci] Full Article

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Can-Fite Announces Late-Breaking Abstract Presentation on Namodenoson™ Phase II Results

Can-Fite BioPharma Ltd. announced that a late-breaking abstract detailing results from the company’s recently completed multicenter Phase II trial in patients with advanced liver cancer has been accepted for oral presentation. [Press release from Can-Fite BioPharma Ltd. discussing research presented at the 54^th Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago] Press Release

Spring Bank Announces Positive Results from the Recently Completed Phase II Chronic Hepatitis B ACHIEVE Trial and Additional Inarigivir Studies

Spring Bank Pharmaceuticals, Inc. announced robust results from the recently completed inarigivir Phase II dose escalation ACHIEVE trial for patients with chronic hepatitis B virus. [Press release from Spring Bank Pharmaceuticals, Inc. discussing research presented at the 2019 Annual Meeting of the European Association for the Study of the Liver (EASL) International Liver Congress (ILC), Vienna] Press Release

Arrowhead Preclinical Data Demonstrates RNAi Therapy Prevents and Reverses Alpha-1 Liver Disease

Arrowhead Pharmaceuticals Inc. presented preclinical data demonstrating that sustained reduction of mutant Z-AAT protein by RNA interference (RNAi) substantially reversed the alpha-1 antitrypsin deficiency disease phenotype in the PiZ mouse model. [Press release from Arrowhead Pharmaceuticals Inc. discussing research presented at the 2019 Annual Meeting of the European Association for the Study of the Liver (EASL) International Liver Congress (ILC), Vienna] Press Release

ContraVir Pharmaceuticals to Present CRV431 Phase I Data

Dr. Daren Ure, Director of Research and Development, ContraVir Pharmaceuticals, Inc. presented a study where subjects were treated with escalating doses of CRV431 administered as a single dose to assess safety, tolerability and pharmacokinetic profiles. [Press release from ContraVir Pharmaceuticals, Inc. discussing research presented at the 2019 Annual Meeting of the European Association for the Study of the Liver (EASL) International Liver Congress (ILC), Vienna] Press Release

Viking Therapeutics Presents New Data from Phase II Study of VK2809 in Patients with Non-Alcoholic Fatty Liver Disease (NAFLD) and Elevated LDL-Cholesterol

Viking Therapeutics, Inc. announced the presentation of new results form the company’s 12-week Phase II study of VK2809, its novel liver-selective thyroid receptor beta agonist in patients with NAFLD and elevated low-density lipoprotein (LDL) cholesterol. [Press release from Viking Therapeutics, Inc. discussing research presented at the 2019 Annual Meeting of the European Association for the Study of the Liver (EASL) International Liver Congress (ILC), Vienna] Press Release

Gilead Presents New Data in Nonalcoholic Steatohepatitis (NASH)

Gilead Sciences, Inc. announced new data from the company’s clinical research program in NASH being presented. The data support Gilead’s efforts to develop combination therapies to target different aspects of NASH, evaluate the utility of noninvasive tests for the identification of patients living with the disease and advance overall understanding of the complexities and burden of NASH. [Press release from Gilead Sciences, Inc. discussing research presented at the 2019 Annual Meeting of the European Association for the Study of the Liver (EASL) International Liver Congress (ILC), Vienna] Press Release

Genkyotex to Present Updated Interim Results from Phase II Trial of GKT831 in Primary Biliary Cholongitis

Genkyotex announced that it presented an update on the previously reported interim efficacy results from its Phase II trial of GKT831 in primary biliary cholangitis. [Press release from Genkyotex discussing research presented at the 2019 Annual Meeting of the European Association for the Study of the Liver (EASL) International Liver Congress (ILC), Vienna] Press Release

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Gilead Sciences and Novo Nordisk Announce Intent to Initiate a Clinical Collaboration in NASH

Gilead Sciences, Inc. and Novo Nordisk A/S announced that the companies intend to collaborate on a clinical trial combining compounds from their respective pipelines in nonalcoholic steatohepatitis (NASH). The intended clinical trial will be a proof of concept study combining Novo Nordisk’s semaglutide and Gilead’s cilofexor and firsocostat the treatment of patients with NASH. [Gilead Sciences, Inc.] Press Release

LSK BioPharma and Jiangsu Hengrui Medicine Announce FDA Clearance to Initiate a Phase III Clinical Trial in Advanced Hepatocellular Carcinoma (HCC)

LSK BioPharma (LSKB) and Jiangsu Hengrui Medicine, Co., Ltd. announced that the companies have received FDA clearance to initiate a clinical trial in the United States in first-line patients with advanced HCC, evaluating the safety and efficacy of LSKB’s rivoceranib, a selective VEGFR-2 inhibitor commonly known as apatinib, in combination with Hengrui’s camrelizumab, a humanized anti-PD-1 monoclonal antibody currently under FDA review in China for classic Hodgkin’s Lymphoma. [LSK BioPharma] Press Release

Albireo Announces FDA Clearance of IND to Commence Phase II Trial of Elobixibat for the Treatment of NAFLD/NASH

Albireo Pharma, Inc. announced that its Investigational New Drug application (IND) has cleared the required 30 day review by the FDA and is in effect for a Phase II clinical trial of elobixibat, a first-in-class, once-daily, orally-available ileal bile acid transporter inhibitor, for the treatment of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). [Albireo Pharma, Inc.] Press Release

Galmed Pharmaceuticals Announces Successful Completion of End of Phase II Meeting with FDA and Plan for Start of Phase III

Galmed Pharmaceuticals Ltd. announced that the company has completed its End-of-Phase II meeting with the FDA and reached general agreement on key aspects of the Phase III/IV development and registration plan for Aramchol and on the pivotal registration study ARMOR. [Galmed Pharmaceuticals Ltd.] Press Release

Poxel Announces Favorable Results for PXL065 Phase Ia Single Ascending Dose Trial

POXEL SA announced favorable results from the Phase Ia two-part study that included three single doses of PXL065 and a single dose of Actos^®. PXL065, the deuterium-stabilized R-stereoisomer of pioglitazone, is a mitochondrial pyruvate carrier inhibitor being developed for the treatment of nonalcoholic steatohepatitis. [POXEL SA] Press Release

Gilead Announces New Grant Programs Supporting Investigator-Sponsored Research in Liver Diseases

Gilead Sciences, Inc. announced the launch of five new global grants programs to continue to support investigator-sponsored research in chronic hepatitis C virus (HCV) and hepatitis B virus, HCV and HIV co-infection, nonalcoholic steatohepatitis and primary sclerosing cholangitis. [Gilead Sciences, Inc.] Press Release

Clinical Network to Support Liver Disease Research Trials Set Up by Perspectum Diagnostics and SC Liver

SC Liver Research Consortium (SC Liver) and Perspectum Diagnostics have developed a major US-based clinical network to provide clinical trial services that support the development of drugs for liver disorders. [SC Liver Research Consortium (Business Wire, Inc.)] Press Release

Blue Faery Grants Liver Cancer Research Award

Blue Faery: The Adrienne Wilson Liver Cancer Association announced the annual Blue Faery Award for Excellence in Liver Cancer Research. Blue Faery created the award to recognize medical professionals who develop innovative research in hepatocellular carcinoma. [Blue Faery (24-7 Press Release Newswire)] Press Release

Universities Will Soon Announce Action against Scientists Who Broke NIH Rules, Agency Head Says

Some US universities will announce in the next week or two actions they have taken to prevent foreign governments from taking unfair advantage of research funded by the National Institutes of Health (NIH) in Bethesda, Maryland, NIH Director Francis Collins said. Some researchers could be fired, Collins suggested. [ScienceInsider] Editorial

Impact Factors Are Still Widely Used in Academic Evaluations

Almost half of research-intensive universities consider journal impact factors when deciding whom to promote, a survey of North American institutions has found. The data imply that many universities are evaluating the performance of their staff using a metric that has been widely criticized as a crude and misleading proxy for the quality of scientists’ work. [Nature News] Editorial

NEW European Society for Medical Oncology (ESMO) 2019 Congress
September 27-October 1, 2019
Barcelona, Spain

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

NEW Postdoctoral Fellow – Fatty Liver Disease Research (Northeast Ohio Medical Universtiy)

NEW Staff Scientist – Liver Disease Research (National Institute of Diabetes and Digestive and Kidney Diseases)

NEW Cell Biologist – Regenerative Medicine & Liver Disease (Hepatx Corporation)

Postdoctoral Research Scholarship – Liver Function & Disease (Karolinska Institutet)

Postdoctoral Research Fellow – Biology of Liver Cancer (Boston Children’s Hospital)

Postdoctoral Fellow – Alcoholic Liver Disease Research (Northeast Ohio Medical University)

Professor/Associate Professor – Cancer Biology (Norwegian University of Science and Technology)

Postdoctoral Position – Stem Cell Biology (University of Zurich)

Assistant Professor – Computational Biology/Stem Cell Biology (University of Illinois at Chicago)

Postdoctoral Research Associate – Liver DIseases (University of Illinois at Chicago)

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