Hepatic Cell News Volume 3.35 | Sep 20 2019

TOP STORY

Rilpivirine Attenuates Liver Fibrosis through Selective STAT1-Mediated Apoptosis in Hepatic Stellate Cells

The effects of RPV on hepatic steatosis, inflammation and fibrogenesis were studied in a nutritional mouse model of non-alcoholic fatty liver disease, carbon tetrachloride-induced fibrosis and bile duct ligation-induced fibrosis. Primary human hepatic stellate cells and human cell lines LX-2 and Hep3B were used to investigate the underlying molecular mechanisms. [Gut] Abstract

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HPD Degradation Regulated by the TTC36-STK33-PELI1 Signaling Axis Induces Tyrosinemia and Neurological Damage

Researchers demonstrated that molecular chaperone TTC36, which is highly expressed in liver, was associated with 4-hydroxyphenylpyruvic acid dioxygenase (HPD) and reduced the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation resulted in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. [Nat Commun] Full Article

Inactivation of NF-κB2 (p52) Restrains Hepatic Glucagon Response via Preserving PDE4B Induction

Mechanistically, p52 bound to phosphodiesterase 4B promoter to inhibit its transcription and promoted cAMP accumulation, thus augmenting the glucagon response through cAMP/PKA signaling. The anti-diabetic drug metformin and ginsenoside Rb1 lowered blood glucose at least in part by inhibiting p52 activation. [Nat Commun] Full Article

Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

Using gain- and loss-of-function approaches in mice, investigators demonstrated that while hepatocyte-specific interferon regulatory factor-2 binding protein 2 (Irf2bp2) knockout exacerbated high-fat diet-induced hepatic steatosis, insulin resistance and inflammation, hepatic Irf2bp2 overexpression protected mice from these metabolic disorders. Moreover, the inhibitory role of IRF2BP2 on hepatosteatosis was conserved in a human hepatic cell line in vitro. [Hepatology] Abstract

HBV-Encoded miR-2 Functions as an Oncogene by Downregulating TRIM35 but Upregulating RAN in Liver Cancer Cells

An miRNA encoded by hepatitis B virus (HBV) was identified by Solexa sequencing in HBV-positive hepatocellular carcinoma (HCC) specimens and further verified in serum samples from HCC patients with HBV infection and in HBV-positive HCC cell lines. To evaluate the roles of HBV-miR-2 in liver cancer cells, the authors determined cell viability and migration/invasion ability by gain-of-function experiment in HBV(-) liver cancer cells and loss-of-function experiments in Huh7 cells stably expressing HBV-miR-2 and HepG2.2.15 cells. [EBioMedicine] Full Article

DPEP1 Is a Direct Target of miR-193a-5p and Promotes Hepatoblastoma Progression by PI3K/Akt/mTOR Pathway

Investigators showed that dipeptidase 1 (DPEP1) was significantly upregulated and was associated with poor prognosis in hepatoblastoma patients. In vitro and in vivo assays indicated that silencing DPEP1 significantly suppressed hepatoblastoma cell proliferation, migration, and invasion, while DPEP1 overexpression exhibited the opposite effect. [Cell Death Dis] Full Article

Discovery and Development of TMPRSS6 Inhibitors Modulating Hepcidin Levels in Human Hepatocytes

Scientists report that treatment with a peptidomimetic inhibitor affecting TMPRSS6 activity increased hepcidin production in hepatic cells. Moreover, similar effects were observed when using non-peptidic inhibitors obtained through optimization of hits from high-throughput screening. [Cell Chem Biol] Abstract | Graphical Abstract

Robust, Long-Term Culture of Endoderm-Derived Hepatic Organoids for Disease Modeling

The authors generated and characterized the hepatic organoid culture (eHEPO) system using human induced pluripotent stem cell-derived EpCAM-positive endodermal cells as an intermediate. eHEPOs could be produced within two weeks and expanded long term without any loss of differentiation capacity to mature hepatocytes. [Stem Cell Reports] Full Article | Graphical Abract

Liver Sinusoidal Endothelial Cell ICAM-1 Mediated Tumor/Endothelial Crosstalk Drives the Development of Liver Metastasis by Initiating Inflammatory and Angiogenic Responses

Researchers performed in vitro co-cultures and an in vivo model of liver metastasis of colorectal cancer. ICAM-1 blockade in the liver sinusoidal endothelial cells (LSECs) decreased the adhesion and transmigration of tumor cells through an LSEC in vitro and vivo. Cocultures of C26 cells and LSECs contained higher amounts of IL-1β, IL-6, PGE-2, TNF-α and ICAM-1 than monocultures. [Sci Rep] Full Article

Levosimendan Pretreatment Improves Survival of Septic Rats after Partial Hepatectomy and Suppresses iNOS Induction in Cytokine-Stimulated Hepatocytes

In remnant livers, levosimendan inhibited inducible nitric oxide synthase (iNOS) gene expression. In primary cultured rat hepatocytes stimulated by IL-1β, levosimendan suppressed nitric oxide production by inhibiting iNOS promoter activity and stability of its mRNA. [Sci Rep] Full Article

MicroRNA-370 Functions as a Tumor Suppressor in Hepatocellular Carcinoma via Inhibition of the MAPK/JNK Signaling Pathway by Targeting BEX2

It was determined that BEX2 was highly expressed and miR-370 was poorly expressed in hepatocellular carcinoma cell lines and tissues. The cell line presenting with the highest BEX2 expression and the lowest miR-370 expression was selected for subsequent gain- and loss-of-function experimentation. [J Hum Genet] Abstract

Spatial Sorting Enables Comprehensive Characterization of Liver Zonation

Scientists showed how zonated surface markers could be used to sort hepatocytes from defined lobule zones with high spatial resolution. They applied transcriptomics, microRNA array measurements and mass spectrometry proteomics to reconstruct spatial atlases of multiple zonated features. [Nat Metab] Abstract

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Molecular Mechanisms of Circular RNAs, Transforming Growth Factor-β, and Long Noncoding RNAs in Hepatocellular Carcinoma

An interesting yet-to-be resolved concept is whether the hepatocellular carcinoma (HCC)-promoting role of transforming growth factor-beta (TGF-β) pathways is limited to a subset of HCC patients, or if it is involved in the whole process of HCC development. This review summarizes recent advancements to highlight the roles of circRNAs, lncRNAs, and TGF-β in HCC. [Cancer Med] Full Article

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

Positive Results from Novartis Five-Year VERIFY Study in Type 2 Diabetes Demonstrate Long-Term Clinical Benefits of Early Combination Treatment with Galvus^® and Metformin

Novartis announced the key results from the Phase IV clinical study VERIFY evaluating the long-term efficacy and safety of early combination treatment strategy with metformin plus vildagliptin compared to the traditional stepwise approach with metformin as initial therapy followed by vildagliptin, added at the time of metformin failure. [Novartis] Press Release

Pew Funds Six Research Teams to Pursue Scientific Discoveries

The Pew Charitable Trusts announced the six pairs of researchers who will make up its 2019 class of Innovation Fund investigators. These investigators- alumni of Pew’s biomedical programs in the United States and Latin America- partner on interdisciplinary research to tackle some of the most complex questions in human biology and disease. [The Pew Charitable Trusts] Press Release

Kashmir’s Communication Blackout Is a ‘Devastating Blow’ for Academics, Researchers Say

Six professors from India’s top science institutions have appealed to the government to lift the blockade of academic and research institutions in Indian-controlled Kashmir. The blockade has been a “devastating blow,” the six write in an open letter published September 18^th [ScienceMagazine] Editorial

New Journal Seeks Typically Overlooked Studies

On September 18, Cambridge University Press launched an open-access journal that will address issues in research by taking a different approach to publishing. The journal, Experimental Results, will include findings that have inconclusive or negative results and articles that reproduce or dispute existing research. [The Scientist] Editorial

US Awards $3 Million to Fill Gaps in Medical Marijuana Research

The US government will spend $3 million to find out if marijuana can relieve pain, but none of the money will be used to study the part of the plant that gets people high. Nine research grants announced are for work on CBD, the trendy ingredient showing up in cosmetics and foods, and hundreds of less familiar chemicals. THC research was excluded. [STAT News] Editorial

NEW Translational Research in Viral Hepatitis: Addressing the Gaps for Cure
January 23-25, 2020
Athens, Greece

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NEW Postdoctoral Researchers – Liver Diseases (Albert Einstein College of Medicine)

Research Technologist – Intestinal Stem Cell Biology (STEMCELL Technologies Inc.)

Postdoctoral Researcher – Liver Cell-Cell Interactions (Flanders Institute for Biotechnology)

Group Leader – Immunology (University Hospital Düsseldorf)

Postdoctoral Researcher – Liver Disease (Albert Einstein College of Medicine)

Senior Researcher – Inflammatory Diseases (Genentech, Inc.)

Postdoctoral Researcher – Microbiome in IBD (GIGA-Medical Genomics Unit)

Postdoctoral Fellow – Designer Probiotics (Massachusetts General Hospital)

Principal Researcher – Systems Disease Biology (Boehringer Ingelheim)

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

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