Gene Expression 17(3) Abstracts

Return to Gene Expression>

Gene Expression, Vol. 17, pp. 173-186, 2017
1052-2166/17 $90.00 + .00
DOI: https://doi.org/10.3727/105221617X
695519
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved


Invited Review

Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance

Bin Gao,* Ming-Jiang Xu,* Adeline Bertola,*† Hua Wang,*‡ Zhou Zhou,* and Suthat Liangpunsakul§¶

*Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
Université Côte d’Azur, INSERM, Centre Méditerranéen de Médecine Moléculaire, Nice, France
‡Department of Oncology, The First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, P.R. China
§Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA

Alcoholic liver disease (ALD), a leading cause of chronic liver injury worldwide, comprises a range of disorders including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Over the last five decades, many animal models for the study of ALD pathogenesis have been developed. Recently, a chronic-plus-binge ethanol feeding model was reported. This model induces significant steatosis, hepatic neutrophil infiltration, and liver injury. A clinically relevant model of high-fat diet feeding plus binge ethanol was also developed, which highlights the risk of excessive binge drinking in obese/overweight individuals. All of these models recapitulate some features of the different stages of ALD and have been widely used by many investigators to study the pathogenesis of ALD and to test for therapeutic drugs/components. However, these models are somewhat variable, depending on mouse genetic background, ethanol dose, and animal facility environment. This review focuses on these models and discusses these variations and some methods to improve the feeding protocol. The pathogenesis, clinical relevance, and translational studies of these models are also discussed.

Key words: Miscellaneous metabolic liver diseases; Liver diseases; Animal models; Alcoholic liver disease (ALD); Inflammation and injury; Molecular basis

Address correspondence to Dr. Bin Gao, NIAAA/NIH, 5625 Fishers Lane, Bethesda, MD 20892, USA. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 17, pp. 187-205, 2017
1052-2166/17 $90.00 + .00
DOI: https://doi.org/10.3727/105221617X
695050
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved


C57BL/6 Substrains Exhibit Different Responses to Acute Carbon Tetrachloride Exposure: Implications for Work Involving Transgenic Mice

Jennifer M. McCracken,* Prabhakar Chalise,† Shawn M. Briley,‡ Katie L. Dennis,§ Lu Jiang,* Francesca E. Duncan,‡ and Michele T. Pritchard*

*Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
†Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA
‡Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA
§Department of Pathology, University of Kansas Medical Center, Kansas City, KS, USA

Biological differences exist between strains of laboratory mice, and it is becoming increasingly evident that there are differences between substrains. In the C57BL/6 mouse, the primary substrains are called 6J and 6N. Previous studies have demonstrated that 6J and 6N mice differ in response to many experimental models of human disease. The aim of our study was to determine if differences exist between 6J and 6N mice in terms of their response to acute carbon tetrachloride (CCl4) exposure. Mice were given CCl4
once and were euthanized 12 to 96 h later. Relative to 6J mice, we found that 6N mice had increased liver injury but more rapid repair. This was because of the increased speed with which necrotic hepatocytes were removed in 6N mice and was directly related to increased recruitment of macrophages to the liver. In parallel, enhanced liver regeneration was observed in 6N relative to 6J mice. Hepatic stellate cell activation occurred earlier in 6N mice, but there was no difference in matrix metabolism between substrains. Taken together, these data demonstrate specific and significant differences in how the C57BL/6 substrains respond to acute CCl4, which has important implications for all mouse studies utilizing this model.

Key words: Carbon tetrachloride; Hepatic injury; Liver regeneration; Hepatic inflammation

Address correspondence to Michele T. Pritchard, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. Tel: 913-588-0383; Fax: 913-588-7501; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 17, pp. 207-218, 2017
1052-2166/17 $90.00 + .00
DOI: https://doi.org/10.3727/105221617X
695438
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved


The Thyromimetic KB2115 (Eprotirome) Induces Rat Hepatocyte Proliferation

Marta Szydlowska,1 Monica Pibiri,1 Andrea PerraElisabetta Puliga, Sandra Mattu, Giovanna M. Ledda-ColumbanoAmedeo Columbano, and Vera P. Leoni

Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy

Although the hepatomitogenic activity of T3 is well established, the wide range of harmful effects exerted by this hormone precludes its use in regenerative therapy. The aim of this study was to investigate whether an agonist of TRβ, KB2115 (Eprotirome), could exert a mitogenic effect in the liver, without most of the adverse T3/TRα-dependent side effects. F-344 rats treated with KB2115 for 1 week displayed a massive increase in bromodeoxyuridine incorporation (from 20% to 40% vs. 5% of controls), which was associated with increased mitotic activity in the absence of significant signs of liver toxicity. Noteworthy, while cardiac hypertrophy typical of T3 was not observed, beneficial effects, such as lowering blood cholesterol levels, were associated to KB2115 administration. Following a single dose of KB2115, hepatocyte proliferation was evident as early as 18 h, demonstrating its direct mitogenic effect. No increase in serum transaminase levels or apoptosis was observed prior to or concomitantly with the S phase. While KB2115-induced mitogenesis was not associated to enhance expression of c-fos, c-jun, and c-myc, cyclin D1 levels rapidly increased. In conclusion, KB2115 induces hepatocyte proliferation without overt toxicity. Hence, this agent may be useful for regenerative therapies in liver transplantation or other surgical settings.

Key words: Thyromimetics; Cyclin D1; Regenerative medicine; Hepatocyte proliferation

1These authors provided equal contribution to this work.
Address correspondence to Amedeo Columbano, Ph.D., Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy. Tel: +39-070-6758345; Fax: +39-070-666062; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 17, pp. 219-235, 2017
1052-2166/17 $90.00 + .00
DOI: https://doi.org/10.3727/105221617X
695762
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved


Role and Regulation of p65/β-Catenin Association During Liver Injury and Regeneration: A “Complex” Relationship

Kari Nejak-Bowen,*† Akshata Moghe,‡ Pamela Cornuet,* Morgan Preziosi,* Shanmugam Nagarajan,*† and Satdarshan P. Monga*†‡

*Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
†Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
‡Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

An important role for β-catenin in regulating p65 (a subunit of NF-κB) during acute liver injury has recently been elucidated through use of conditional β-catenin knockout mice, which show protection from apoptosis through increased activation of p65. Thus, we hypothesized that the p65/β-catenin complex may play a role in regulating processes such as cell proliferation during liver regeneration. We show through in vitro and in vivo studies that the p65/β-catenin complex is regulated through the TNF-α pathway and not through Wnt signaling. However, this complex is unchanged after partial hepatectomy (PH), despite increased p65 and β-catenin nuclear translocation as well as cyclin D1 activation. We demonstrate through both in vitro silencing experiments and chromatin immunoprecipitation after PH that β-catenin, and not p65, regulates cyclin D1 expression. Conversely, using reporter mice we show p65 is activated exclusively in the nonparenchymal (NPC) compartment during liver regeneration. Furthermore, stimulation of macrophages by TNF-α induces activation of NF-κB and subsequent secretion of Wnts essential for β-catenin activation in hepatocytes. Thus, we show that β-catenin and p65 are activated in separate cellular compartments during liver regeneration, with p65 activity in NPCs contributing to the activation of hepatocyte β-catenin, cyclin D1 expression, and subsequent proliferation.

Key words: p65; Wnt; β-Catenin; Liver injury; Tumor necrosis factor-α (TNF-α); Liver regeneration (LR); Partial hepatectomy (PH); Proliferation; Cyclin D1

Address correspondence to Kari Nejak-Bowen, M.B.A., Ph.D., School of Medicine, University of Pittsburgh, S405A BST, 200 Lothrop Street, Pittsburgh, PA 15261, USA. Tel: (412) 648-2116; Fax: (412) 648-1916; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 17, pp. 237-249, 2017
1052-2166/17 $90.00 + .00
DOI: https://doi.org/10.3727/105221617X
695195
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved


tomm22 Knockdown-Mediated Hepatocyte Damages Elicit Both the Formation of Hybrid Hepatocytes and Biliary Conversion to Hepatocytes in Zebrafish Larvae

Jianchen Wu,*† Tae-Young Choi,*1 and Donghun Shin*

*Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
†Tsinghua University School of Medicine, Beijing, P.R. China

The liver has a highly regenerative capacity. In the normal liver, hepatocytes proliferate to restore lost liver mass. However, when hepatocyte proliferation is impaired, biliary epithelial cells (BECs) activate and contribute to hepatocytes. We previously reported in zebrafish that upon severe hepatocyte ablation, BECs extensively contribute to regenerated hepatocytes. It was also speculated that BEC-driven liver regeneration might occur in another zebrafish liver injury model in which temporary knockdown of the mitochondrial import gene tomm22 by morpholino antisense oligonucleotides (MO) induces hepatocyte death. Given the importance of multiple BEC-driven liver regeneration models for better elucidating the mechanisms underlying innate liver regeneration in the diseased liver, we hypothesized that BECs would contribute to hepatocytes in tomm22 MO-injected larvae. In this MO-based liver injury model, by tracing the lineage of BECs, we found that BECs significantly contributed to hepatocytes. Moreover, we found that surviving, preexisting hepatocytes become BEC–hepatocyte hybrid cells in tomm22 MO-injected larvae. Intriguingly, both the inhibition of Wnt/β-catenin signaling and macrophage ablation suppressed the formation of the hybrid hepatocytes. This new liver injury model in which both hepatocytes and BECs contribute to regenerated hepatocytes will aid in better understanding the mechanisms of innate liver regeneration in the diseased liver.

Key words: Liver regeneration; Macrophage; Oval cells; Liver progenitor cells

1Current affiliation: Department of Genetic Resources Research, National Marine Biodiversity Institute of Korea, Seocheon-gun, Chungcheongnam-do 33662, Republic of Korea.
Address correspondence to Donghun Shin, Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, 3501 5th Avenue #5063, Pittsburgh, PA 15260, USA. Tel: 1-412-624-2144; Fax: 1-412-383-2211; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 17, pp. 237-249, 2017
1052-2166/17 $90.00 + .00
DOI: https://doi.org/10.3727/105221617X
695195
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved


Review

A Review of the Scaffold Protein Menin and its Role in Hepatobiliary Pathology

Laurent Ehrlich,* Chad Hall,† Fanyin Meng,*‡§ Terry Lairmore,† Gianfranco Alpini,*‡§ and Shannon Glaser*‡§

*Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
†Department of Surgery, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
‡Research, Central Texas Veterans Health Care System, Temple, TX, USA
§Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, USA

Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome with neuroendocrine tumorigenesis of the parathyroid glands, pituitary gland, and pancreatic islet cells. The MEN1 gene codes for the canonical tumor suppressor protein, menin. Its protein structure has recently been crystallized, and it has been investigated in a multitude of other tissues. In this review, we summarize recent advancements in understanding the structure of the menin protein and its function as a scaffold protein in histone modification and epigenetic gene regulation. Furthermore, we explore its role in hepatobiliary autoimmune diseases, cancers, and metabolic diseases. In particular, we discuss how menin expression and function are regulated by extracellular signaling factors and nuclear receptor activation in various hepatic cell types. How the many signaling pathways and tissue types affect menin’s diverse functions is not fully understood. We show that small-molecule inhibitors affecting menin function can shed light on menin’s broad role in pathophysiology and elucidate distinct menin-dependent processes. This review reveals menin’s often dichotomous function through analysis of its role in multiple disease processes and could potentially lead to novel small-molecule therapies in the treatment of cholangiocarcinoma or biliary autoimmune diseases.

Key words: Biliary epithelium; Fibrosis; Transforming growth factor-β (TGF-β); Mixed lineage leukemia (MLL); Histone deacetylase; Cholangiocarcinoma (CCA); Hepatocellular carcinoma (HCC); JunD; Pancreas; Immunology; Metabolic disease

Address Correspondence to Shannon Glaser, Ph.D., Associate Professor, Texas A&M Health Science Center, College of Medicine, 1901 South 1st Street, Building 205, Temple, TX 76569, USA. Tel: 254-743-1044; Fax: 254-743-0378; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it