Gene Expression 17(4) Abstracts

Return to Gene Expression>

Gene Expression, Vol. 17, pp. 265-275, 2017
1052-2166/17 $90.00 + .00
DOI: https://doi.org/10.3727/105221617X14968563796227
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Invited Review

GC-1: A Thyromimetic With Multiple Therapeutic Applications in Liver Disease

Amedeo Columbano,*1 Grazia Chiellini,†1 and Marta Anna Kowalik*1

*Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
†Department of Surgical, Medical and Molecular Pathology, University of Pisa, Pisa, Italy

Thyroid hormones (THs), namely, 3,5,3′-triiodo-l-thyronine (T3) and 3,5,3′,5′-tetraiodo-l-thyronine (thyroxine or T4), influence a variety of physiological processes that have important implications in fetal development, metabolism, cell growth, and proliferation. While THs elicit several beneficial effects on lipid metabolism and improve myocardial contractility, these therapeutically desirable effects are associated to a thyrotoxic state that severely limits the possible use of THs as therapeutic agents. Therefore, several efforts have been made to develop T3 analogs that could retain the beneficial actions (triglyceride, cholesterol, obesity, and body mass lowering) without the adverse TH-dependent side effects. This goal was achieved by the synthesis of TRβ-selective agonists. In this review, we summarize the current knowledge on the effects of one of the best characterized TH analogs, the TRβ1-selective thyromimetic, GC-1. In particular, we review some of the effects of GC-1 on different liver disorders, with reference to its possible clinical application. A brief comment on the possible therapeutic use of GC-1 in extrahepatic disorders is also included.

Key words: Thyromimetics; Hepatocellular carcinoma; Regenerative medicine; Liver cell proliferation; Thyroid hormone receptor

1These authors provided equal contribution to this work.

Address correspondence to Marta Anna Kowalik, Ph.D., Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy. Tel: +39-070-6758346; 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. 277-287, 2017
1052-2166/17 $90.00 + .00
DOI: https://doi.org/10.3727/105221617X15042750874156
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Invited Review

Hepatic Ischemia/Reperfusion: Mechanisms of Tissue Injury, Repair, and Regeneration

Takanori Konishi and Alex B. Lentsch

Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, USA

Hepatic ischemia/reperfusion (I/R) injury is a major complication of liver surgery, including liver resection, liver transplantation, and trauma surgery. Much has been learned about the inflammatory injury response induced by I/R, including the cascade of proinflammatory mediators and recruitment of activated leukocytes. In this review, we discuss the complex network of events that culminate in liver injury after I/R, including cellular, protein, and molecular mechanisms. In addition, we address the known endogenous regulatory mediators that function to maintain homeostasis and resolve injury. Finally, we cover more recent insights into how the liver repairs and regenerates after I/R injury, a setting in which physical mass remains unchanged, but functional liver mass is greatly reduced. In this regard, we focus on recent work highlighting a novel role of CXC chemokines as important regulators of hepatocyte proliferation and liver regeneration after I/R injury.

Key words: Hepatic injury; Necrosis; Hepatic inflammation; Liver regeneration

Address correspondence to Alex B. Lentsch, Ph.D., Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267-0558, USA. Tel: (513) 558-8674; Fax: (513) 558-8677; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 17, pp. 289-299, 2017
1052-2166/17 $90.00 + .00
DOI: https://doi.org/10.3727/105221617X695825
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Gene Expression in the Liver Remnant Is Significantly Affected by the Size of Partial Hepatectomy: An Experimental Rat Study

Michelle Meier,* Anders Riegels Knudsen,* Kasper Jarlhelt Andersen,* Niels Christian Bjerregaard,* Uffe Birk Jensen,†‡ and Frank Viborg Mortensen*

*Department of Surgical Gastroenterology, Section for Upper Gastrointestinal and Hepato-Pancretico-Biliary Surgery, Aarhus University Hospital, Aarhus, Denmark
†Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
‡Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark

Extended hepatectomies may result in posthepatectomy liver failure, a condition with a high mortality. The main purpose of the present study was to investigate and compare the gene expression profiles in rats subjected to increasing size of partial hepatectomy (PH). Thirty Wistar rats were subjected to 30%, 70%, or 90% PH, sham operation, or no operation. Twenty-four hours following resection, liver tissue was harvested and genome-wide expression analysis was performed. Cluster analysis revealed two main groupings, one containing the PH(90%) and one containing the remaining groups [baseline, sham, PH(30%), and PH(70%)]. Categorization of specific affected molecular pathways in the PH(90%) group revealed a downregulation of cellular homeostatic function degradation and biosynthesis, whereas proliferation, cell growth, and cellular stress and injury were upregulated in the PH(90%) group. After PH(90%), the main upregulated pathways were mTOR and ILK. The main activated upstream regulators were hepatocyte growth factor and transforming growth factor. With decreasing size of the future liver remnant, the liver tended to prioritize expression of genes involved in cell proliferation and differentiation at the expense of genes involved in metabolism and body homeostasis. This prioritizing may be an essential molecular explanation for posthepatectomy liver failure.

Key words: Hepatectomy; Regeneration; Liver failure; Gene expression; Microarray analysis

Address correspondence to Anders Riegels Knudsen, M.D., Ph.D., Department of Surgical Gastroenterology, Section for Upper Gastrointestinal and Hepato-Pancretico-Biliary Surgery, Aarhus University Hospital, Noerrebrogade 44, building 1c, DK-8000 Aarhus, Denmark. Tel: 0045-21-43-44-04; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 17, pp. 301-312, 2017
1052-2166/17 $90.00 + .00
DOI: https://doi.org/10.3727/105221617X15016197658871
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Cell Death and Prognosis of Mortality in Alcoholic Hepatitis Patients Using Plasma Keratin-18

Benjamin L. Woolbright,* Brian W. Bridges,† Winston Dunn,† Jody C. Olson,† Steven A. Weinman,† and Hartmut Jaeschke*

*Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
†Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA

Alcoholic liver disease encompasses the progressive stages of liver dysfunction that culminates in alcoholic cirrhosis (AC) and in severe cases alcoholic hepatitis (AH). Currently, prognostic scores have limited specificity and sensitivity. Plasma keratin-18 (K18) levels are elevated during liver disease and may be biomarkers of outcome. The objective of this study was to determine if total K18 (M65) or caspase-cleaved K18 (M30) levels were different between AC and AH patients. M65 and M30 levels were measured in the plasma of consented healthy controls and patients with AC and AH. Cell death was assessed by TUNEL staining and caspase activity. M65 and M30 values were significantly higher in AC patients compared to healthy controls and further increased in AH patients. The M65 values and the M30/M65 ratios of nonsurviving AH patients were significantly elevated above their surviving counterparts and healthy controls. Statistical analysis indicated that M30/M65 ratios outperformed current indices for accurately distinguishing the prognosis of AH patients. These scores occurred with minimal increase in plasma cell death markers such as ALT and AST. Serum caspase activity, TUNEL staining, and M30 immunohistochemistry in biopsies indicated that serum and tissue values may not correlate well with overall cell death. In conclusion, both M65 and M30 differentiate AH from AC patients, and M65 values and the M30/M65 ratio are capable of predicting early stage mortality; however, they may not accurately reflect pure hepatocyte cell death in these populations, as they do not strongly correlate with traditional cell death markers.

Key words: Alcoholic hepatitis (AH); Liver injury; Necrosis; Apoptosis; Cirrhosis

Address correspondence to Hartmut Jaeschke, Ph.D., Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS 1018, Kansas City, KS 66160, USA. Tel: 913 588 7969; 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. 313-326, 2017
1052-2166/17 $90.00 + .00
DOI: https://doi.org/10.3727/105221617X15034976037343
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Increased YAP Activation Is Associated With Hepatic Cyst Epithelial Cell Proliferation in ARPKD/CHF

Lu Jiang,* Lina Sun,*1 Genea Edwards,* Michael Manley Jr.,* Darren P. Wallace,†‡ Seth Septer,§2 Chirag Manohar,* Michele T. Pritchard,*‡ and Udayan Apte*‡

*Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
†Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
‡The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
§Department of Gastroenterology, Children’s Mercy Hospital, Kansas City, KS, USA

Autosomal recessive polycystic kidney disease/congenital hepatic fibrosis (ARPKD/CHF) is a rare but fatal genetic disease characterized by progressive cyst development in the kidneys and liver. Liver cysts arise from aberrantly proliferative cholangiocytes accompanied by pericystic fibrosis and inflammation. Yes-associated protein (YAP), the downstream effector of the Hippo signaling pathway, is implicated in human hepatic malignancies such as hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma, but its role in hepatic cystogenesis in ARPKD/CHF is unknown. We studied the role of the YAP in hepatic cyst development using polycystic kidney (PCK) rats, an orthologous model of ARPKD, and in human ARPKD/CHF patients. The liver cyst wall epithelial cells (CWECs) in PCK rats were highly proliferative and exhibited expression of YAP. There was increased expression of YAP target genes, Ccnd1 (cyclin D1) and Ctgf (connective tissue growth factor), in PCK rat livers. Extensive expression of YAP and its target genes was also detected in human ARPKD/CHF liver samples. Finally, pharmacological inhibition of YAP activity with verteporfin and short hairpin (sh) RNA-mediated knockdown of YAP expression in isolated liver CWECs significantly reduced their proliferation. These data indicate that increased YAP activity, possibly through dysregulation of the Hippo signaling pathway, is associated with hepatic cyst growth in ARPKD/CHF.

Key words: Proliferation; Cyst; Hippo kinase; Fibrosis; Inflammation

1Current Address: Department of Pediatrics, the Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, P.R. China.
2Current Address: Department of Pediatric Gastroenterology, University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, CO, USA.
Address correspondence to Udayan Apte, Ph.D., DABT, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS1018, Kansas City, KS 66160, USA. Tel: (913) 588-9247; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 17, pp. 327-340, 2017
1052-2166/17 $90.00 + .00
DOI: https://doi.org/10.3727/105221617X15042723767876
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

The Cholangiocyte Adenosine–IL-6 Axis Regulates Survival During Biliary Cirrhosis

Elise G. Lavoie,*† Michel Fausther,*† Jessica R. Goree,*† and Jonathan A. Dranoff*†

*Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
†Research Service, Central Arkansas VA Healthcare System, Little Rock, AR, USA

Epithelial response to injury is critical to the pathogenesis of biliary cirrhosis, and IL-6 has been suggested as a mediator of this phenomenon. Several liver cell types can secrete IL-6 following activation by various signaling molecules including circulating adenosine. The aims of this study were to assess whether adenosine can induce IL-6 secretion by cholangiocytes via the A2b adenosine receptor (A2bAR) and to determine the effect of A2bAR-sensitive IL-6 release on injury response in biliary cirrhosis. Human normal cholangiocyte H69 cells were used for in vitro studies to determine the mechanism by which adenosine and the A2bAR induce release of IL-6. In vivo, control and A2bAR-deficient mice were used to determine the roles of A2bAR-sensitive IL-6 release in biliary cirrhosis induced by common bile duct ligation (BDL). Additionally, the response to exogenous IL-6 was assessed in C57BL/6 and A2bAR-deficient mice. Adenosine induced IL-6 mRNA expression and protein secretion via A2bAR activation. Although activation of A2bAR induced cAMP and intracellular Ca2+ signals, only the Ca2+ signals were linked to IL-6 upregulation. After BDL, A2bAR-deficient mice have impaired survival, which is further impaired by exogenous IL-6; however, decreased survival is not due to changes in fibrosis and no changes in inflammatory cells. Exogenous IL-6 is associated with the increased presence of bile infarcts. Extracellular adenosine induces cholangiocyte IL-6 release via the A2bAR. This signaling pathway is important in the pathogenesis of injury response in biliary cirrhosis but does not alter fibrosis. Adenosine upregulates IL-6 release by cholangiocytes via the A2bAR in a calcium-sensitive fashion. Mice deficient in A2bAR experience impaired survival after biliary cirrhosis induced by common bile duct ligation independent of changes in fibrosis.

Key words: Adenosine; Interleukin-6 (IL-6); Adenosine receptor; Cholangiocyte; Liver fibrosis; Biliary cirrhosis

Address correspondence to Jonathan A. Dranoff, M.D., University of Arkansas for Medical Sciences, 4301 West Markham Street #567, Little Rock, AR 72205, USA. Tel: +1-501-686-7840; Fax: +1-501-686-6248; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it