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Horm Metab Res 2011; 43(4): 268-274
DOI: 10.1055/s-0031-1271692
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Ceruloplasmin Expression in Rat Liver Cells is Attenuated by Insulin: Role of FoxO Transcription Factors

M. Leyendecker1 , P. Korsten2 , 10 , R. Reinehr3 , B. Speckmann4 , D. Schmoll5 , W. A. Scherbaum6 , S. R. Bornstein7 , A. Barthel7 , 8 , 11 , L.-O. Klotz1 , 9
  • 1Leibniz-Institut für Umweltmedizinische Forschung (IUF), Düsseldorf, Germany
  • 2Zentrum Innere Medizin, Abteilung Nephrologie und Rheumatologie, Universitätsmedizin Göttingen, Göttingen, Germany
  • 3Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University, Düsseldorf, Germany
  • 4Institute for Biochemistry and Molecular Biology I, Heinrich-Heine-University, Düsseldorf, Germany
  • 5Sanofi-Aventis, R & D Diabetes Division, Frankfurt, Germany
  • 6Department of Endocrinology, Diabetes and Rheumatology, Heinrich-Heine-University, Düsseldorf, Germany
  • 7Medizinische Klinik und Poliklinik III, Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
  • 8Endokrinologikum Ruhr, Bochum, Germany
  • 9Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
  • 10PK is equal first author
  • 11AB is equal last author
Further Information

Publication History

received 30.11.2010

accepted 13.01.2011

Publication Date:
17 February 2011 (online)

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Abstract

The phosphoinositide 3′-kinase (PI3 K)/Akt pathway controls the activity of a number of proteins important in the regulation of apoptosis and cell proliferation. FoxO (forkhead box, class O) transcription factors, substrates of the Ser/Thr kinase Akt, control the expression of several target genes that are crucial to the defense against oxidative stress, the regulation of cell cycle, and apoptosis in mammalian cells. Here, expression of ceruloplasmin (CP), the major copper-containing protein in blood released by the liver, was investigated. We observed a significant downregulation of CP mRNA levels after insulin treatment in H4IIE rat hepatoma cells. The PI3K inhibitor wortmannin counteracted this insulin effect on CP mRNA levels, indicating that the PI3K/Akt cascade is involved in the regulation of CP expression. Stimulation of FoxO1 was induced in H4IIE rat hepatoma cells expressing a conditionally active FoxO1 construct, resulting in significant upregulation of CP mRNA levels. This upregulation was prevented in the presence of insulin. In parallel, mRNAs of established FoxO target genes were analyzed: like CP mRNA, selenoprotein P and glucose 6-phosphatase mRNAs were upregulated by FoxO1, which was prevented by insulin. The same effects of insulin on CP mRNA levels were detected in primary rat hepatocytes. Furthermore, CP release into cell culture media was analyzed with primary hepatocytes and found to be attenuated by insulin. In line with its insulin-mimetic effects on cultured cells, Cu2+ imitated the effect of insulin on CP expression and caused a downregulation of CP mRNA levels in rat hepatoma cells.

Key words

ceruloplasmin - liver - insulin - FoxO - oxidative stress - copper - diabetes mellitus

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Correspondence

Dr. L.-O. Klotz

University of Alberta

Faculty of Pharmacy and

Pharmaceutical Sciences

3126 Dentistry/ Pharmacy

Centre

Edmonton, Alberta

Canada T6G 2N8

Phone: +1/780/492 5783

Fax: +1/780/492 1217

Email: larsoliver.klotz@ualberta.ca

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