Human Aldehyde Oxidase 1 Interacts with ATP-binding Cassette Transporter-1 and Modulates its Activity in Hepatocytes

A. Sigruener; C. Buechler; E. Orsó; A. Hartmann; P. J. Wild; L. Terracciano; M. Roncalli; S. R. Bornstein; G. Schmitz

doi:10.1055/s-2007-992129

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2007; 39(11): 781-789
DOI: 10.1055/s-2007-992129

Original Basic

Human Aldehyde Oxidase 1 Interacts with ATP-binding Cassette Transporter-1 and Modulates its Activity in Hepatocytes

A. Sigruener¹ , C. Buechler¹ , E. Orsó¹ , A. Hartmann² , P. J. Wild³ , L. Terracciano⁴ , M. Roncalli⁵ , S. R. Bornstein⁶ , G. Schmitz¹

¹Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Medical Center, Regensburg, Germany
²Institute of Pathology, Regensburg University Medical Center, Regensburg, Germany
³Institute of Pathology, University Hospital Zürich, Zürich, Switzerland
⁴Institute of Pathology, University Hospital, Basel, Switzerland
⁵Department of Pathology, Humanitas Clinical Institute of Rozzano, University of Milan, Rozzano, Milano, Italy
⁶Medical Clinic III, Medical Faculty Carl Gustav Carus, University of Technology, Dresden, Germany

Abstract

AOX1, a member of the cytosolic molybdenum hydroxylase family, has been identified by us earlier as an ABCA1-interacting protein. AOX1 is well-described as xenobiotic metabolizing enzyme, which upon oxidation of acetaldehyde and retinaldehyde to acetic acid and retinoic acid generates reactive oxygen species. Here we show that knock-down of AOX1 in HepG2 by small interfering RNA significantly reduced ABCA1-dependent lipid efflux and enhanced phagocytic uptake of microspheres similar to ABCA1 deficiency, without affecting ABCA1 mRNA and protein levels. ABCA1 and AOX1 are coexpressed in human hepatocytes, kidney proximal tubular epithelial cells, Leydig, and adrenocortical cells. Expression of ABCA1 and AOX1 was investigated by immunohistochemistry in liver tissue arrays. A strong AOX1 expression was found in normal liver, and in cirrhosis. In contrast, hepatocellular carcinomas showed either a complete loss or reduced expression of AOX1. Significant correlations were found between reduced AOX1 expression and tumor stage, or metastatic or regional lymph node states. Deregulation was also observed for ABCA1 expression but to a lesser extent. Our findings show that the interaction of ABCA1 with AOX1 modulates ABCA1-linked cellular functions such as lipid efflux and phagocytosis in hepatocytes, and the reduced expression of AOX1 in malignant transformed hepatocytes supports the differentiation dependent upregulation of AOX1.

Key words

AOX1 - ABCA1 - HepG2 - siRNA - efflux

Full Text

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Correspondence

Prof.Dr.med. G. Schmitz

Institute of Clinical Chemistry

Regensburg University Medical Center

Franz-Josef-Strauss-Allee 11

93042 Regensburg

Germany

Phone: +49/941/944 62 01

Fax: +49/941/944 62 02

Email: gerd.schmitz@klinik.uni-regensburg.de