Human aldehyde oxidase 1 interacts with ATP-binding cassette transporter-1 and modulates its activity in hepatocytes

A0X1, a member of the cytosolic molybdenum hydroxylase family, has been identified by us earlier as an ABCA1 -interacting protein. A0X1 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 A0X1 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 A0X1 are coexpressed in human hepatocytes, kidney proximal tubular epithelial cells, Leydig, and adrenocortical cells. Expression of ABCA1 and A0X1 was investigated by immunohistochernistry in liver tissue arrays. A strong A0X1 expression was found in normal liver, and in cirrhosis. In contrast, hepatocellular carcinomas showed either a complete loss or reduced expression of A0X1. Significant correlations were found between reduced A0X1 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 A0X1 modulates ABCA1-linked cellular functions such as lipid efflux and phagocytosis in hepatocytes, and the reduced expression of A0X1 in malignant transformed hepatocytes supports the differentiation dependent upregulation of A0X1.