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

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.

Effects of Selenium Deficiency on Aldehyde Oxidase 1 in Rats

“…Recently, AOX1 was identified as an ATP-binding cassette transporter A1 (ABCA1) interacting protein to affect ABCA1-dependent phospholipid and cholesterol efflux. 45) AOX1 has also been reported to be essential for adipogenesis from the fact that a knockdown of AOX1 in preadipocytes led to impaired lipid storage and adiponectin release in the differentiated cells. 46) Thus, elucidation of the physiological functions of AOX1 has just begun.…”

Microarray gene expression profiling in meningiomas: Differential expression according to grade or histopathological subtype

“…Furthermore, the frequent presence of ADAMTSL3 mutations has been reported in colorectal cancer (48) and decreased ADAMTSL3 mRNA expression, as observed in colorectal malignancy (48), may contribute to the progression of meningiomas. Finally, complete loss or reduced expression of AOX1, a xenobiotic metabolizing enzyme, has been reported in hepatocellular carcinomas, with a significant correlation between AOX1 expression and tumour stage (49).…”

Whole-Genome Sequencing of Growth Hormone (GH)-Secreting Pituitary Adenomas

“…Several genes involved in Ca 2ϩ -and ATP -signaling were somatically affected (Table 2). Ca 2ϩ -signaling: C2CD3, RYR1, SSR3 (18), ACTN4 (19), UBR4 (20); ATP -signaling: SUPV3L1 (21), ATPAF2, ATAD2B, DICER1 (22), AOX1 (23).…”