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Protein tyrosine phosphatase inhibition down-regulates ligand-induced ABCA1 expression

      Highlights

      • Certain phosphatase inhibitors down-regulate ligand-induced ABCA1 expression.
      • This occurs through protein tyrosine, but not serine/threonine, phosphatases.
      • Down-regulation is predominantly a transcriptional effect.
      • Protein tyrosine phosphatase inhibition decreases LXR/RXR promoter activity.

      Abstract

      Objective

      ATP-binding cassette transporter (ABC)-A1 is an important protein of cholesterol homoeostasis and atherosclerosis as it is the major lipid transporter responsible for the export of cholesterol from cells. Many studies have examined kinase regulation of ABCA1 expression. In contrast, very little is known about whether dephosphorylation events play a role in ABCA1 expression. In this study, we explored the involvement of phosphatases in the regulation of ABCA1 expression.

      Methods and results

      We observed that general protein tyrosine phosphatase inhibitors ablated ABCA1 protein and mRNA when stimulated with synthetic ligands. This effect is transcriptional, and appears to involve the nuclear receptor, retinoid X receptor (RXR).

      Conclusion

      Our data demonstrate that inhibition of protein tyrosine phosphatases down-regulates ABCA1 expression, indicating a new level of regulation of a key protein in cholesterol export.

      Keywords

      Abbreviations:

      ABC (ATP-binding cassette), CHO-7 (Chinese hamster ovary-7), HDL (high-density lipoprotein), LXR (liver X receptor), Na3VO4 (sodium orthovanadate), PBGD (porphobilinogen deaminase), PTP (protein tyrosine phosphatase), RXR (retinoid X receptor)
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