2. Academic Validation
  3. Regulation of ABCG4 transporter expression by sterols and LXR ligands

Regulation of ABCG4 transporter expression by sterols and LXR ligands

  • Biochim Biophys Acta Gen Subj. 2021 Jan;1865(1):129769. doi: 10.1016/j.bbagen.2020.129769.
Alryel Yang 1,  Amjad Z Alrosan 1,  Laura J Sharpe 2,  Andrew J Brown 2,  Richard Callaghan 3,  Ingrid C Gelissen 4
Affiliations

Affiliations

  • 1 Sydney Pharmacy School, Faculty of Medicine and Health, Pharmacy Bank Building A15, Science Road, The University of Sydney, Sydney, NSW 2006, Australia.
  • 2 School of Biotechnology and Biomolecular Sciences, Chancellery Walk, The University of New South Wales, Kensington, NSW 2033, Australia.
  • 3 Research School of Biology and Medical School, Linnaeus Way, Australian National University, ACT 2600, Australia.
  • 4 Sydney Pharmacy School, Faculty of Medicine and Health, Pharmacy Bank Building A15, Science Road, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: [email protected].
PMID: 33141061 DOI: 10.1016/j.bbagen.2020.129769
Abstract

Background: Oxysterols, which are derivatives of Cholesterol produced by enzymic or non-enzymic pathways, are potent regulators of cellular lipid homeostasis. Sterol homeostasis in the brain is an important area of interest with regards to neurodegenerative conditions like Alzheimer's disease (AD). Brain cells including neurons and astrocytes express sterol transporters belonging to the ABC transporter family of proteins, including ABCA1, ABCG1 and ABCG4, and these transporters are considered of interest as therapeutic targets. Although regulation of ABCA1 and ABCG1 is well established, regulation of ABCG4 is still controversial, in particular whether the transporter is an Liver X receptor (LXR) target. ABCG4 is thought to transport Cholesterol, oxysterols and Cholesterol synthesis intermediates, and was recently found on the blood brain barrier (BBB), implicated in amyloid-beta export. In this study, we investigate the regulation of ABCG4 by oxysterols, cholesterol-synthesis intermediates and Cholesterol itself.

Methods: ABC transporter expression was measured in neuroblastoma and gliablastoma cell lines and cells overexpressing ABCG4 in response to synthetic LXR ligands, oxysterols and cholesterol-synthesis intermediates.

Results: In contrast to previous reports, ABCG4 expression was induced by a synthetic LXR ligand in U87-MG astrocytes but not in neuroblastoma and BBB endothelial cell lines. In addition, ABCG4 protein was stabilized by Cholesterol as was previously shown for ABCG1. ABCG4 protein was furthermore stabilized by cholesterol-synthesis intermediates, desmosterol, lathosterol and lanosterol.

Conclusions: These results identify new aspects of the post-translational control of ABCG4 that warrant further exploration into the role of this transporter in the maintenance of sterol homeostasis in the brain.

Keywords

ABC transporters; Astrocytes; Blood-brain barrier endothelium; Cholesterol; Lipid homeostasis; Neurons; Oxysterols.

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