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Temporary sequestration of cholesterol and phosphatidylcholine within extracellular domains of ABCA1 during nascent

Masato Ishigami1, Fumihiko Ogasawara1, Kohjiro Nagao2

  • 1Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan.

Scientific Reports
|April 20, 2018
PubMed

Insights

The ATP-binding cassette protein A1 (ABCA1) sequesters lipids within its extracellular domains during high-density lipoprotein (HDL) formation. This finding supports a mechanism where lipids are temporarily held before acquiring apolipoprotein A-I.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Science

Background:

  • High-density lipoprotein (HDL) levels are crucial for preventing coronary artery disease.
  • ATP-binding cassette protein A1 (ABCA1) and apolipoprotein A-I (apoA-I) are key in nascent HDL biogenesis.
  • The precise mechanism of nascent HDL generation by ABCA1 remains debated, with direct and indirect loading models proposed.

Purpose of the Study:

  • To investigate the mechanism of lipid transfer from ABCA1 to apoA-I during nascent HDL formation.
  • To determine the role of ABCA1's extracellular domains (ECDs) in lipid acquisition.

Main Methods:

  • Utilized trypsin treatment on BHK/ABCA1 cells to probe ABCA1 structure and function.
  • Monitored the release of phosphatidylcholine (PC) and cholesterol following trypsin digestion.
  • Assessed the correlation between ECD digestion, lipid release, and ABCA1 ATPase activity.
  • Compared lipid release in ABCA1-expressing cells versus ABCG1-expressing cells.

Main Results:

  • Trypsin treatment rapidly released PC and cholesterol from BHK/ABCA1 cells.
  • The kinetics of lipid release mirrored the digestion of ABCA1 ECDs and release of ECD fragments.
  • Lipid release was dependent on ABCA1 ATPase activity.
  • No significant lipid release was observed from ABCG1-expressing cells, which lack large ECDs.

Conclusions:

  • The large extracellular domains of ABCA1 serve as trypsin-sensitive sites involved in lipid transport.
  • Lipids transported by ABCA1 are temporarily sequestered within these ECDs during nascent HDL biogenesis.
  • This supports a model where ABCA1 ECDs play a direct role in mediating lipid transfer for HDL formation.

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