Deficiency in the Lipid Exporter ABCA1 Impairs Retrograde Sterol Movement and Disrupts Sterol Sensing at the Endoplasmic Reticulum.

Abstract

Cellular cholesterol homeostasis involves sterol sensing at the endoplasmic reticulum (ER) and sterol export from the plasma membrane (PM). Sterol sensing at the ER requires efficient sterol delivery from the PM; however, the macromolecules that facilitate retrograde sterol transport at the PM have not been identified. ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol and phospholipid export to apolipoprotein A-I for the assembly of high density lipoprotein (HDL). Mutations in ABCA1 cause Tangier disease, a familial HDL deficiency. Several lines of clinical and experimental evidence suggest a second function of ABCA1 in cellular cholesterol homeostasis in addition to mediating cholesterol efflux. Here, we report the unexpected finding that ABCA1 also plays a key role in facilitating retrograde sterol transport from the PM to the ER for sterol sensing. Deficiency in ABCA1 delays sterol esterification at the ER and activates the SREBP-2 cleavage pathway. The intrinsic ATPase activity in ABCA1 is required to facilitate retrograde sterol transport. ABCA1 deficiency causes alternation of PM composition and hampers a clathrin-independent endocytic activity that is required for ER sterol sensing. Our finding identifies ABCA1 as a key macromolecule facilitating bidirectional sterol movement at the PM and shows that ABCA1 controls retrograde sterol transport by modulating a certain clathrin-independent endocytic process.

• Authors: Yoshio Yamauchi, Noriyuki Iwamoto, Maximillian A Rogers, Sumiko Abe-Dohmae, Toyoshi Fujimoto, Catherine C Y Chang, Masato Ishigami, Takuma Kishimoto, Toshihide Kobayashi, Kazumitsu Ueda, Koichi Furukawa, Ta-Yuan Chang, Shinji Yokoyama
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 39 Pg. 23464-77 (Sep 25 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26198636 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• ABCA1 protein, mouse
• ATP Binding Cassette Transporter 1
• Srebf2 protein, mouse
• Sterol Regulatory Element Binding Protein 2
• Sterols

Topics

• ATP Binding Cassette Transporter 1 (metabolism)
• Animals
• Biological Transport
• Cells, Cultured
• Endoplasmic Reticulum (metabolism)
• Lipid Metabolism
• Mice
• Sterol Regulatory Element Binding Protein 2 (metabolism)
• Sterols (metabolism)