title: 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.affiliation: From the Department of Biochemistry II, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, yyoshio@med.nagoya-u.ac.jp.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamauchi
authors.affiliation: the Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Iwamoto
authors.affiliation: the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755.
authors.forename: Maximillian A
authors.initials: MA
authors.lastname: Rogers
authors.affiliation: the Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Abe-Dohmae
authors.affiliation: the Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Fujimoto
authors.affiliation: the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755.
authors.forename: Catherine C Y
authors.initials: CC
authors.lastname: Chang
authors.affiliation: the Institute for Integrated Cell-Material Sciences and Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Ishigami
authors.affiliation: the Lipid Biology Laboratory, RIKEN, Wako, Saitama 351-0198, Japan, and.
authors.forename: Takuma
authors.initials: T
authors.lastname: Kishimoto
authors.affiliation: the Lipid Biology Laboratory, RIKEN, Wako, Saitama 351-0198, Japan, and.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: the Institute for Integrated Cell-Material Sciences and Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Ueda
authors.affiliation: From the Department of Biochemistry II, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Furukawa
authors.affiliation: the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, Ta.Yuan.Chang@Dartmouth.edu.
authors.forename: Ta-Yuan
authors.initials: TY
authors.lastname: Chang
authors.affiliation: the Nutritional Health Science Research Center and Department of Food and Nutritional Sciences, Chubu University, Kasugai 487-8501, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Yokoyama
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D013261:Sterols / Q000378:metabolism*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols; C577833:Abca1 protein, mouse; C497391:Srebf2 protein, mouse
keywords: ABC transporter; abca1; cholesterol; cholesterol regulation; endocytosis; lipid trafficking; lipid transport