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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.
Highlights
Little is known about how mammalian cells modulate retrograde sterol transport for cellular cholesterol homeostasis
ATP-binding cassette transporter A1 (ABCA1) Deficiency Leads to Hyperactivation of sterol regulatory element-binding protein-2 (SREBP-2) Pathway—We hypothesize that ABCA1 may have an additional role in cholesterol homeostasis that does not require extracellular cholesterol acceptors
We determined cholesterol release to serum-free medium, after cells were labeled with [3H]cholesterol and its distribution in cells reached steady state. The result of this experiment showed that in both WT and Abca1Ϫ/Ϫ cells, cholesterol release to serum-free medium in 6 h was at a minimal level (0.85 Ϯ 0.02 and 0.93 Ϯ 0.11%, respectively). These results suggest that ABCA1 may play an undisclosed role in cellular cholesterol homeostasis, independent of extracellular sterol acceptors
Summary
Little is known about how mammalian cells modulate retrograde sterol transport for cellular cholesterol homeostasis. The sterol removal is regulated by cholesterol release from the PM mainly to high density lipoprotein (HDL) It involves the ATP-binding cassette transporters, ABCA1 and ABCG1 [3]; ABCA1 plays a predominant role in cholesterol efflux [5]. In a mouse model of hypoxic advanced atherosclerotic plaques, ABCA1 expression and cell cholesterol release are decreased, but HMG-CoA reductase (HMGR) expression and sterol synthesis are increased, resulting in the accumulation of free sterol in macrophages [13]. These puzzling observations cannot be satisfactorily explained by the assumption that ABCA1 functions only in cellular sterol release, suggesting that ABCA1 may have additional functions. Novel function of ABCA1 in regulation of cellular cholesterol homeostasis
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