title: Akt inhibition promotes ABCA1-mediated cholesterol efflux to ApoA-I through suppressing mTORC1.
abstract: ATP-binding cassette transporter A1 (ABCA1) plays an essential role in mediating cholesterol efflux to apolipoprotein A-I (apoA-I), a major housekeeping mechanism for cellular cholesterol homeostasis. After initial engagement with ABCA1, apoA-I directly interacts with the plasma membrane to acquire cholesterol. This apoA-I lipidation process is also known to require cellular signaling processes, presumably to support cholesterol trafficking to the plasma membrane. We report here that one of major signaling pathways in mammalian cells, Akt, is also involved. In several cell models that express ABCA1 including macrophages, pancreatic beta cells and hepatocytes, inhibition of Akt increases cholesterol efflux to apoA-I. Importantly, Akt inhibition has little effect on cells expressing non-functional mutant of ABCA1, implicating a specific role of Akt in ABCA1 function. Furthermore, we provide evidence that mTORC1, a major downstream target of Akt, is also a negative regulator of cholesterol efflux. In cells where mTORC1 is constitutively activated due to tuberous sclerosis complex 2 deletion, cholesterol efflux to apoA-I is no longer sensitive to Akt activity. This suggests that Akt suppresses cholesterol efflux through mTORC1 activation. Indeed, inhibition of mTORC1 by rapamycin or Torin-1 promotes cholesterol efflux. On the other hand, autophagy, one of the major pathways of cholesterol trafficking, is increased upon Akt inhibition. Furthermore, Akt inhibition disrupts lipid rafts, which is known to promote cholesterol efflux to apoA-I. We therefore conclude that Akt, through its downstream targets, mTORC1 and hence autophagy, negatively regulates cholesterol efflux to apoA-I.
authors.affiliation: Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Fumin
authors.initials: F
authors.lastname: Dong
authors.affiliation: Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Zhongcheng
authors.initials: Z
authors.lastname: Mo
authors.affiliation: Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Walaa
authors.initials: W
authors.lastname: Eid
authors.affiliation: Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Courtney
authors.affiliation: Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zha
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D001693:Biological Transport, Active / Q000235:genetics; D002460:Cell Line; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D002784:Cholesterol; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C577836:ABCA1 protein, human; C577833:Abca1 protein, mouse