title: Calpain-mediated ABCA1 degradation: post-translational regulation of ABCA1 for HDL biogenesis.
abstract: Helical apolipoproteins remove cellular phospholipid and cholesterol to generate nascent HDL and this reaction is the major source of plasma HDL. ABCA1 is mandatory and rate-limiting for this reaction. Besides regulation of the gene expression by transcriptional factors including LXR, AP2 and SREBP, the ABCA1 activity is regulated post-translationally by calpain-mediated proteolytic degradation of ABCA1 protein that occurs in the early endosome after its endocytosis. When the HDL biogenesis reaction is ongoing as helical apolipoproteins interact with ABCA1, ABCA1 becomes resistant to calpain and is recycled to cell surface after endocytosis. Biogenesis of HDL is most likely to take place on cell surface. Clearance rate of ABCA1 by this mechanism is also retarded by various factors that interact with ABCA1, such as α1-syntrophin, LXRβ and calmodulin. Physiological relevance of the retardation by these factors is not entirely clear. Pharmacological inhibition of the calpain-mediated ABCA1 degradation results in the increase of the ABCA1 activity and HDL biogenesis in vitro and in vivo, and potentially suppresses atherogenesis. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
authors.affiliation: Food and Nutritional Sciences, College of Bioscience and Biotechnology, Chubu University, Matsumoto-cho 1200, Kasugai 487-8501, Japan. syokoyam@med.nagoya-cu.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Reijiro
authors.initials: R
authors.lastname: Arakawa
authors.forename: Cheng-Ai
authors.initials: CA
authors.lastname: Wu
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Iwamoto
authors.forename: Rui
authors.initials: R
authors.lastname: Lu
authors.forename: Maki
authors.initials: M
authors.lastname: Tsujita
authors.forename: Sumiko
authors.initials: S
authors.lastname: Abe-Dohmae
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D050197:Atherosclerosis / Q000517:prevention & control; D041702:BALB 3T3 Cells; D002147:Calmodulin / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000201:enzymology / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000096:biosynthesis*; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis; D011809:Quinones / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002147:Calmodulin; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011809:Quinones; D051844:alpha-Synuclein; C001081:diphenoquinone; D002154:Calpain