calpain and diphenoquinone

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).

Topics: alpha-Synuclein; Animals; Aorta; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; BALB 3T3 Cells; Calmodulin; Calpain; Endocytosis; Endosomes; Lipoproteins, HDL; Liver X Receptors; Mice; Orphan Nuclear Receptors; Protein Processing, Post-Translational; Protein Transport; Proteolysis; Quinones; Rabbits

Expression of ABCA1 is regulated by transcription of the gene and calpain-mediated proteolytic degradation, and inhibition ABCA1 degradation results in increased ABCA1 and HDL biogenesis in vitro. We examined whether this approach could be a potential antiatherogenic treatment. Although probucol inhibits both the activity and degradation of ABCA1, its oxidized products, spiroquinone and diphenoquinone, reduce degradation of ABCA1 without inhibiting its activity or altering transcription of the ABCA1 gene. Accordingly, both compounds enhanced apolipoprotein A-I/ABCA1-dependent generation of HDL in vitro, and increased hepatic ABCA1 and plasma HDL without increasing antioxidant activity in plasma when given to rabbits. Both compounds also decreased vascular lipid deposition in cholesterol-fed rabbits. We therefore conclude that stabilization of ABCA1 against calpain-mediated degradation is a novel and potentially important strategy to increase HDL formation and prevent atherosclerosis. Spiroquinone and diphenoquinone are potential seeds for development of such drugs.

Topics: Animals; Anticholesteremic Agents; Antioxidants; Apolipoprotein A-I; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; BALB 3T3 Cells; Blotting, Western; Calpain; Cell Line; Cholesterol, HDL; Green Fluorescent Proteins; Humans; Lipoproteins, HDL; Macrophages; Male; Mice; Microscopy, Confocal; Probucol; Quinones; Rabbits; Reverse Transcriptase Polymerase Chain Reaction; Transfection