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Journal of Lipid Research, Vol. 47, 107-114, January 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Janus kinase 2 modulates the lipid-removing but not protein-stabilizing interactions of amphipathic helices with ABCA1

Chongren Tang^*, Ashley M. Vaughan^*, G. M. Anantharamaiah and John F. Oram^1,*

^* Division of Metabolism, Endocrinology, and Nutrition, University of Alabama at Birmingham Medical Center, Birmingham, AL 35294
Department of Medicine, University of Washington, Seattle, WA 98195, Department of Medicine, Biochemistry, and Molecular Genetics and Atherosclerotic Research Unit, University of Alabama at Birmingham Medical Center, Birmingham, AL 35294

Published, JLR Papers in Press, October 6, 2005.

¹ To whom correspondence should be addressed. e-mail: joram{at}u.washington.edu

ABCA1 mediates the transport of cellular cholesterol and phospholipids to HDL apolipoproteins. Apolipoprotein A-I (apoA-I) interactions with ABCA1-expressing cells elicit several responses, including removing cellular lipids, stabilizing ABCA1 protein, and activating Janus kinase 2 (JAK2). Here, we used synthetic apolipoprotein-mimetic peptides to characterize the relationship between these responses. Peptides containing one amphipathic helix of L- or D-amino acids (2F, D-2F, or 4F) and a peptide containing two helices (37pA) all promoted ABCA1-dependent cholesterol efflux, competed for apoA-I binding to ABCA1-expressing cells, blocked covalent cross-linking of apoA-I to ABCA1, and inhibited ABCA1 degradation. 37pA was cross-linked to ABCA1, confirming the direct binding of amphipathic helices to ABCA1. 2F, 4F, 37pA, and D-37pA all stimulated JAK2 autophosphorylation. Inhibition of JAK2 greatly reduced peptide-mediated cholesterol efflux, peptide binding to ABCA1-expressing cells, and peptide cross-linking to ABCA1, indicating that these processes require an active JAK2. In contrast, apoA-I and peptides stabilized ABCA1 protein even in the absence of an active JAK2, implying that this process is independent of JAK2 and lipid efflux-promoting binding of amphipathic helices to ABCA1. These findings show that amphipathic helices coordinate the activity of ABCA1 by several distinct mechanisms that are likely to involve different cell surface binding sites.

Supplementary key words ATP binding cassette transporter A1 • cholesterol efflux • atherosclerosis • HDL

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