MOUSE APOLIPOPROTEIN-J - CHARACTERIZATION OF A GENE IMPLICATED IN ATHEROSCLEROSIS

Apolipoprotein J (apoJ), a glycoprotein associated with subclasses of plasma high density lipoproteins (HDL), was found to accumulate in aor tic lesions in a human subject with transplantation-associated arterio sclerosis and in mice fed a high-fat atherogenic diet. Foam cells pres ent in mouse aortic valve lesions expressed apoJ mRNA, suggesting loca l synthesis contributes to apoJ's localization in atherosclerotic plaq ue. As a prerequisite for elucidating the physiological function of ap oJ by using a mouse model, cDNA clones representing the mouse homolog of apoJ were isolated, characterized, and sequenced. The nucleotide se quence predicts a 448 amino acid, 50,260 dalton protein. There was 81% nucleotide sequence similarity between mouse and human apoJ, and 75% similarity at the amino acid level. Mouse apoJ contains six potential N-glycosylation sites, a potential Arg-Ser cleavage sire to generate a lpha and beta subunits, a cluster of five cysteine residues in each su bunit, three putative amphipathic helices, and four potential heparin- binding domains. Southern blot analysis indicates that the gene encomp asses similar to 23 kb of DNA. Recombinant inbred strains were used to map apoJ to mouse chromosome 14, tightly linked to Mtv-11. All of the transcribed portions of the gene were cloned and analyzed, and all in tron-exon boundaries were defined. The first of the 9 exons is untrans lated. Single exons encode the signal peptide, the cysteine-rich domai n in the a subunit, two potential amphipathic helices Banking a hepari n-binding consensus sequence, and a potential amphipathic helix overla pping a heparin-binding domain, supporting their potential functional significance in apoJ. A variety of mouse tissues constitutively expres s a 1.9 kb apoJ mRNA, with apparently identical transcriptional start sites utilized in all tissues tested. ApoJ mRNA was most abundant in s tomach, liver, brain, and testis, with intermediate levels in heart, o vary, and kidney. The high degree of similarity between mouse and huma n apoJ, in structure and distribution of the gene product, gene struct ure, and deposition in atherosclerotic plaques, suggests that the mous e is an ideal model with which to elucidate the role of apoJ in HDL me tabolism and atherogenesis. - Jordan-Starck, T.C., S.D. Lund, D.P. Wit te, B.J. Aronow, C.A. Ley, W.D. Stuart, D.K. Swertfeger, L.R. Clayton, S.F. Sells, B. Paigen, and J.A.K. Harmony. Mouse apolipoprotein J: ch aracterization of a gene implicated in atherosclerosis.