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J Biol Chem, Vol. 273, Issue 18, 11218-11224, May 1, 1998

Immunolocalization of Acyl-Coenzyme A:Cholesterol O-Acyltransferase in Macrophages

Nadia KhelefDagger §, Xavier Buton, Nanda Beatini, Hongxing Wangparallel , Vardiella Meiner**Dagger Dagger , Ta-Yuan Chang§§, Robert V. Farese Jr.**, Frederick R. MaxfieldDagger , and Ira Tabas¶¶

From the Dagger  Department of Biochemistry, Cornell University Medical School, New York, New York 10021, the § Institut Pasteur, 75724 Paris Cedex 15, France, the Departments of  Medicine and ¶¶ Anatomy and Cell Biology, Columbia University, New York, New York 10032, the parallel  Department of Medicine, Mt. Sinai School of Medicine, New York, New York 10029, the ** Gladstone Foundation for Cardiovascular Research and University of California, San Francisco, California 94141, the Dagger Dagger  Department of Genetics, Hadassah University Hospital, Jerusalem 91120, Israel, and the §§ Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755

Macrophages in atherosclerotic lesions accumulate large amounts of cholesteryl-fatty acyl esters ("foam cell" formation) through the intracellular esterification of cholesterol by acyl-coenzyme A:cholesterol O-acyltransferase (ACAT). In this study, we sought to determine the subcellular localization of ACAT in macrophages. Using mouse peritoneal macrophages and immunofluorescence microscopy, we found that a major portion of ACAT was in a dense reticular cytoplasmic network and in the nuclear membrane that colocalized with the luminal endoplasmic reticulum marker protein-disulfide isomerase (PDI) and that was in a similar distribution as the membrane-bound endoplasmic reticulum marker ribophorin. Remarkably, another portion of the macrophage ACAT pattern did not overlap with PDI or ribophorin, but was found in as yet unidentified cytoplasmic structures that were juxtaposed to the nucleus. Compartments containing labeled beta -very low density lipoprotein, an atherogenic lipoprotein, did not overlap with the ACAT label, but rather were embedded in the dense reticular network of ACAT. Furthermore, cell-surface biotinylation experiments revealed that freshly harvested, non-attached macrophages, but not those attached to tissue culture dishes, contained ~10-15% of ACAT on the cell surface. In summary, ACAT was found in several sites in macrophages: a cytoplasmic reticular/nuclear membrane site that overlaps with PDI and ribophorin and has the characteristics of the endoplasmic reticulum, a perinuclear cytoplasmic site that does not overlap with PDI or ribophorin and may be another cytoplasmic structure or possibly a unique subcompartment of the endoplasmic reticulum, and a cell-surface site in non-attached macrophages. Understanding possible physiological differences of ACAT in these locations may reveal an important component of ACAT regulation and macrophage foam cell formation.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.


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