title: Perilipin 2 (PLIN2)-deficiency does not increase cholesterol-induced toxicity in macrophages.
abstract: Interventions on macrophages/foam cells to redirect intracellular cholesterol towards efflux pathways could become a very valuable addition to our therapeutic arsenal against atherosclerosis. However, certain manipulations of the cholesteryl ester cycle, such as the inhibition of ACAT1, an ER-resident enzyme that re-esterifies cholesterol, are not well tolerated. Previously we showed that targeting perilipin-2 (PLIN2), a major lipid droplet (LD)-associated protein in macrophages, prevents foam cell formation and protects against atherosclerosis. Here we have assessed the tolerance of PLIN2-deficient bone marrow derived macrophages (BMM) to several lipid loading conditions similar to the found during atherosclerosis development, including exposure to modified low-density lipoprotein (mLDL) and 7-ketocholesterol (7-KC), a free cholesterol (FC) metabolite, in media with or without cholesterol acceptors. BMM isolated from mice that do or do not express PLIN2 were tested for apoptosis (TUNEL and cleaved caspase-3), ER stress (CHOP induction and XBP-1 splicing), and inflammation (TNF-α and IL-6 mRNA levels). Like in other cell types, PLIN2 deficiency impairs LD buildup in BMM. However, while most stress parameters were elevated in macrophages under ACAT inhibition and 7-KC loading, PLIN2 inactivation was well tolerated. The data support the safety of targeting PLIN2 to prevent foam cell formation and atherosclerosis.
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, United States of America.
authors.forename: Se-Hee
authors.initials: SH
authors.lastname: Son
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Goo
authors.forename: Benny H
authors.initials: BH
authors.lastname: Chang
authors.forename: Antoni
authors.initials: A
authors.lastname: Paul
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D050197:Atherosclerosis / Q000378:metabolism* / Q000517:prevention & control; D001391:Azo Compounds; D015153:Blotting, Western; D018929:Cell Culture Techniques; D008078:Cholesterol, LDL / Q000378:metabolism* / Q000633:toxicity; D017931:DNA Primers / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D005487:Foam Cells / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000378:metabolism; D007653:Ketocholesterols / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D000070780:Perilipin-2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001391:Azo Compounds; D008078:Cholesterol, LDL; D017931:DNA Primers; D015850:Interleukin-6; D007653:Ketocholesterols; D008565:Membrane Proteins; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C011049:oil red O; C003001:7-ketocholesterol