Perilipin 2 (PLIN2)-deficiency does not increase cholesterol-induced toxicity in macrophages

• Published in: PloS one 2012-03, Vol.7 (3), p.e33063
• Main Authors: Son, Se-Hee, Goo, Young-Hwa, Chang, Benny H, Paul, Antoni
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Apoptosis; Apoptosis - physiology; Arteriosclerosis; Atherosclerosis; Atherosclerosis - metabolism; Atherosclerosis - prevention & control; Azo Compounds; Biology; Blotting, Western; Bone marrow; Caspase; Caspase-3; Cell Culture Techniques; Cholesterol; Cholesterol, LDL - metabolism; Cholesterol, LDL - toxicity; Cytokines; Data processing; Deactivation; DNA Primers - genetics; Efflux; Endoplasmic reticulum; Endoplasmic Reticulum Stress - physiology; Enzymes; Esterification; Esters; Foam Cells - metabolism; Foams; Gene expression; Health aspects; In Situ Nick-End Labeling; Inactivation; Inflammation; Inflammatory diseases; Inhibition; Interleukin 6; Interleukin-6 - metabolism; Ketocholesterols - metabolism; Lipid metabolism; Lipids; Lipoproteins; Low density lipoproteins; Macrophages; Macrophages - metabolism; Medicine; Membrane Proteins - deficiency; Metabolites; Mice; Mice, Inbred C57BL; mRNA; Oxidative stress; Pathogenesis; Perilipin-2; Proteins; Residential density; Reverse Transcriptase Polymerase Chain Reaction; RNA; Rodents; Splicing; Stress; Toxicity; Tumor necrosis factor- alpha; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0033063

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.