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Amplified macropinocytosis of cholesteryl ester by macrophages from diabetic mice is dependent on PI3‐Kinase and stimulates the secretion of TNF‐α.
Author(s) -
Guest Christopher B.,
Hartman Mathew E,
O’Connor Jason C.,
Sovari Ali A.,
Freund Gregory G.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a485
Subject(s) - scavenger receptor , cd36 , cholesteryl ester , endocrinology , chemistry , medicine , foam cell , pinocytosis , abca1 , pharmacology , cholesterol , endocytosis , receptor , biochemistry , lipoprotein , transporter , gene
Type 2 diabetes mellitus (DM) is associated with accelerated atherosclerosis, which accounts for approximately 75% of all diabetes‐related deaths. Here we investigate the link between diabetes and macrophage cholesteryl ester (CE) uptake. When given CE intraperitoneally (IP), macrophages (PerMΦs) from diabetic ( db/db ) mice showed a 58% increase in cholesteryl ester uptake over PerMΦs from control ( db/+ ) mice. To model this we exposed RAW 264.7 cells (RAW) to diabetic glycemic and insulinemic conditions and induced a synergistic 50% increase in cholesteryl ester uptake. To examine the mechanism of uptake we looked at the classical scavenger receptors SR‐A and CD36. Interestingly, uptake of CE was independent of SR‐A, and CD36 as confirmed by antibody blocking and siRNA knockdown experiments in RAW cells. We inhibited either micropinocytosis with nystatin (NY) or macropinocytosis with cytochalsin D (CC) or wortmannin (WM). NY failed to decrease CE uptake in RAW cells. WM reduced CE uptake by 45% in both db/db PerMΦ and the RAW cell model of diabetes. In addition, CC decreased uptake in RAW cells in diabetic and non‐diabetic conditions, 51% and 35 % respectively. Interestingly, mice injected with CE secreted TNF‐α. Taken together this suggests a novel mechanism for two important harbingers of atherosclerosis‐ amplified CE uptake and CE dependent TNF‐α secretion.