Defective phagocytosis of apoptotic cells by macrophages in atherosclerotic lesions of ob/ob mice and reversal by a fish oil diet.
BACKGROUND
The complications of atherosclerosis are a major cause of death and disability in type 2 diabetes. Defective clearance of apoptotic cells by macrophages (efferocytosis) is thought to lead to increased necrotic core formation and inflammation in atherosclerotic lesions.


OBJECTIVE
To determine whether there is defective efferocytosis in a mouse model of obesity and atherosclerosis.


RESULTS
We quantified efferocytosis in peritoneal macrophages and in atherosclerotic lesions of obese ob/ob or ob/ob;Ldlr(-/-) mice and littermate controls. Peritoneal macrophages from ob/ob and ob/ob;Ldlr(-/-) mice showed impaired efferocytosis, reflecting defective phosphatidylinositol 3-kinase activation during uptake of apoptotic cells. Membrane lipid composition of ob/ob and ob/ob;Ldlr(-/-) macrophages showed an increased content of saturated fatty acids (FAs) and decreased omega-3 FAs (eicosapentaenoic acid and docosahexaenoic acid) compared to controls. A similar defect in efferocytosis was induced by treating control macrophages with saturated free FA/BSA complexes, whereas the defect in ob/ob macrophages was reversed by treatment with eicosapentaenoic acid/BSA or by feeding ob/ob mice a fish oil diet rich in omega-3 FAs. There was also defective macrophage efferocytosis in atherosclerotic lesions of ob/ob;Ldlr(-/-) mice and this was reversed by a fish oil-rich diet.


CONCLUSIONS
The findings suggest that in obesity and type 2 diabetes elevated levels of saturated FAs and/or decreased levels of omega-3 FAs contribute to decreased macrophage efferocytosis. Beneficial effects of fish oil diets in atherosclerotic cardiovascular disease may involve improvements in macrophage function related to reversal of defective efferocytosis and could be particularly important in type 2 diabetes and obesity.
Li
Suzhao
S
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA. sl2181@columbia.edu
Sun
Yu
Y
Liang
Chien-Ping
CP
Thorp
Edward B
EB
Han
Seongah
S
Jehle
Andreas W
AW
Saraswathi
Viswanathan
V
Pridgen
Brian
B
Kanter
Jenny E
JE
Li
Rong
R
Welch
Carrie L
CL
Hasty
Alyssa H
AH
Bornfeldt
Karin E
KE
Breslow
Jan L
JL
Tabas
Ira
I
Tall
Alan R
AR
D054392:Adipokines / Q000378:metabolism; D000821:Animal Feed; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D050197:Atherosclerosis / Q000178:diet therapy / Q000473:pathology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000178:diet therapy / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism; D005395:Fish Oils / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000502:physiology*; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000178:diet therapy* / Q000473:pathology*; D010587:Phagocytosis / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics
D054392:Adipokines; D005227:Fatty Acids; D015525:Fatty Acids, Omega-3; D005395:Fish Oils; D008563:Membrane Lipids; D011973:Receptors, LDL; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt