Fatty acids modulate the effect of darglitazone on macrophage CD36 expression.
BACKGROUND
Scavenger receptor-mediated uptake of cholesterol by macrophages in the arterial wall is believed to be proatherogenic. Thiazolidinediones are peroxisome proliferator-activated receptor gamma (PPARgamma)-agonists, which are used in the treatment of type II diabetes. They reduce atherogenesis in LDL receptor deficient and ApoE knockout mice, but up-regulate CD36, which may contribute to foam cell formation. The dyslipidaemia in type II diabetes is characterized by high levels of nonesterified fatty acids. Therefore we tested the effect of fatty acids and how fatty acids and the thiazolidinedione darglitazone interact in their effect on CD36 expression in human monocytes and macrophages.


METHODS
Flow cytometry and reverse transcription-polymerase chain reaction were used to study CD36 expression. Cellular lipids were analyzed with high performance liquid chromatography.


RESULTS
Darglitazone increased CD36 mRNA and protein expression in human macrophage cells. In the presence of 5% human serum, darglitazone increased the accumulation of triglycerides, but did not affect cholesterol ester levels. In the presence of albumin-bound oleic or linoleic acid, darglitazone did not increase CD36 mRNA, cell-surface CD36 protein or triglyceride content. Fatty acids per se increased CD36 mRNA and protein.


CONCLUSIONS
The increase in CD36 in macrophages suggests a role for fatty acids in the regulation of foam cell formation. The results also suggest that the potentially proatherogenic CD36 up-regulating effect of thiazolidinediones in macrophages might not be present when the cells have access to physiological levels of albumin-bound fatty acids.
Svensson
L
L
The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. Linda.Svensson@wlab.gu.se
Camejo
G
G
Cabré
A
A
Vallvé
J-C
JC
Pedreño
J
J
Norén
K
K
Wiklund
O
O
Hultén
L M
LM
D001161:Arteriosclerosis / Q000188:drug therapy / Q000209:etiology; D018955:CD36 Antigens / Q000187:drug effects / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
D018955:CD36 Antigens; D005227:Fatty Acids; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D013844:Thiazoles; D045162:Thiazolidinediones; C089948:darglitazone