Scavenger receptor expressed by endothelial cells I (SREC-I) mediates the uptake of acetylated low density lipoproteins by macrophages stimulated with lipopolysaccharide.
Scavenger receptor expressed by endothelial cells I (SREC-I) is a novel endocytic receptor for acetylated low density lipoprotein (LDL). Here we show that SREC-I is expressed in a wide variety of tissues, including macrophages and aortas. Lipopolysaccharide (LPS) robustly stimulated the expression of SREC-I in macrophages. In an initial attempt to clarify the role of SREC-I in the uptake of modified lipoproteins as well as in the development of atherosclerosis, we generated mice with a targeted disruption of the SREC-I gene by homologous recombination in embryonic stem cells. To exclude the overwhelming effect of the type A scavenger receptor (SR-A) on the uptake of Ac-LDL, we further generated mice lacking both SR-A and SREC-I (SR-A(-/-);SREC-I(-/-)) by cross-breeding and compared the uptake and degradation of Ac-LDL in the isolated macrophages. The contribution of SR-A and SREC-I to the overall degradation of Ac-LDL was 85 and 5%, respectively, in a non-stimulated condition. LPS increased the uptake and degradation of Ac-LDL by 1.8-fold. In this condition, the contribution of SR-A and SREC-I to the overall degradation of Ac-LDL was 90 and 6%, respectively. LPS increased the absolute contribution of SR-A and SREC-I by 1.9- and 2.3-fold, respectively. On the other hand, LPS decreased the absolute contribution of other pathways by 31%. Consistently, LPS did not increase the expression of other members of the scavenger receptor family such as CD36. In conclusion, SREC-I serves as a major endocytic receptor for Ac-LDL in LPS-stimulated macrophages lacking SR-A, suggesting that it has a key role in the development of atherosclerosis in concert with SR-A.
Tamura
Yoshiaki
Y
Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Osuga
Jun-ichi
J
Adachi
Hideki
H
Tozawa
Ryu-ichi
R
Takanezawa
Yasukazu
Y
Ohashi
Ken
K
Yahagi
Naoya
N
Sekiya
Motohiro
M
Okazaki
Hiroaki
H
Tomita
Sachiko
S
Iizuka
Yoko
Y
Koizumi
Hiroyuki
H
Inaba
Toshihiro
T
Yagyu
Hiroaki
H
Kamada
Nobuo
N
Suzuki
Hiroshi
H
Shimano
Hitoshi
H
Kadowaki
Takashi
T
Tsujimoto
Masafumi
M
Arai
Hiroyuki
H
Yamada
Nobuhiro
N
Ishibashi
Shun
S
D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001161:Arteriosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001693:Biological Transport, Active; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004705:Endocytosis; D015870:Gene Expression; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D014018:Tissue Distribution
D018955:CD36 Antigens; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; C032629:acetyl-LDL