The critical role of ABCG1 and PPARγ/LXRα signaling in TLR4 mediates inflammatory responses and lipid accumulation in vascular smooth muscle cells.
Toll-like receptor 4 (TLR4) plays critical roles in vascular inflammation, lipid accumulation and atherosclerosis development. However, the mechanisms underlying these processes are still not well established, especially in vascular smooth muscle cells (VSMCs). ATP-binding cassette transporter G1 (ABCG1) is one of the key genes mediating inflammation and cellular lipid accumulation. The function of TLR4 in regulating the expression of ABCG1 and the underlying molecular mechanisms remain to be elucidated. In this study, we cultured VSMCs from the thoracic aortas of mice and treated the cells with 50 μg/ml oxidized low-density lipoprotein (oxLDL) to activate TLR4 signaling. We observed that activating TLR4 with oxLDL induced inflammatory responses and lipid accumulation in VSMCs. The expression of peroxisome proliferator-activated receptor gamma (PPARγ), liver X receptor alpha (LXRα) and ABCG1 was inhibited by TLR4 activation. However, these effects could be reversed by knocking out TLR4. PPARγ activation by rosiglitazone rescued LXRα and ABCG1 expression and reduced TLR4-induced inflammation and lipid accumulation. Silencing PPARγ expression with a specific small interfering RNA (siRNA) inhibited LXRα and ABCG1 expression and, importantly, enhanced TLR4-induced inflammation and lipid accumulation. In conclusion, ABCG1 expression was down-regulated by TLR4, which induces inflammation and lipid accumulation in VSMCs via PPARγ/LXRα signaling. These findings indicate a novel molecular mechanism underlying TLR4-induced inflammation and lipid accumulation.
Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, NO.10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People's Republic of China.|Department of Neurology, Chengdu Military General Hospital, Chengdu, People's Republic of China.
Xiaojie
X
Cao
Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, NO.10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People's Republic of China.
Lili
L
Zhang
Department of Occupational Health, Faculty of Preventive Medicine, Third Military Medical University, NO.30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
Chunhai
C
Chen
Department of Neurology, Chengdu Military General Hospital, Chengdu, People's Republic of China.
Qingsong
Q
Wang
Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, NO.10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People's Republic of China.
Lu
L
Guo
Department of Occupational Health, Faculty of Preventive Medicine, Third Military Medical University, NO.30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
Qinlong
Q
Ma
Department of Occupational Health, Faculty of Preventive Medicine, Third Military Medical University, NO.30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
Ping
P
Deng
Department of Occupational Health, Faculty of Preventive Medicine, Third Military Medical University, NO.30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
Gang
G
Zhu
Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, NO.10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People's Republic of China.
Binghu
B
Li
Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, NO.10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People's Republic of China.
Yan
Y
Pi
Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, NO.10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People's Republic of China.
Chunyan
C
Long
Department of Occupational Health, Faculty of Preventive Medicine, Third Military Medical University, NO.30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
Lei
L
Zhang
Department of Occupational Health, Faculty of Preventive Medicine, Third Military Medical University, NO.30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
Zhengping
Z
Yu
Department of Occupational Health, Faculty of Preventive Medicine, Third Military Medical University, NO.30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People's Republic of China. lunazhou00@163.com.
Zhou
Z
Zhou
Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, NO.10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People's Republic of China. lijingcheng11@aliyun.com.
Jingcheng
J
Li
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D007249:Inflammation / Q000473:pathology*; D050356:Lipid Metabolism / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000494:pharmacology; D000071518:Liver X Receptors / Q000378:metabolism*; D018345:Mice, Knockout; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D047495:PPAR gamma / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000378:metabolism*
C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D047495:PPAR gamma; D045162:Thiazolidinediones; D051197:Toll-Like Receptor 4; C099252:oxidized low density lipoprotein; D000077154:Rosiglitazone
ATP-binding cassette transporter G1; Lipid accumulation; Peroxisome proliferator-activated receptor gamma; Toll-like receptor 4; Vascular smooth muscle cells