PMID- 27807703 OWN - NLM STAT- MEDLINE DCOM- 20170515 LR - 20181202 IS - 1432-0878 (Electronic) IS - 0302-766X (Linking) VI - 368 IP - 1 DP - 2017 Apr TI - The critical role of ABCG1 and PPARgamma/LXRalpha signaling in TLR4 mediates inflammatory responses and lipid accumulation in vascular smooth muscle cells. PG - 145-157 LID - 10.1007/s00441-016-2518-3 [doi] AB - 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 mug/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 (PPARgamma), liver X receptor alpha (LXRalpha) and ABCG1 was inhibited by TLR4 activation. However, these effects could be reversed by knocking out TLR4. PPARgamma activation by rosiglitazone rescued LXRalpha and ABCG1 expression and reduced TLR4-induced inflammation and lipid accumulation. Silencing PPARgamma expression with a specific small interfering RNA (siRNA) inhibited LXRalpha 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 PPARgamma/LXRalpha signaling. These findings indicate a novel molecular mechanism underlying TLR4-induced inflammation and lipid accumulation. FAU - Cao, Xiaojie AU - Cao X AD - 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. AD - Department of Neurology, Chengdu Military General Hospital, Chengdu, People's Republic of China. FAU - Zhang, Lili AU - Zhang L AD - 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. FAU - Chen, Chunhai AU - Chen C AD - 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. FAU - Wang, Qingsong AU - Wang Q AD - Department of Neurology, Chengdu Military General Hospital, Chengdu, People's Republic of China. FAU - Guo, Lu AU - Guo L AD - 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. FAU - Ma, Qinlong AU - Ma Q AD - 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. FAU - Deng, Ping AU - Deng P AD - 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. FAU - Zhu, Gang AU - Zhu G AD - 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. FAU - Li, Binghu AU - Li B AD - 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. FAU - Pi, Yan AU - Pi Y AD - 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. FAU - Long, Chunyan AU - Long C AD - 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. FAU - Zhang, Lei AU - Zhang L AD - 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. FAU - Yu, Zhengping AU - Yu Z AD - 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. FAU - Zhou, Zhou AU - Zhou Z AD - 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. FAU - Li, Jingcheng AU - Li J AD - 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. LA - eng PT - Journal Article DEP - 20161102 PL - Germany TA - Cell Tissue Res JT - Cell and tissue research JID - 0417625 RN - 0 (ABCG1 protein, mouse) RN - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 1) RN - 0 (Lipoproteins, LDL) RN - 0 (Liver X Receptors) RN - 0 (PPAR gamma) RN - 0 (Thiazolidinediones) RN - 0 (Toll-Like Receptor 4) RN - 0 (oxidized low density lipoprotein) RN - 05V02F2KDG (Rosiglitazone) SB - IM MH - ATP Binding Cassette Transporter, Subfamily G, Member 1/*metabolism MH - Animals MH - Down-Regulation/drug effects MH - Gene Silencing/drug effects MH - Inflammation/*pathology MH - *Lipid Metabolism/drug effects MH - Lipoproteins, LDL/pharmacology MH - Liver X Receptors/*metabolism MH - Mice, Knockout MH - Models, Biological MH - Muscle, Smooth, Vascular/pathology MH - Myocytes, Smooth Muscle/drug effects/*metabolism/*pathology MH - PPAR gamma/*metabolism MH - Rosiglitazone MH - Signal Transduction/drug effects MH - Thiazolidinediones/pharmacology MH - Toll-Like Receptor 4/deficiency/*metabolism OTO - NOTNLM OT - ATP-binding cassette transporter G1 OT - Lipid accumulation OT - Peroxisome proliferator-activated receptor gamma OT - Toll-like receptor 4 OT - Vascular smooth muscle cells EDAT- 2016/11/04 06:00 MHDA- 2017/05/16 06:00 CRDT- 2016/11/04 06:00 PHST- 2016/04/05 00:00 [received] PHST- 2016/09/27 00:00 [accepted] PHST- 2016/11/04 06:00 [pubmed] PHST- 2017/05/16 06:00 [medline] PHST- 2016/11/04 06:00 [entrez] AID - 10.1007/s00441-016-2518-3 [pii] AID - 10.1007/s00441-016-2518-3 [doi] PST - ppublish SO - Cell Tissue Res. 2017 Apr;368(1):145-157. doi: 10.1007/s00441-016-2518-3. Epub 2016 Nov 2.