The critical role of ABCG1 and PPAR gamma/LXR alpha signaling in TLR4 mediates inflammatory responses and lipid accumulation in vascular smooth muscle cells

摘要

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 mu g/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 (PPAR gamma), liver X receptor alpha (LXR alpha) and ABCG1 was inhibited by TLR4 activation. However, these effects could be reversed by knocking out TLR4. PPAR gamma activation by rosiglitazone rescued LXR alpha and ABCG1 expression and reduced TLR4-induced inflammation and lipid accumulation. Silencing PPAR gamma expression with a specific small interfering RNA (siRNA) inhibited LXR alpha 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 PPAR gamma/LXR alpha signaling. These findings indicate a novel molecular mechanism underlying TLR4-induced inflammation and lipid accumulation.