Toll-like receptor (TLR) signaling plays a fundamental role in the induction and progression of autoimmune disease. In the present study, we showed that lipopolysaccharide (LPS), a TLR4 ligand, functions as an antagonist of peroxisome proliferator-activated receptor alpha (PPARα), a nuclear transcription factor. Using endotoxin induced uveitis (EIU) as a model, we found that TLR was negatively regulated by PPARα. Our data revealed that treatment with the PPARα agonist fenofibrate dramatically prevented LPS-induced uveitis and inhibited TLR/ Nuclear factor-kappaB (NF-κB) signaling during inflammation. Evaluation of the severity of anterior uveitis further showed that PPARα agonist treatment significantly decreased inflammatory cell infiltration, total protein concentration, vessel density, inflammatory cytokine production, and clinical scores in the anterior section of the eye during EIU. Moreover, fenofibrate administration recovered retinal function and decreased the production of inflammatory cytokines, retinal vascular leukostasis, and inflammatory cell infiltration into the posterior section of the eyes during EIU. In vitro studies further showed that down-regulation or deletion of PPARα led to increased TLR4 levels and the activation of NF-κB signaling in RPE cells and also blocked the anti-inflammatory effects of fenofibrate. Furthermore, activation or up-regulation of PPARα decreased TLR4 levels and inhibited the NF-κB signaling pathway induced by LPS in RPE cells. In TLR4-expressing reporter cells, activation or up-regulation of PPARα partially inhibited the activation of NF-κB and also decreased TLR4 transcriptional activity. In conclusion, the activation of PPARα represents a novel therapeutic strategy for human uveitis, as PPARα negatively regulates TLR4 activity and therefore exerts anti-inflammatory actions.
This article is available online at http://www.jlr.org progression and increased severity of diabetic complications. The dysregulation of hepatic VLDL secretion is believed to be the mechanism underlying increases in TG-related VLDL and is responsible for the pathogenesis of hepatic insulin resistance in type 2 diabetes, representing a principal target for clinical intervention.Fenofi brate, a fi brate-derived drug, was widely used in the treatment of dyslipidemia in diabetic patients for decades prior to the use of statins ( 3, 4 ). Fibrate drugs reduce plasma TG-related VLDLs, raise plasma HDLs ( 5 ), and have a modest effect on LDL cholesterol levels ( 6 ). Fenofi brate acts as a specifi c agonist of PPAR ␣ , a nuclear hormone receptor that functions as a transcription factor and regulates the expression of a number of genes involved in lipid metabolism and insulin resistance. Fenofibrate has been reported to reduce the body weight gain upon high-fat diet (HFD) stimulation ( 7 ). PPAR ␣ lowers serum TG by infl uencing many genes involved in VLDL production, lipid traffi cking, and TG-rich lipoprotein clearance ( 8 ). For example, PPAR ␣ increases the expression of liver microsomal TG transfer protein (MTTP), a protein that mediates the lipidation of apoB100 to form a nascent VLDL ( 9 ); the expression of liver LPL, an enzyme that mediates the clearance of TG-rich VLDL and chylomicrons ( 10 ); and the synthesis of apoC-III ( 11 ), apoA-II ( 12 ), and apoA-V ( 13 ). However, the precise genes underlying the suppressive effect of PPAR ␣ agonists on hepatic VLDL metabolism currently are not well understood.The VLDL receptor (VLDLR), a member of the LDL receptor (LDLR) family, is widely expressed in the heart, skeletal muscles, adipose tissues, and macrophages ( 14, 15 ). However, its levels are barely detectable in the liver under normal conditions. VLDLR mediates the uptake of VLDL by peripheral tissues through LPL-dependent lipolysis or receptor-mediated endocytosis (16)(17)(18)(19), and thus Abstract The liver and the VLDL receptor (VLDLR) play major roles in TG and VLDL metabolism. However, the exact role of liver VLDLR is not well known because of the absence of or diffi culty in detecting VLDLR in the liver. In this study, we demonstrate that fenofi brate, a PPAR␣ agonist and widely used TG-lowering drug, markedly upregulated hepatic VLDLR, which is essential for lowering TG. This study also shows that the distinct regulatory roles of PPAR␣ agonists on VLDLR in the liver and peripheral tissues including adipose tissues, heart, and skeletal muscles are due to the pattern of expression of PPAR␣. The in vivo portion of our study demonstrated that oral fenofi brate robustly increased liver VLDLR expression levels in hyperlipidemic and diabetic mice and signifi cantly reduced the increase in serum TG observed in wt mice after feeding with high-fat diet (HFD) but not in Vldlr ؊ / ؊ mice or Ppar␣ Dyslipidemia is considered one of the major risk factors for the pathogenic progression of many diseases, including CVD...
These results confirmed the strong association between CTNND2 polymorphism and myopia. The minor allele C of rs6885224 was protective against myopia in this study but was a risk allele in a previous study.
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