Oxidized low-density lipoprotein and peroxisome-proliferator-activated receptor α down-regulate platelet-activating-factor receptor expression in human macrophages

2001 ◽  
Vol 354 (1) ◽  
pp. 225-232 ◽  
Author(s):  
Delphine HOURTON ◽  
Philippe DELERIVE ◽  
Jana STANKOVA ◽  
Bart STAELS ◽  
M. John CHAPMAN ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Platelet Activating Factor ◽  
Density Lipoprotein ◽  
Receptor Expression ◽  
Peroxisome Proliferator ◽  
Low Density ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Mrna ◽  
Paf Receptor ◽  
Pparα Agonist

Regulation of the expression of platelet-activating factor (PAF) receptor by atherogenic lipoproteins might contribute to atherogenesis. We show that progressive oxidation of low-density lipoprotein (LDL) gradually inhibits PAF receptor expression on the macrophage cell surface. We tested the effect of oxidized LDL (oxLDL) on PAF receptor expression in human monocytes that do not contain peroxisome-proliferator-activated receptor γ (PPARγ), a nuclear receptor activated by oxLDL. OxLDL decreased by 50% (P ⩽0.001) and by 29% (P⩽0.05) the binding of PAF and the expression of PAF receptor mRNA respectively. Next we demonstrated that progressive oxidation of LDLs significantly activated PPARα-dependent transcription in transfected mouse aortic endothelial cells. Finally we demonstrated, in mature macrophages, that fenofibrate (20µM), a specific PPARα agonist, but not the specific PPARγ agonist BRL49653 (20nM), significantly decreased both PAF binding and PAF receptor mRNA expression, by 65% and 40% (P⩽0.001) respectively. Additionally, another PPARα agonist, Wy14,643, decreased PAF receptor promoter activity by 70% (P⩽0.05) in transfected THP-1 cells, suggesting the involvement of the proximal promoter region (-980 to -500) containing a series of four nuclear factor (NF)-κB motifs. Thus PPARα might be involved in the down-regulation of PAF receptor gene expression by oxLDLs in human monocytes/macrophages. The oxidation of one or more lipid components of LDLs might result in the formation of natural activators of PPARα. It is hypothesized that such activators might modulate inflammation and apoptosis upon atherogenesis by decreasing the expression of PAF receptor.

scholarly journals Endotoxin suppresses rat hepatic low-density lipoprotein receptor expression

1996 ◽  
Vol 313 (3) ◽  
pp. 873-878 ◽  
Author(s):  
Wei LIAO ◽  
Mats RUDLING ◽  
Bo ANGELIN
Keyword(s):  
Time Course ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Receptor Expression ◽  
Plasma Lipoproteins ◽  
Low Density ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Receptor Mrna

Endotoxin induces hyperlipidaemia in experimental animals. In the current study, we investigated whether endotoxin alters hepatic low-density lipoprotein (LDL) receptor expression in rats. Endotoxin treatment suppressed hepatic LDL receptor expression in a dose- and time-dependent manner. Eighteen hours after intraperitoneal injection of increasing amounts of endotoxin, LDL receptor and its mRNA levels were determined by ligand blot and solution hybridization respectively. LDL receptor expression was inhibited by about 70% at a dose of 500 μg/100 g body weight. However, LDL receptor mRNA levels were markedly increased in all endotoxin-treated groups at this time point (by 83–136%; P < 0.001). Time-course experiments showed that LDL receptor expression was already reduced by 48% 4 h after endotoxin injection and was maximally reduced (by 63–65%) between 8 and 18 h. Changes in hepatic LDL receptor mRNA showed a different pattern. By 4 h after endotoxin injection, LDL receptor mRNA had decreased by 78% (P < 0.001). However, by 8 h after endotoxin injection, LDL receptor mRNA had returned to levels similar to controls, and 18 and 24 h after endotoxin injection, they were increased by about 60% (P < 0.05). Separation of plasma lipoproteins by FPLC demonstrated that endotoxin-induced changes in plasma triacylglycerols and cholesterol were due to accumulation of plasma apolipoprotein B-containing lipoproteins among very-low-density lipoprotein, intermediate-density lipoprotein and LDL. It is concluded that endotoxin suppresses hepatic LDL receptor expression in vivo in rats.

scholarly journals Perfluorooctanoic Acid Induces Liver and Serum Dyslipidemia in Humanized PPARα Mice Fed an American Diet

2021 ◽  
Author(s):  
Jennifer J. Schlezinger ◽  
Tuulia Hyotylainen ◽  
Tim Sinioja ◽  
Catherine Boston ◽  
Hannah Puckett ◽  
...  
Keyword(s):  
Serum Concentration ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Perfluorooctanoic Acid ◽  
Null Point ◽  
Peroxisome Proliferator ◽  
Low Density ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Total Liver

Per- and polyfluoroalkyl substances (PFAS) are pervasive in the environment resulting in nearly universal detection in people. Human serum PFAS concentrations are strongly associated with increased serum low-density lipoprotein cholesterol (LDL-C), and growing evidence suggests an association with serum triacylglycerides (TG). Here, we tested the hypothesis that perfluorooctanoic acid (PFOA) dysregulates liver and serum triacylglycerides in human peroxisome proliferator activated receptor α (hPPAR α)-expressing mice fed an American diet. Mice were exposed to PFOA (3.3 mg/l) in drinking water for 6 weeks resulting in a serum concentration of 48 ± 9 μg/ml. In male and female hPPAR α mice, PFOA increased total liver TG and TG substituted with saturated and monounsaturated fatty acids. Lack of expression of hPPARα alone also increased total liver TG, and PFOA treatment had little effect on liver TG in null mice. In hPPARα mice, PFOA neither significantly increased nor decreased serum TG; however, there was a modest increase in TG associated with very low-density cholesterol particles in both sexes. Across studies, a non-monotonic effect of PFOA on serum TG is evident, with the serum PFOA concentration in this study falling near the null point between increasing and decreasing serum TG. Intriguingly, in female PPARα null mice, PFOA significantly increased serum TG, with a similar trend in males. PFOA also modified fatty acid and TG homeostasis-related gene expression in liver, in a hPPARα-dependent manner, but not in adipose. The results reveal the importance of context (serum concentration and genotype) in determining the effect of PFOA on lipid homeostasis.

scholarly journals Effect of Lutein in the expression of PPARα and LDLR in hypercholesterolemic male Wistar Rats

2018 ◽  
Vol 7 (4) ◽  
pp. 684 ◽  
Author(s):  
Soundarya Priyadharsini K. ◽  
Nirmala P. ◽  
Ashok Kumar P. ◽  
Krishna Prasad T.
Keyword(s):  
Wistar Rats ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Low Density ◽  
Peroxisome Proliferator Activated Receptor ◽  
Group I ◽  
Male Wistar Rats

Background: Hyperlipidemia is a well known risk factor for cardiovascular disease, especially atherosclerotic coronary artery disease. Peroxisome proliferator activated receptor α (PPARα), a member of this nuclear receptor family, has emerged as an important player in this scenario, with evidence supporting a central co-ordinated role in the regulation of fatty acid oxidation, lipid and lipoprotein metabolism and inflammatory and vascular responses, all of which would be predicted to reduce atherosclerotic risk. The low-density lipoprotein (LDL) receptor (LDLR) is the primary pathway for removal of cholesterol from the circulation, and its activity is meticulously governed by intracellular cholesterol levels. Hence in this study we investigated the effect of Lutein on PPARα and LDLR expression in liver of wistar rats.Methods: Male Wistar rats were divided into 6 groups of 6 each. Group I served as control. Group II III, IV, V and VI rats were received high cholesterol diet. Group III was treated with Atorvastatin 5mg/kg. Group IV, V and VI rats were treated with 25mg/kg, 50mg/kg and 100mg/kg of Lutein. After 16 weeks, liver tissue samples were collected from all the groups of animals to evaluate the expression of PPARα and LDLR.Results: The expression of Peroxisome proliferator activated receptor α and low-density lipoprotein (LDL) receptor (LDLR) was significantly increased in Lutein treated hypercholesterolemic male wistar rats.Conclusions: The results of this study indicate that Lutein activates LDL receptor and PPARα in hypercholesterolemic male wistar rats.

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