Adult ; Case-Control Studies ; Fatty Liver ; genetics ; metabolism ; Female ; Genotype ; Humans ; Male ; Middle Aged ; PPAR alpha ; genetics ; Polymorphism, Genetic

OBJECTIVETo study the effect of peroxisome proliferators activated receptors (PPAR) alpha, gamma ligand on ATP-binding cassette transporter A1 (ABCA1) and caveolin-1 expressions and cholesterol, ox-LDL contents in human monocyte derived foam cells.

METHODMalondialdehyde (MDA) was measured by TBARS method, ox-LDL detected by ELISA method, cholesterol measured by fluorescence spectrophotometric method, ABCA1, caveolin-1 mRNA and protein expressions determined by RT-PCR and Western blot, in human monocytes, foam cells [human monocyte-derived macrophage induced by myristate acetate (PMA) further treated with 50 mg/L ox-LDL for 24 h], foam cells plus 10 micromol/L pioglitazone for 48 h, foam cells plus 5 micromol/L clofibrate for 48 h.

RESULTThe intracellular total cholesterol (TC), free cholesterol (FC), cholesteryl ester (CE), ox-LDL and lipid peroxide were significantly increased and the membrane expressions of ABCA1, caveolin-1 were down-regulated in foam cells compared to monocytes (all P < 0.05) and these changes were significantly attenuated by cotreatment with PPARalpha, gamma ligand.

CONCLUSIONThe anti-atherosclerosis effects of PPARalpha, gamma ligand are related to reducing cholesterol contents and up-regulating ABCA1, caveolin-1 expressions in foam cells.

ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; metabolism ; Caveolin 1 ; metabolism ; Cell Line ; Cholesterol ; genetics ; metabolism ; Foam Cells ; metabolism ; Gene Expression ; Humans ; Malondialdehyde ; metabolism ; Monocytes ; metabolism ; PPAR alpha ; metabolism ; PPAR gamma ; metabolism

BACKGROUNDThe chronic pathological changes in vascular walls of hypertension may exert destructive effects on multiple organ systems. Accumulating evidence indicates that inflammatory reactions are involved in the pathological changes of hypertension. Three peroxisome proliferator-activated receptors (PPARs) have been identified: PPARalpha, PPARbeta/delta, and PPARgamma, all of which have multiple biological effects, especially the inhibition of inflammation. The aim of this study was to evaluate PPAR isoforms expression profile in important organs of spontaneously hypertensive rats (SHR) and to understand the modulation of endogenous PPAR isoforms under inflammatory condition.

METHODSTissues (kidney, liver, heart, and brain) were dissected from SHR and age-matched control Wistar-Kyoto rats (WKY) to investigate the abundance of PPAR isoforms and PPAR-responsive genes (acyl-CoA oxidase and CD36). The expression of CCAAT/enhancer-binding protein delta (C/EBPdelta), which can trans-activate PPARgamma expression, was also observed. The inflammatory response was analyzed by the expression of inflammatory mediators inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, interleukin-1 beta (IL-1beta), and tumor necrosis factor alpha (TNFalpha), and formation of carbonyl and nitrated proteins.

RESULTSThe expressions of 3 PPAR isoforms and PPAR-responsive genes were markedly upregulated in SHR compared with those of WKY. Specifically, the expression of PPARalpha protein in the kidney, liver, heart and brain increased by 130.76%, 91.48%, 306.24%, and 90.70%; PPARbeta/delta upregulated by 109.34%, 161.98%, 137.04%, and 131.66%; PPARgamma increased by 393.76%, 193.17%, 559.29%, and 591.18%. In consistent with the changes in PPARgamma, the expression of C/EBPdelta was also dramatically elevated in SHR. Inflammatory mediators expressions were significantly increased in the most organs of SHR than WKY. As a consequence, increased formation of carbonyl and nitrated proteins were also observed in the most organs of SHR.

CONCLUSIONSThese findings suggest an enhanced inflammatory response in the organs of SHR, which might play a key role in pathogenesis of hypertension and secondary organ complications. Changes (increases) in PPARs expression may reflect a compensatory mechanism to the inflammatory status of hypertensive rats.

Animals ; Blood Pressure ; Blotting, Western ; E-Selectin ; genetics ; metabolism ; Gene Expression ; Hypertension ; genetics ; metabolism ; physiopathology ; Inflammation ; genetics ; metabolism ; physiopathology ; Interleukin-1beta ; genetics ; metabolism ; Male ; PPAR alpha ; genetics ; metabolism ; PPAR delta ; genetics ; metabolism ; PPAR gamma ; genetics ; metabolism ; Peroxisome Proliferator-Activated Receptors ; genetics ; metabolism ; Plethysmography ; methods ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Necrosis Factor-alpha ; genetics ; metabolism ; Vascular Cell Adhesion Molecule-1 ; genetics ; metabolism

The plasticizer di(2-ethylhexyl) phthalate (DEHP) has been widely used in the manufacture of polyvinyl chloride-containing products such as medical and consumer goods. Humans can easily be exposed to it because DEHP is ubiquitous in the environment. Recent research on the adverse effects of DEHP has focused on reproductive and developmental toxicity in rodents and/or humans. DEHP is a representative of the peroxisome proliferators. Therefore, peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways are the expected mode of action of several kinds of DEHP-induced toxicities. In this review, we summarize DEHP kinetics and its mechanisms of carcinogenicity and reproductive and developmental toxicity in relation to PPARα. Additionally, we give an overview of the impacts of science policy on exposure sources.
Animals ; Diethylhexyl Phthalate ; toxicity ; Environmental Pollutants ; toxicity ; Haplorhini ; Humans ; Mice ; PPAR alpha ; genetics ; metabolism ; Plasticizers ; toxicity ; Rats

PURPOSE: Obesity is a risk factor for asthma and type II diabetes. Peroxisome proliferator-activated receptor (PPAR)-gamma has been suggested to regulate inflammatory responses in diabetes and asthma. We investigated whether PPAR-alpha, PPAR-gamma, adiponectin receptors (AdipoR1, AdipoR2), leptin, and tumor necrosis factor (TNF)-alpha are expressed in rat lung tissues and whether the expression differs between obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long Evans Tokushima Otsuka (LETO) rats. MATERIALS AND METHODS: Obese and lean rats were given with a high fat diet or a 30% restricted diet for 32 weeks, and their blood glucose levels and weights were monitored. After 32 weeks, mRNA levels of PPAR-alpha, PPAR-gamma, AdipoR1, AdipoR2, leptin, and TNF-alpha in lung tissues were measured using real time PCR. RESULTS: PPAR-alpha, PPAR-gamma, AdipoR1, AdipoR2, leptin, and TNF-alpha were expressed in both obese and lean rat lung tissues. Increased serum glucose levels on intraperitoneal glucose tolerance testing and a higher weight gain at 32 weeks were observed in OLETF control rats compared to OLETF diet restricted rats. PPAR-gamma expression was markedly elevated in obese control and diet restricted rats compared to lean rats, although PPAR-gamma expression in obese rats was not affected by diet restriction. Leptin was highly expressed in OLETF rats compared to LETO rats. TNF-alpha expression was enhanced in OLETF control rats compared LETO diet restricted rats, and decreased by diet restriction. PPAR-alpha, AdipoR1, and AdipoR2 expression were not significantly different between obese and lean rats. CONCLUSION: PPAR-gamma was highly expressed in the lung tissues of obese rats and may be a novel treatment target for regulating lung inflammation associated with obesity.
Animals ; Body Weight ; Glucose Tolerance Test ; Leptin/genetics/metabolism ; Lung/*metabolism ; Male ; Obesity/genetics/*metabolism ; PPAR gamma/genetics/*metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Long-Evans ; Receptors, Adiponectin/genetics/metabolism ; Tumor Necrosis Factor-alpha/genetics/metabolism

OBJECTIVETo study the expression of peroxisome proliferators-activated receptor (PPAR) in human glioma tissue and its influence on tumor growth.

METHODSExpression of PPAR mRNA in glioma tissue was determined by real-time reverse transcription polymerase chain reaction (RT-PCR). Subsequently, MTT (3-(4, 5)-dimethylthiahiazo(-z-y1)-3, 5-di-phenytetrazoliumromide) assay, flow cytometry, reactive oxygen species assay kit and Western blotting were used to assay U87 cells with agonist activity of PPAR.

RESULTSThe data demonstrated that the expression of PPAR in glioma was low and negatively correlated with its pathological grade. Activation of PPAR suppresses tumor cell proliferation, delays the cell cycle at G1 phrase, and induces apoptosis and accumulation of reactive oxygen species (ROS) in U87 cells.

CONCLUSIONThe expression of PPAR mRNA in human glioma was low. PPAR protein plays a critical role in the progression of glioma via the PPAR signal pathway.

Apoptosis ; Cell Cycle Checkpoints ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression ; Glioma ; genetics ; metabolism ; physiopathology ; Humans ; PPAR alpha ; genetics ; metabolism ; Signal Transduction

Objective To investigate the effects of long noncoding RNA H19 on lipid accumulation of macrophages under high fat stress and its mechanism. Methods Human THP-1 cells-derived macrophages were incubated with ox-LDL, and the effects of H19 siRNA intervention on lipid accumulation was observed. The THP-1 cells were divided into control group (conventional culture), ox-LDL group, siRNA negative control (NC siRNA) combined with ox-LDL treatment group, and H19 siRNA combined with ox-LDL treatment group. Oil red O staining was used to determine the lipid accumulation in cells, and cholesterol concentration was analyzed by enzymatic method; ATP assay kit for detecting celluar ATP content; colorimetry was used to detect the levels of oxidative stress indicators and ELISA was used to detect the levels of monocyte chemoattractant protein-1 (MCP-1) in the cell supernatant. Western blot analysis was used to detect the protein expression of ATP binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor α (PPARα), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and nuclear factor κB p-p65 (NF-κB p-p65). Results Knockdown H19 significantly inhibited intracellular lipid accumulation, decreased total cholesterol (TC) and cholesterol ester (CE) content, and decreased CE/TC ratio. Knockdown H19 significantly alleviated cell damage including an increase in ATP content, a decrease in oxidative stress levels and a decrease in MCP-1 levels, which caused by high-fat stress. H19 siRNA upregulated expression of ABCA1, PPARα and PGC-1α in THP-1 derived macrophages, downregulated NF-κB signal pathway. Conclusion Knockdown H19 upregulates PGC-1α expression in THP-1 cells and downregulates NF-κB pathway, which promotes cholesterol reverse transport, reduces inflammatory reaction and inhibits lipid accumulation.
Humans ; Adenosine Triphosphate ; Cholesterol ; NF-kappa B ; PPAR alpha ; RNA, Long Noncoding/genetics* ; RNA, Small Interfering/genetics* ; THP-1 Cells ; Macrophages/metabolism* ; Lipid Metabolism

This study was aimed to investigate the influence of PPARalpha agonist on the expression of TF (tissue factor) in THP-1 cells. THP-1 cells were pretreated with different concentrations of PPARalpha agonist (fenofibrate) for definite time. Lipopolysaccharide (LPS)-induced TF mRNA and protein levels were detected by RT-PCR and Western blot respectively. The results showed that fenofibrate decreased tissue factor protein and mRNA expression in supernatants of LPS-stimulated human monocytes in a concentration-dependent manner (P < 0.05 - 0.01, n = 5). It is concluded that fenofibrate inhibit TF expression induced by LPS in THP-1 cells, which may be involved in the anti-atherosclerotic effects of PPARalpha agonist.
Depression, Chemical ; Fenofibrate ; pharmacology ; Humans ; Leukemia, Monocytic, Acute ; metabolism ; pathology ; Lipopolysaccharides ; antagonists & inhibitors ; pharmacology ; PPAR alpha ; agonists ; RNA, Messenger ; biosynthesis ; genetics ; Thromboplastin ; biosynthesis ; genetics ; Tumor Cells, Cultured

BACKGROUNDAgeing is associated with increased incidence of dyslipidemia. To investigate potential molecular mechanisms, the effects of age and fibrate administration on peroxisome proliferator-activated receptor alpha (PPARalpha) expression in livers of young and old rats were studied.

METHODSA total of 16 young (2-month-old) and 16 old rats (24-month-old) were randomly assigned to a control group and fenofibrate group (fenofibrate in a total therapeutic dosage of 0.5% in ratio to each treated rat weight in 14 days). RT-PCR was applied to evaluate hepatic mRNA expression of PPARalpha and its target genes. Western blotting was used to determine PPARalpha protein level in liver tissue.

RESULTSWhen compared with 2-month-old rats, the liver tissue from 24-month-old rats showed reduced expression of PPARalpha mRNA (52%, P < 0.05) and protein (109%, P < 0.01). Consequently, the mRNA levels of PPAR target genes, LPL, ACO, ACS and CPT-1 were markedly lowered by 19%, 8%, 13% and 9% respectively, and apoCIII increased by 24% in livers from 24-month-old rats, compared with values obtained from 2-month-old rats (P < 0.05). Fenofibrate therapy significantly lowered plasma triglyceride and total cholesterol levels in old rats, accompanied with improvement in hepatic expression of genes, including LPL, ACO, ACS, CPT-1 and apoCIII, but no change was found in PPARalpha expression in livers from either 24-month or 2-month-old rats.

CONCLUSIONSThe decrease in the hepatic PPARalpha expression is probably directly related to the lipid metabolic disturbances observed in old animals. The beneficial effects of fenofibrate administration in old rats suggests that fibrates may be useful for treating lipid disturbances in old people.

Aging ; metabolism ; Animals ; Fenofibrate ; pharmacology ; therapeutic use ; Hyperlipidemias ; drug therapy ; etiology ; Lipids ; blood ; Liver ; metabolism ; Male ; PPAR alpha ; genetics ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo study the effect and mechanism of berberine (BER) on the proliferation and differentiation of adipocytes.

METHODSThe proliferation of 3T3-L1 pre-adipocytes was detected by XTT method. Lipid droplets accumulated in the cytoplasm of adipocytes in the differentiating process were observed by oil red O staining and quantified by colorimetry. The expressions of peroxisome proliferation activated receptor gamma (PPARgamma), CAAT/enhancer binding protein alpha (C/EBPalpha) mRNA and protein were detected by Real-time PCR and Western blotting respectively.

RESULTSIntervention with BER in concentration below 10 micromol/L for 24 h showed insignificant effect on the proliferation of adipocytes, as compared with that in the control group (P > 0.05); but that in concentrations 20, 40 and 80 micromol/L revealed significant suppressive effect; that in different concentrations acting for 48 h and 72 h could affect the proliferation and the effect displayed a dose-dependent manner, i. e. the higher the concentration of BER, the more apparent the suppression, showing significant difference as compared with those in the control group (P <0.05 or P <0.01). The pre-adipocyte treated with 10 micromol/L BER showed that the lipid droplets in the cytoplasm significantly lessened, so did the expression of differentiation related factor PPAR gamma mRNA as well as the expressions of C/EBPalpha mRNA and protein, as compared with those in the blank control group and the group intervened with rosiglitazone, the difference was significant (P < 0.05 or P < 0.01).

CONCLUSIONSBER can suppress the proliferation and differentiation of 3T3-L1 pre-adipocytes, reduce the accumulation of lipid drops in the adipocyte differentiating process, which may be associated with its effects in decreasing the expressions of adipocyte differentiation related gene PPARgamma, C/EBPalpha mRNA and protein. The study provides a basis for applying BER on the prevention and treatment of such metabolic related diseases as obesity.

3T3-L1 Cells ; Adipocytes ; cytology ; drug effects ; metabolism ; Animals ; Berberine ; pharmacology ; CCAAT-Enhancer-Binding Protein-alpha ; genetics ; metabolism ; Cell Proliferation ; drug effects ; Gene Expression ; drug effects ; Mice ; PPAR gamma ; genetics ; metabolism ; RNA, Messenger ; genetics ; metabolism