OBJECTIVETo explore the time course of renin-angiotensin system (RAS), peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma change in an animal model of alcoholic cardiomyopathy (ACM).

METHODSAdult rats were divided into three groups: ACM group (A, 10% alcohol as drinking water plus 5 ml 60% alcohol.kg(-1).d(-1) per gavage in the 1st week; 10% alcohol as drinking water plus 10 ml 60% alcohol/kg bid per gavage in the 2nd week, 20% alcohol as drinking water plus 15 ml 60% alcohol/kg bid per gavage during week 3 to week 16), ACM/ARB group(B, A + Irbesartan 5 mg.kg(-1).d(-1) per gavage) and control group (C). mRNA expressions and activities of renin, angiotensin, ACE and AT1 were detected with RT-PCR and radioimmunoassay methods. Protein expressions of PPARalpha and PPARgamma were determined with Western blot. Echocardiogram, optic (HE) and electron microscope examinations were also performed. Parameters were obtained at 2 or 6 months (n = 7 - 10 each).

RESULTSCompared with group C, LV/BW ratio was significantly increased and LVEF significantly decreased, activities and expressions of Ang I, Ang II and renin were gradually increased, protein expressions of PPARalpha were gradually decreased at 2 and 6 months in group A (all P < 0.05). These changes could be partly attenuated by Irbesartan.

CONCLUSIONActivated RAS and decreased protein expressions of PPARalpha and PPARgamma contributed to the development of ACM.

Animals ; Cardiomyopathy, Alcoholic ; metabolism ; Disease Models, Animal ; Male ; PPAR alpha ; metabolism ; PPAR gamma ; metabolism ; Rats ; Rats, Wistar ; Renin-Angiotensin System

Animals ; Fatty Liver ; etiology ; metabolism ; Humans ; Liver ; metabolism ; PPAR alpha ; physiology

Retinopathy is a major cause of morbidity in diabetes and remains the primary cause of new blindness. Therefore, it is necessary to find new drug to treat diabetic retinopathy. Type 2 diabetes mellitus (T2DM) rats were induced by injection (ip) with streptozotocin (STZ) 35 mg x kg(-1) and fed with a high-carbohydrate/high-fat diet 2 weeks later. From week 17 to 32, diabetic rats were given different doses of berberine 75, 150, and 300 mg x kg(-1), fenofibrate 100 mg x kg(-1) and rosiglitazone 4 mg x kg(-1), separately. Retinal structure was observed with hematoxylin-eosin staining and peroxisome proliferator-activated receptors (PPARs) alpha/delta/gamma protein expressions were detected by immunohistochemistry. The retina of control rats was thicker than that of other groups, 16 weeks treatment with berberine (150 and 300 mg x kg(-1)) and rosiglitazone 4 mg x kg(-1) thickened the diabetic retina, but no difference existed in retinal structure among groups. Both berberine (150 and 300 mg x kg(-1)) and rosiglitazone 4 mg x kg(-1) significantly decreased PPARy expression in diabetic retina; while berberine (150 and 300 mg x kg(-1)) and fenofibrate 100 mg x kg(-1) obviously increased both PPARalpha and PPARdelta expressions in diabetic retina. Berberine modulates PPARalpha/delta/gamma protein levels in diabetic retina which may contribute to ameliorate retinopathy complication induced by STZ and a high-carbohydrate/high-fat diet. It is expected that berberine might be a more beneficial drug to treat diabetic retinal complication comparing with fenofibrate and rosiglitazone.
Animals ; Berberine ; pharmacology ; Diabetes Mellitus, Experimental ; metabolism ; Diabetes Mellitus, Type 2 ; metabolism ; Diabetic Retinopathy ; metabolism ; Fenofibrate ; pharmacology ; Hypoglycemic Agents ; pharmacology ; Male ; PPAR alpha ; metabolism ; PPAR delta ; metabolism ; PPAR gamma ; metabolism ; Rats ; Rats, Wistar ; Retina ; metabolism ; pathology ; Thiazolidinediones ; pharmacology

OBJECTIVETo explore the changes on the content of substrate, the activity of correlative enzyme and the mRNA and protein expressions of beta(3)-adrenoceptor and peroxisome proliferator-activated receptor alpha (PPARalpha) in human failing heart.

METHODPapillary muscles from 20 patients with heart failure during mitral valves replacement and 6 control subjects died of non-cardiac accidents were obtained and free fat acid (FFA), lactic acid (LD) and the activity of Na(+)K(+)-ATPase and Ca(2+)Mg(2+)-ATPase, protein and mRNA expressions of beta(3)-adrenergic receptor and PPARalpha were measured.

RESULTIn the failing heart, the contents of fat acid, LD and expression of beta(3)-adrenoceptor mRNA and protein were significantly higher while the activity of Na(+)K(+)-ATPase and Ca(2+)Mg(2+)-ATPase, expressions of PPARalpha at mRNA and protein levels were significantly lower than those in control myocardium.

CONCLUSIONMetabolic remodeling (upregulation of beta(3)-adrenoceptor and downregulation of PPARalpha) might contribute to the pathophysiology of heart failure.

Adult ; Female ; Heart Failure ; metabolism ; Humans ; Male ; Middle Aged ; Myocardium ; metabolism ; PPAR alpha ; metabolism ; Receptors, Adrenergic, beta-3 ; metabolism

Cell Transformation, Neoplastic ; metabolism ; Humans ; Liver Neoplasms ; metabolism ; Non-alcoholic Fatty Liver Disease ; metabolism ; PPAR alpha ; metabolism

A series of tetrahydroisoquinoline derivatives were prepared and their peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonistic activities were evaluated to obtain more potent PPAR agonist. All of them were new compounds, and their structures were confirmed by 1H NMR and HR-MS. Three compounds exhibited higher agonistic activities of PPARgamma than that of the comparison, six compounds exhibited higher agonistic activities of PPARalpha than that of the comparison, and compound 8a was discovered as a highly potent PPARalpha/gamma agonist that is much more active than that of WY14643 and rosiglitazone. The development of potent PPAR agonists may offer a new choice for the treatment of diabetes.
Drug Design ; HEK293 Cells ; Humans ; Hypoglycemic Agents ; chemical synthesis ; chemistry ; pharmacology ; PPAR alpha ; agonists ; metabolism ; PPAR gamma ; agonists ; metabolism ; Structure-Activity Relationship ; Tetrahydroisoquinolines ; chemical synthesis ; chemistry ; pharmacology ; Transfection

OBJECTIVETo investigate the effects of peroxisome proliferator activated receptor-alpha (PPAR-a) activation on oleic acid (OA)-induced steatosis and hepatic expression of heme oxygenase-1 (HO-1) using an in vitro cell model system.

METHODSA steatosis human hepatocyte in vitro model system was established by treating HepG2 cells with 0.2 mmol/L of oleic acid for 24 hours. The steatosis cells were then divided into four groups for an additional 24 hours of treatment with 0.2 mmol/L of oleic acid alone (model control group) or with 5, 10 or 50 pnol/L of fenofibrate (FF, a selective PPAR-a agonist; experimental groups). Untreated HepG2 cells served as non-steatosis controls. Effect of PPAR-a activation on fat accumulation was detected by Oil Red O staining and on intracellular triglyceride (TG) levels by enzymatic assay. mRNA and protein expression of PPAR-alpha and HO-1 were quantified by real-time PCR and immunocytochemistry, respectively. One-way ANOVA and the LSD t-test were used for between-group comparisons, and correlation analysis was performed with the Pearson's correlation coefficient.

RESULTSThe steatosis model control cells showed significantly increased TG deposition (379.98 +/- 23.19 mg/g protein, vs. non-steatosis controls F = 148.56, P< 0.01), significantly decreased mRNA and protein expression of PPAR-alpha (0.42 +/- 0.38,F= 177.64,P< 0.01 and 0.47 +/- 0.14, F= 120.76,P< 0.01) and HO-1 (0.36 +/- 0.66, F= 74.77,P< 0.01 and 0.26 +/- 0.10,F= 119.90,P<0.01). FF (5, 10 and 50 micromol/L) inhibited the steatosis induced by OA in a concentration-dependent manner (294.00 +/- 19.80, 250.33 +/- 9.96, and 196.99 +/- 9.14, F = 148.56, P <0.01) and increased the mRNA and protein expression of PPAR-alpha (0.55 +/- 0.65, 0.85 +/- 0.61, and 1.31 +/- 0.36,F= 177.64,P< 0.01; 0.82 + 0.11, 1.31 +/- 0.16, and 1.75 +/- 0.13, F= 120.76,P <0.01) and HO-1 (0.62 +/- 0.05, 0.84 +/- 0.07, and 1.30 +/- 0.11,F= 74.77,P <0.01; 0.44 +/- 0.08, 0.81 +/- 0.08, 1.20 +/- 0.10,F= 119.90,P< 0.01).

CONCLUSIONActivation of PPAR-a prevents OA-induced steatosis in HepG2 cells, and HO-1 may function as a downstream effector of this mechanism.

Fatty Liver ; chemically induced ; Heme Oxygenase-1 ; metabolism ; Hep G2 Cells ; Humans ; Oleic Acid ; pharmacology ; PPAR alpha ; metabolism ; Triglycerides ; metabolism

OBJECTIVETo investigate the effects of carnitine on cardiac function, collagen contents, peroxisome proliferator-activated receptor alpha (PPARalpha) and retinoid X receptor alpha (RXRct) expressions in a rat alcoholic cardiomyopathy modeL.

METHODSAdult male Wistar rats were randomly divided into alcohol group (A) , alcohol/carnitine group (B) and control group. Six months later, protein expressions of collagen I, collagen III, matrix metalloproteinase-9 (MMP-9) and Smad-3 were determined by immunohistochemical staining. Protein expressions of PPARalpha and RXRalpha were detected by Western blot.

RESULTSExpressions of collagen I, collagen III, MMP-9 and Smad-3 were significantly increased in groups A and B compared to group C (P < 0.01 or P < 0.05). Expressions of PPARalpha and RXRalpha (0.156 and 0.192, respectively, in group A; 0.248 and 0.385, respectively, in group B) were decreased compared to group C (P < 0.01 or P < 0.05). These changes were significantly attenuated by carnitine (all P < 0.05, group B vs. group A). Moreover, PPARalpha and RXRalpha positively correlated with EF and FS, and negatively correlated LVEDd, collagen I , collagen III, MMP-9 and Smad-3 (all P < 0.01).

CONCLUSIONPPARalpha and RXRalpha downregulation is significantly correlated with cardiac dysfunction in this alcoholic cardiomyopathy model, carnitine ameliorated the cardiac fibrosis and remodeling possibly through upregulating the metabolic pathways of PPARalpha and RXRalpha.

Animals ; Cardiomyopathy, Alcoholic ; metabolism ; pathology ; prevention & control ; Carnitine ; therapeutic use ; Male ; Myocardium ; metabolism ; pathology ; PPAR alpha ; metabolism ; Rats ; Rats, Wistar ; Retinoid X Receptor alpha ; metabolism

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

This study investigated the mechanism of Zexie Decoction(ZXD) in promoting white adipose tissue browning/brown adipose tissue activation based on the GLP-1R/cAMP/PKA/CREB pathway. A hyperlipidemia model was induced by a western diet(WD) in mice, and the mice were divided into a control group, a model group(WD), and low-, medium-, and high-dose ZXD groups. An adipogenesis model was induced in 3T3-L1 cells in vitro, and with forskolin(FSK) used as a positive control, low-, medium-, and high-dose ZXD groups were set up. Immunohistochemistry and immunofluorescence results showed that compared with the WD group, ZXD promoted the expression of UCP1 in white and brown adipose tissues, and also upregulated UCP1, CPT1β, PPARα, and other genes in the cells. Western blot analysis showed a dose-dependent increase in the protein expression of PGC-1α, UCP1, and PPARα with ZXD treatment, indicating that ZXD could promote the white adipose tissue browning/brown adipose tissue activation. Hematoxylin-eosin(HE) staining results showed that after ZXD treatment, white and brown adipocytes were significantly reduced in size, and the mRNA expression of ATGL, HSL, MGL, and PLIN1 was significantly upregulated as compared with the results in the WD group. Oil red O staining and biochemical assays indicated that ZXD improved lipid accumulation and promoted lipolysis. Immunohistochemistry and immunofluorescence staining for p-CREB revealed that ZXD reversed the decreased expression of p-CREB caused by WD. In vitro intervention with ZXD increased the protein expression of CREB, p-CREB, and p-PKA substrate, and increased the mRNA level of CREB. ELISA detected an increase in intracellular cAMP concentration with ZXD treatment. Molecular docking analysis showed that multiple active components in Alismatis Rhizoma and Atractylodis Macrocephalae Rhizoma could form stable hydrogen bond interactions with GLP-1R. In conclusion, ZXD promotes white adipose tissue browning/brown adipose tissue activation both in vivo and in vitro, and its mechanism of action may be related to the GLP-1R/cAMP/PKA/CREB pathway.
Mice ; Animals ; Adipose Tissue, Brown ; Molecular Docking Simulation ; PPAR alpha/metabolism* ; Adipose Tissue, White ; RNA, Messenger/metabolism*