Although glucose-lowering treatment shows some risk lowering effects in cardiovascular diseases, risks of macrovascular and microvascular complications have still remained, and development of new therapeutic strategies is needed. Recent data have shown that peroxisome proliferator activated receptor-alpha (PPAR-alpha) plays a pivotal role in the regulation of lipid homeostasis, fatty acid oxidation, cellular differentiation, and immune response such as inflammation or vascularization related to diabetic complication. This review will re-examine the metabolic role of PPAR-alpha, summarize data from clinical studies on the effect of PPAR-alpha agonist in diabetes, and will discuss the possible therapeutic role of PPAR-alpha activation.
Cardiovascular Diseases ; Diabetes Complications ; Fibric Acids ; Homeostasis ; Inflammation ; PPAR alpha*

Although glucose-lowering treatment shows some risk lowering effects in cardiovascular diseases, risks of macrovascular and microvascular complications have still remained, and development of new therapeutic strategies is needed. Recent data have shown that peroxisome proliferator activated receptor-alpha (PPAR-alpha) plays a pivotal role in the regulation of lipid homeostasis, fatty acid oxidation, cellular differentiation, and immune response such as inflammation or vascularization related to diabetic complication. This review will re-examine the metabolic role of PPAR-alpha, summarize data from clinical studies on the effect of PPAR-alpha agonist in diabetes, and will discuss the possible therapeutic role of PPAR-alpha activation.
Cardiovascular Diseases ; Diabetes Complications ; Fibric Acids ; Homeostasis ; Inflammation ; PPAR alpha*

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

BACKGROUND: Long-term use of topical steroids for inflammatory skin diseases can induce complications, and efforts to find a better treatment are being continued. Peroxisome proliferator activated receptor alpha (PPARalpha) suppresses the skin's inflammatory reaction, maintains the homeostasis of the skin, and plays an important role in skin barrier function. OBJECTIVE: This study analyzed the effects of a skin moisturizer containing PPARalpha activator on various inflammatory skin diseases causing facial erythema and evaluated the observed improvements. METHODS: The PPARa activator used for this study is composed of supercritical extracts from Euryale ferox, Euphorbia lathyris, and Rosa multiflora, which showed significant effects in the transactivation assay compared to Wy14643. Moisturizer containing PPARalpha was applied to the faces of 31 patients with symmetric facial erythema, with PPARalpha applied on one-half of the face and a control moisturizer on the other half of the face twice a day for 2 weeks. The percentage of erythema index, erythema index, skin hydration, and transepidermal water loss was checked to evaluate treatment effect. Both patients and clinicians each assessed the improvement of erythema on both sides of a patient's face. RESULTS: Moisturizer containing PPARalpha agonist significantly improved erythema index measured with Mexameter MX18(R) and percentage of erythema index by polarization color imaging system (DermaVision-PRO(R)) (p<0.05). However, there was no significant improvement in skin hydration and transepidermal water loss. Improvement of erythema was also shown on both the patient and clinician graded assessments. CONCLUSION: Topical PPARalpha agonist applied during clinical practice was relatively safe and effective. This can be applied clinically to various inflammatory skin diseases causing erythema.
Erythema* ; Euphorbia ; Homeostasis ; Humans ; PPAR alpha* ; Rosa ; Skin ; Skin Diseases ; Steroids ; Transcriptional Activation

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

OBJECTIVE: To explore the molecular pathological mechanism of liver metabolic disorder in severe spinal muscular atrophy (SMA). METHODS: The transgenic mice with type Ⅰ SMA (Smn^-/- SMN2^0tg/2tg) and littermate control mice (Smn^+/- SMN2^0tg/2tg) were observed for milk suckling behavior and body weight changes after birth. The mice with type Ⅰ SMA mice were given an intraperitoneal injection of 20% glucose solution or saline (15 μL/12 h), and their survival time was recorded. GO enrichment analysis was performed using the RNA-Seq data of the liver of type Ⅰ SMA and littermate control mice, and the results were verified using quantitative real-time PCR. Bisulfite sequencing was performed to examine CpG island methylation level in Fasn gene promoter region in the liver of the neonatal mice. RESULTS: The neonatal mice with type Ⅰ SMA showed normal milk suckling behavior but had lower body weight than the littermate control mice on the second day after birth. Intraperitoneal injection of glucose solution every 12 h significantly improved the median survival time of type Ⅰ SMA mice from 9±1.3 to 11± 1.5 days (P < 0.05). Analysis of the RNA-Seq data of the liver showed that the expression of the target genes of PPARα related to lipid metabolism and mitochondrial β oxidation were down-regulated in the liver of type Ⅰ SMA mice. Type Ⅰ SMA mice had higher methylation level of the Fasn promoter region in the liver than the littermate control mice (76.44% vs 58.67%). In primary cultures of hepatocytes from type Ⅰ SMA mice, treatment with 5-AzaC significantly up-regulated the expressions of the genes related to lipid metabolism by over 1 fold (P < 0.01). CONCLUSION Type Ⅰ SMA mice have liver metabolic disorder, and the down-regulation of the target genes of PPARα related to lipid and glucose metabolism due to persistent DNA methylation contributes to the progression of SMA.
Mice ; Animals ; PPAR alpha ; Liver Diseases ; Muscular Atrophy, Spinal/genetics* ; Mice, Transgenic ; Body Weight ; Glucose

The present study demonstrates the effect of fibrates, agonists of PPARalpha on cytokines-induced proliferation in primary cultured astrocytes. Alone or combination treatment with cytokines, such as IL-1beta (10 ng/ml), IFNgamma (10 ng/ml), and TNF-alpha (10 ng/ml) cause a significant increase of cell proliferation in a time-dependent manner. Treatment of astrocytes with bezafibrate and fenofibrate (0, 5, and 10 micrometer) reduced the IFNgamma and IL-1beta-induced cell proliferation in a dose-dependent manner. To address the involvement of IL-6 on the IFNgamma and IL-1beta-induced cell proliferation, released IL-6 level was measured. IFNgamma and IL-1beta cause an increase of released IL-6 protein level in a time-dependent manner. Furthermore, pretreatment with IL-6 antibody (0, 0.1, 1, 2.5, and 5 ng/ml) dose-dependently inhibited the IFNgamma and IL-1beta-induced cell proliferation. However, bezafibrate and fenofibrate did not affect increased mRNA and protein levels of IL-6 in IFNgamma and IL-1beta-stimulated astrocytes. Taken together, these results clearly suggest that activation of PPARalpha attenuates the IFNgamma and IL-1beta-induced cell proliferation through IL-6 independent pathway.
Astrocytes ; Bezafibrate ; Cell Proliferation ; Cytokines ; Fenofibrate ; Fibric Acids ; Interleukin-6 ; PPAR alpha ; RNA, Messenger ; Tumor Necrosis Factor-alpha

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

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 investigate the association between ten single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors (PPAR&alpha;, β, γ) with apolipoprotein A I/apolipoprotein B100 (ApoA I/ApoB100) ratio and the additional role of a gene-gene interactions among the 10 SNPs.

METHODSParticipants were recruited under the framework of the Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu Province (PMMJS) cohort population survey in the urban community of Jiangsu province of China.A total of 630 subjects were randomly selected and no individual was related.Ten SNPs (rs135539, rs4253778, rs1800206, rs2016520, rs9794, rs10865710, rs1805192, rs709158, rs3856806 and rs4684847) were selected from the HapMap database,which covered PPAR&alpha;, PPARβ and PPARγ. A linear regression model was used to analyze the relations between ten SNPs in the PPARs and ApoA I/ApoB100 ratio level. Mean difference and 95% CI were calculated. Interactions were explored by using the method of Generalized Multifactor Dimensionality Reduction (GMDR).

RESULTSAfter adjusting for age, gender, smoking status, alcohol consumption, occupational physical activity, high-fat diet as well as low-fiber diet, both rs1800206 and rs3856806 were significantly associated with a decreased level of ApoA I/ApoB100 ratio, mean difference (95% CI) values were -1.19 (-1.88 to -0.50) and -0.77 (-1.40 to -0.14). Whereas rs4253778 was significantly associated with an increased level of ApoA I/ApoB100 ratio, Mean difference (95% CI) values was 0.80 (0.08 to 1.52). GMDR analysis showed a significant gene-gene interaction among rs4253778, rs1800206 of PPAR&alpha;, rs9794, rs2016520 of PPARβ and rs10865710, rs3856806, rs709158, rs1805192 of PPARγ for eight-dimension models (P = 0.01), in which prediction accuracy was 0.624 and cross-validation consistency was 7/10.

CONCLUSIONSThe rs1800206 of PPAR&alpha; and rs3856806 of PPARγ are significantly associated with a decreased level of ApoA I/ApoB100 ratio while rs4253778 of PPAR&alpha; is associated with an increased level of ApoA I/ApoB100 ratio. There is a gene-gene interaction between multiple SNPs.

Apolipoprotein A-I ; genetics ; Apolipoprotein B-100 ; genetics ; China ; Diet, High-Fat ; Epistasis, Genetic ; Gene Frequency ; Genotype ; Humans ; Metabolic Syndrome ; PPAR alpha ; genetics ; PPAR delta ; PPAR gamma ; genetics ; Polymorphism, Single Nucleotide