Peroxisome proliferator-activated receptors as targets to treat metabolic diseases:Focus on the adipose tissue,liver,and pancreas

The world is experiencing reflections of the intersection of two pandemics:Obesity and coronavirus disease 2019.The prevalence of obesity has tripled since 1975 worldwide,representing substantial public health costs due to its comorbidities.The adipose tissue is the initial site of obesity impairments.During excessive energy intake,it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs.The pancreas is one of the organs most affected by obesity.Once lipotoxicity becomes chronic,there is an increase in insulin secretion by pancreatic beta cells,a surrogate for type 2 diabetes mellitus(T2DM).These alterations threaten the survival of the pancreatic islets,which tend to become dysfunctional,reaching exhaustion in the long term.As for the liver,lipotoxicity favors lipogenesis and impairs beta-oxidation,resulting in hepatic steatosis.This silent disease affects around 30%of the worldwide population and can evolve into end-stage liver disease.Although therapy for hepatic steatosis remains to be defined,peroxisome proliferator-activated receptors(PPARs)activation copes with T2DM management.Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways,leading to insulin resistance relief,improved thermogenesis,and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation.This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases,focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.

Decreased hepatic peroxisome proliferator-activated receptor-γ contributes to increased sensitivity to endotoxin in obstructive jaundice

AIM: To investigate the role of hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) in increased susceptibility to endotoxin-induced toxicity in rats with bile duct ligation during endotoxemia.METHODS: Male Sprague-Dawley rats were subjected to bile duct ligation (BDL). Sham-operated animals served as controls. DNA binding were determined by polymerase chain reaction, Western blotting analysis,and electrophoretic mobility shift assay, respectively.BDL and sham-operated rats received a non-lethal dose of intraperitoneal lipopolysaccharide (LPS) injection (3 mg/kg, i.p.). Additionally, the potential beneficial effects of the PPAR-γ agonist rosiglitazone were determined in BDL and sham-operated rats treated with a non-lethal dose of LPS. Survival was assessed in BDL rats treated with a non-lethal dose of LPS and in sham-operatedrats treated at a lethal dose of LPS (6 mg/kg, i.p.).RESULTS: PPAR-γ activity in rats undergoing BDL wassignificantly lower than in the sham-controls. Hepatic PPAR-γ gene expression was downregulated at both them RNA and protein levels. In a parallel group, serumlevels of pro-inflammatory cytokines were nearly unde-tectable in the sham-operated rats. When challenged with a non-lethal dose of LPS (3 mg/kg), the BDL ratshad approximately a 2.4-fold increase in serum IL-6,a 2.7 fold increase in serum TNF-α, 2.2-fold increasein serum IL-1 and 4.2-fold increase in serum ALT. Thesurvival rate was significantly lower as compared with that in sham-operated group. Additionally, rosiglitazone significantly reduced the concentration of TNF-α, IL-1β, IL-6 and ALT in sham-operated rats, but not in BDL rats, in response to LPS (3 mg/kg). Also, the survival was improved by rosiglita zone in sham-operated rats challenged with a lethal dose of LPS, but not in BDL rats, even with a non-lethal dose of LPS (3 mg/kg).CONCLUSION: Obstructive jaundice downregulates hepatic PPAR-γ expression, which in turn may contributeto hypersensitivity towards endotoxin.

Peroxisome proliferator-activated receptor gamma as a therapeutic target for hepatocellular carcinoma:Experimental and clinical scenarios

Hepatocellular carcinoma(HCC)is the most common type of liver cancer worldwide.Viral hepatitis is a significant risk factor for HCC,although metabolic syndrome and diabetes are more frequently associated with the HCC.With increasing prevalence,there is expected to be>1 million cases annually by 2025.Therefore,there is an urgent need to establish potential therapeutic targets to cure this disease.Peroxisome-proliferator-activated receptor gamma(PPARγ)is a ligand-activated transcription factor that plays a crucial role in the pathophysiology of HCC.Many synthetic agonists of PPARγsuppress HCC in experimental studies and clinical trials.These synthetic agonists have shown promising results by inducing cell cycle arrest and apoptosis in HCC cells and preventing the invasion and metastasis of HCC.However,some synthetic agonists also pose severe side effects in addition to their therapeutic efficacy.Thus natural PPARγagonists can be an alternative to exploit this potential target for HCC treatment.In this review,the regulatory role of PPARγin the pathogenesis of HCC is elucidated.Furthermore,the experimental and clinical scenario of both synthetic and natural PPARγagonists against HCC is discussed.Most of the available literature advocates PPARγas a potential therapeutic target for the treatment of HCC.

Peroxisome proliferator-activated receptor-alpha activation and dipeptidyl peptidase-4 inhibition target dysbiosis to treat fatty liver in obese mice

BACKGROUND Obesity and comorbidities onset encompass gut dysbiosis,altered intestinal permeability,and endotoxemia.Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease(NAFLD)management.Peroxisome proliferator-activated receptor(PPAR)-alpha activation and dipeptidyl-peptidase-4(DPP-4)inhibition alleviate NAFLD,but the mechanism may involve gut microbiota modulation and merits further investigation.AIM To address the effects of PPAR-alpha activation and DPP-4 inhibition(isolated or combined)upon the gut-liver axis,emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice.METHODS Male C57BL/6J mice were fed a control diet(C,10%of energy as lipids)or a highfat diet(HFD,50%of energy as lipids)for 12 wk,when treatments started,forming the groups:C,HF,HFA(HFD+PPAR-alpha agonist WY14643,2.5 mg/kg body mass),HFL(HFD+DPP-4 inhibitor linagliptin,15 mg/kg body mass),and HFC(HFD+the combination of WY14643 and linagliptin).RESULTS The HFD was obesogenic compared to the C diet.All treatments elicited significant body mass loss,and the HFC group showed similar body mass to the C group.All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations.These metabolic benefits restored Bacteroidetes/Firmicutes ratio,resulting in increased goblet cells per area of the large intestine and reduced lipopolysaccharides concentrations in treated groups.At the gene level,treated groups showed higher intestinal Mucin 2,Occludin,and Zo-1 expression than the HFD group.The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals.These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol,reassuring the role of the proposed treatments on NAFLD mitigation.CONCLUSION PPAR alpha activation and DPP-4 inhibition(isolated or combined)tackled NAFLD in dietinduced obese mice by restoration of gut-liver axis.The reestablishment of the intestinal barrier and the rescued phylogenetic gut bacteria distribution mitigated liver steatosis through antiinflammatory signals.These results can cope with NAFLD management by providing pre-clinical evidence that drugs used to treat obesity comorbidities can help to alleviate this silent and harmful liver disease.

The interplay between non-esterified fatty acids and bovine peroxisome proliferator-activated receptors: results of an in vitro hybrid approach

Background: In dairy cows circulating non-esterified fatty acids(NEFA) increase early post-partum while liver and other tissues undergo adaptation to greater lipid metabolism, mainly regulated by peroxisome proliferator-activated receptors(PPAR). PPAR are activated by fatty acids(FA), but it remains to be demonstrated that circulating NEFA or dietary FA activate bovine PPAR. We hypothesized that circulating NEFA and dietary FA activate PPAR in dairy cows.Methods: The dose-response activation of PPAR by NEFA or dietary FA was assessed using HP300 e digital dispenser and luciferase reporter in several bovine cell types. Cells were treated with blood plasma isolated from Jersey cows before and after parturition, NEFA isolated from the blood plasma, FA released from lipoproteins using milk lipoprotein lipase(LPL), and palmitic acid(C16:0). Effect on each PPAR isotype was assessed using specific synthetic inhibitors.Results: NEFA isolated from blood serum activate PPAR linearly up to ~ 4-fold at 400 μmol/L in MAC-T cells but had cytotoxic effect. Addition of albumin to the culture media decreases cytotoxic effects of NEFA but also PPAR activation by ~ 2-fold. Treating cells with serum from peripartum cows reveals that much of the PPAR activation can be explained by the amount of NEFA in the serum(R~2 = 0.91) and that the response to serum NEFA follows a quadratic tendency, with peak activation around 1.4 mmol/L. Analysis of PPAR activation by serum in MAC-T, BFH-12 and BPAEC cells revealed that most of the activation is explained by the activity of PPARδ and PPARγ, but not PPARα. Palmitic acid activated PPAR when added in culture media or blood serum but the activation was limited to PPARδ and PPARα and the response was nil in serum from post-partum cows. The addition of LPL to the serum increased > 1.5-fold PPAR activation.Conclusion: Our results support dose-dependent activation of PPAR by circulating NEFA in bovine, specifically δand γ isotypes. Data also support the possibility of increasing PPAR activation by dietary FA;however, this nutrigenomics approach maybe only effective in pre-partum but not post-partum cows.

Research progress of peroxisome proliferator-activated receptor α in metabolic diseases

Peroxisome proliferator-activated receptorα(PPAR-α)is a transcription factor activated by ligand receptors and is a subfamily of the nuclear receptor superfamily.The PPAR subfamily consists of three subtypes:PPAR-α(NR1C1),PPAR-β/δ(NR1C2)and PPAR-γ(NR1C3).Among them,PPAR-αis the first discovered transcription factor and the main regulator of fatty acid oxidation homeostasis.Some natural and synthetic ligands can activate PPAR-α,and the activation of PPAR-αthrough its ligands can modify many of the cells in the cell.Biological processes,these processes are closely related to the energy metabolism mechanism of metabolic diseases,so it represents an important molecular target for the development of new drugs for the treatment of metabolic diseases.The following summarizes the latest progress of PPAR-αand energy metabolism in terms of the structure and distribution of PPAR-α,its role in different tissues,and its role in metabolic diseases,etc.,providing a theoretical basis for the prevention and treatment of metabolic diseases.

Peroxisome proliferator-activated receptor-γ 34C>G polymorphism and colorectal cancer risk: A meta-analysis

AIM: To investigate the association between peroxisome proliferator-activated receptor-γ (PPAR-γ ) gene polymorphism 34 C>G and colorectal cancer (CRC),a meta-analysis review was performed in this report.METHODS: A systematic literature search and selection of eligible relevant studies were carried out.Nine independent studies with a total number of 4533 cases and 6483 controls were included in the meta-analysis on the association between polymorphism 34 C>G and CRC.RESULTS: There was no evidence for the association between PPAR-γ 34 C>G and CRC if all of the subjects in the nine studies were included.However,CG + GG showed a marginally significant difference from CC (OR = 0.84,95% CI: 0.69-1.01,P = 0.07) in random-effect model.Stratified meta-analysis indicated that PPAR-γ 34 C>G was associated with colon cancer (OR = 0.8,95% CI: 0.65-0.99,P = 0.04) in random-effect model,and the G allele decreased colon cancer risk.No significant association was observed between PPAR-γ 34 C>G and rectal cancer.CONCLUSION: PPAR-γ 34 C>G is associated with colon cancer risk,but not associated with CRC and rectal cancer risk.

Peroxisome proliferator-activated receptor delta+294T>C polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations

Objectives The association of peroxisome prolif-erator -activated receptor delta(PPARD) +294T】C polymorphism and serum lipid levels is inconsistent in several previous studies.Bai Ku Yao is an isolated association of PPARD +294T】C(rs2016520) polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.Methods A total of 609 subjects of Bai Ku Yao and 573 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples.Genotyping of the PPARD +294T】C polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing.Results The levels of serum total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),apolipoprotein(Apo) AI and ApoB were lower in Bai Ku Yao than in Han(P【0.001 for all).The frequency of T and C alleles was 77.50%and 22.50%in Bai Ku Yao,and 72.43%and 27.57%in Han (P【0.01);respectively.The frequency of TT,TC and CC genotypes was 60.59%,33.83%and 5.53%in Bai Ku Yao, and 52.18%,40.50%and 7.32%in Han(P【0.05);respectively. The levels of LDL-C,ApoB and the ratio of ApoAI to ApoB in Bai Ku Yao were different among the three genotypes in females but not in males(P【0.05 for all).The subjects with TT and TC genotypes had lower serum LDL-C and ApoB levels and higher the ratio of ApoAI to ApoB than the CC genotype in females.The levels of TC and ApoB in the total Han population were different among the three genotypes (P【0.05 for all).The C allele carriers had higher serum TC and ApoB levels than the C allele noncarriers.When serum lipid levels were analyzed according to sex,the difference in serum TC levels in Han was significant in males(P【0.01) but not in females,whereas the difference in serum ApoB levels was significant in females(P【0.05)but not in males. Serum TC and ApoB levels were correlated with genotypes in Han(P【0.05 for each) but not in Bai Ku Yao.Serum lipid parameters were also correlated with sex,age,body massindex, alcohol consumption,cigarette smoking,and blood pressure in both ethnic groups.Conclusions These results suggest that the association of PPARD +294T】C polymorphism and serum lipid levels is different between the Bai Ku Yao and Han populations.The discrepancy between the two ethnic groups might partly result from different PPARD +294T】C polymorphism or PPARD gene-enviromental interactions,subgroup of the Yao minority in China.

Peroxisome proliferator-activated receptors for hypertension

Peroxisome proliferator-activated receptors(PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily, which is composed of four members encoded by distinct genes(α, β, γ, and δ). The genes undergo transactivation or transrepression under specific mechanisms that lead to the induction or repression of target gene expression. As is the case with other nuclear receptors, all four PPAR isoforms contain five or six structural regions in four functional domains; namely, A/B, C, D, and E/F. PPARs have many functions, particularly functions involving control of vascular tone, inflammation, and energy homeostasis, and are, therefore, important targets for hypertension, obesity, obesity-induced inflammation, and metabolic syndrome in general. Hence, PPARs also represent drug targets, and PPARα and PPARγ agonists are used clinically in the treatment of dyslipidemia and type 2 diabetes mellitus, respectively. Because of their pleiotropic effects, they have been identified as active in a number of diseases and are targets for the development of a broad range of therapies for a variety of diseases. It is likely that the range of PPARγ agonist therapeutic actions will result in novel approaches to lifestyle and other diseases. The combination of PPARs with reagents or with other cardiovascular drugs, such as diuretics and angiotensin Ⅱ receptor blockers, should be studied.This article provides a review of PPAR isoform characteristics, a discussion of progress in our understanding of the biological actions of PPARs, and a summary of PPAR agonist development for patient management. We also include a summary of the experimental and clinical evidence obtained from animal studies and clinical trials conducted to evaluate the usefulness and effectiveness of PPAR agonists in the treatment of lifestyle-related diseases.

Peroxisome proliferator-activated receptor gamma inhibits hepatic fibrosis in rats

BACKGROUND:Hepatic fibrosis is a necessary step in the development of hepatic cirrhosis.In this study we used lentiviral vector-mediated transfection technology to evaluate the effect of peroxisome proliferator-activated receptor gamma(PPAR-γ) on rat hepatic fibrosis. METHODS:Hepatic fibrosis in rats was induced by CCl4 for 2 weeks(early fibrosis)and 8 weeks(sustained fibrosis).The rats were randomly divided into four groups:normal control, fibrosis,blank vector,and PPAR-γ.They were infected with the recombinant lentiviral expression vector carrying the rat PPAR-γgene by portal vein injection.The liver of the rats was examined histologically and hydroxyproline was assessed.In vitro primary hepatic stellate cells(HSCs)were infected with the recombinant lentiviral expression vector carrying the rat PPAR-γgene.The status of HSC proliferation was measured by the MTT assay.The protein levels of PPAR-γ,α-smooth muscle actin(α-SMA)and type I collagen expression were evaluated by the Western blotting method. RESULTS:In vitro studies revealed that expression of PPAR-γ inhibited expression ofα-SMA and type I collagen in activated HSCs(P<0.01)as well as HSC proliferation(P<0.01).In vivo experiments indicated that in the early hepatic fibrosis group,the hydroxyproline content and the level of collagen I protein in the liver in the PPAR-γtransfected group were not significantly different compared to the hepatic fibrosis group and the blank vector group;whereas the expressions of PPAR-γ andα-SMA were different compared to the hepatic fibrosis group(P<0.01).In the sustained hepatic fibrosis group,there were significant differences in the hydroxyproline content and the expression of PPAR-γ,α-SMA,and type I collagen between each group.CONCLUSION:PPAR-γcan inhibit HSC proliferation and hepatic fibrosis,and suppressα-SMA and type I collagen expression.

Effect of insulin and metformin on methylation and glycolipid metabolism of peroxisome proliferator-activated receptor γcoactivator-1A of rat offspring with gestational diabetes mellitus

Objective:To discuss the effect of insulin and metformin on amethylation and glycolipid metabolism of peroxisome proliferator-activated receptor γ coactivator-1A(PPARGC1A) of rat offspring with gestational diabetes mellitus(GDM).Methods:A total of 45 pregnant rats received the intraperitoneal injection of streptozotocin to establish the pregnant rat model of GDM.A total of 21 pregnant rats with GDM were randomly divided into three groups,with 7ruts in each group,namely the insulin group,metformin group and control group.Rats in the insulin group received the abdominal subcutaneous injection of 1 mL/kg recombinant insulin glargine at 18:00 every day.Rats in the metformin group received the intragastric infusion of metformin hydrochloride at 18:00 every day,with the first dose of 300 mg/kg.The doses of two groups were adjusted every 3 d to maintain the blood glucose level at 2.65-7.62 mmol/L.Rats in the control group received the intragastric infusion of 1 mL normal saline at 18:00 every day.After the natural delivery of pregnant rats.10 offspring rats were randomly selected from each group.At birth,4 wk and 8 wk after the birth of offspring rats,the weight of offspring rats was measured.The blood glucose level of offspring rats was measured at 4wk and 8 wk,while the level of serum insulin,triglyceride and leptin was measured at 8 wk.Results:The weight of offspring rats at birth in the insulin group and metformin group was significantly lower than the one in the control group(P<0.05),and there was no significant difference at 4 wk and 8 wk among three groups(P>0.05).The fasting blood glucose and random blood glucose in the insulin group and metformin group at 4 wk and 8 wk were all significantly lower than ones in the control group(P<0.05);there was no significant difference between the insulin group and metformin group(P>0.05).The expression of PPARGC1 A mRNA in the insulin group and metformin group was significantly higher and the methylation level of PPARGC1 A was significantly lower than the one in the control group(P<0.05),but there was no significant difference between the insulin group and metformin group(P>0.05).Insulin and leptin at 8 wk in the insulin group and metformin group were significantly higher,while triglyceride was significantly lower than the one in the control group(P<0.05);triglyceride level of rats in the insulin group was significantly higher than the one in the metformin group(P<0.05).There was no significant difference in insulin and leptin level of offspring rats between the insulin group and metformin group(P>0.05).Conclusions:GDM can induce the methylation of PPARGC1 A of offspring rats to reduce the expression of PPARGC1 A mRNA and then cause the disorder of glycolipid metabolism when the offspring rats grow up;the insulin or metformin in the treatment of pregnant rats with GDM can reduce the methylation level of PPARGC1 A and thus improve the abnormal glycolipid metabolism of offspring rats.

Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease(NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors(PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation(mitochondrial and peroxisomal)and microsomal omega-oxidation, being markedly decreased by high-fat(HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs.

Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ2 in patients with fatty liver diseases

AIM:To test the occurrence of the Pro12Ala mutation of the peroxisome proliferator-activated receptor-γ (PPARγ)2-gene in patients with non-alcoholic fatty liver disease (NAFLD) or alcoholic fatty liver disease (AFLD).METHODS:DNA from a total of 622 specimens including 259 blood samples of healthy blood donors and 363 histologically categorized liver biopsies of patients with NAFLD (n=263) and AFLD (n=100) were analyzed by Real-time polymerase chain reaction using allele-specific probes.RESULTS:In the NAFLD and the AFLD collective,3% of the patients showed homozygous occurrence of the Ala12 PPARγ2-allele,differing from only 1.5% cases in the healthy population.In NAFLD patients,a high incidence of the Ala12 mutant was not associated with the progression of fatty liver disease.However,we observed a significantly higher risk (odds ratio=2.50,CI:1.05-5.90,P=0.028) in AFLD patients carrying the mutated Ala12 allele to develop inflammatory alterations.The linkage of the malfunctioning Ala12-positive PPARγ2 isoform to an increased risk in patients with AFLD to develop severe steatohepatitis and fibrosis indicates a more prominent anti-inflammatory impact of PPARγ2 in progression of AFLD than of NAFLD.CONCLUSION:In AFLD patients,the Pro12Ala single nuclear polymorphism should be studied more extensively in order to serve as a novel candidate in biomarker screening for improved prognosis.

Role of adipokines and peroxisome proliferator-activated receptors in nonalcoholic fatty liver disease

Intrahepatic fat deposition has been demonstrated in patients with nonalcoholic fatty liver disease(NAFLD). Genetic and environmental factors are important for the development of NAFLD. Diseases such as obesity, diabetes, and hypertension have been found to be closely associated with the incidence of NAFLD. Evi-dence suggests that obesity and insulin resistance are the major factors that contribute to the development of NAFLD. In comparing the factors that contribute to the buildup of excess calories in obesity, an imbalance of energy homeostasis can be considered as the basis. Among the peripheral signals that are generated to regulate the uptake of food, signals from adipose tissue are of major relevance and involve the maintenance of energy homeostasis through processes such as lipo-genesis, lipolysis, and oxidation of fatty acids. Advances in research on adipose tissue suggest an integral role played by adipokines in NAFLD. Cytokines secreted by adipocytes, such as tumor necrosis factor-α, transform-ing growth factor-β, and interleukin-6, are implicated in NAFLD. Other adipokines, such as leptin and adiponectin and, to a lesser extent, resistin and retinol binding protein-4 are also involved. Leptin and adiponectin can augment the oxidation of fatty acid in liver by activating the nuclear receptor super-family of transcription fac-tors, namely peroxisome proliferator-activated receptor(PPAR)-α. Recent studies have proposed downregula-tion of PPAR-α in cases of hepatic steatosis. This re-view discusses the role of adipokines and PPARs with regard to hepatic energy metabolism and progression of NAFLD.

Peroxisome proliferator-activated receptor γ and colorectal cancer

Peroxisome proliferator-activated receptors(PPARs) are members of the nuclear hormone receptor superfamily and ligand-activated transcription factors.PPARγ plays an important role in adipocyte differentiation,lipid storage and energy dissipation in adipose tissue,and is involved in the control of inflammatory reactions as well as in glucose metabolism through the improvement of insulin sensitivity.Growing evidence has demonstrated that activation of PPARγ has an antineoplastic effect in tumors,including colorectal cancer.High expression of PPARγ is detected in human colon cancer cell lines and adenocarcinoma.This review describes the molecular mechanisms by which PPARγ regulates tumorigenesis in colorectal cancer,and examines current clinical trials evaluating PPARγ agonists as therapeutic agents for colorectal cancer.

Role of peroxisome proliferator-activated receptors alpha and gamma in gastric ulcer: An overview of experimental evidences

Peroxisome proliferator-activated receptors(PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Three subtypes, PPARα, PPARβ/δ, and PPARγ, have been identifiedso far. PPARα is expressed in the liver, kidney, small intestine, heart, and muscle, where it activates the fatty acid catabolism and control lipoprotein assembly in response to long-chain unsaturated fatty acids, eicosanoids, and hypolipidemic drugs(e.g., fenofibrate). PPARβ/δ is more broadly expressed and is implicated in fatty acid oxidation, keratinocyte differentiation, wound healing, and macrophage response to very low density lipoprotein metabolism. This isoform has been implicated in transcriptional-repression functions and has been shown to repress the activity of PPARα or PPARγ target genes. PPARγ1 and γ2 are generated from a single-gene peroxisome proliferator-activated receptors gamma by differential promoter usage and alternative splicing. PPARγ1 is expressed in colon, immune system(e.g., monocytes and macrophages), and other tissues where it participates in the modulation of inflammation, cell proliferation, and differentiation. PPARs regulate gene expression through distinct mechanisms: Liganddependent transactivation, ligand-independent repression, and ligand-dependent transrepression. Studies in animals have demonstrated the gastric antisecretory activity of PPARα agonists like ciprofibrate, bezafibrate and clofibrate. Study by Pathak et al also demonstrated the effect of PPARα agonist, bezafibrate, on gastric secretion and gastric cytoprotection in various gastric ulcer models in rats. The majority of the experimental studies is on pioglitazone and rosiglitazone, which are PPARγ activators. In all the studies, both the PPARγ activators showed protection against the gastric ulcer and also accelerate the ulcer healing in gastric ulcer model in rats. Therefore, PPARα and PPARγ may be a target for gastric ulcer therapy. Finally, more studies are also needed to confirm the involvement of PPARs α and γ in gastric ulcer.

Troglitazone, a peroxisome proliferator-activated receptor γ ligand, induces growth inhibition and apoptosis of HepG2 human liver cancer cells

AIM: To examine the effect of troglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) ligand, on the proliferation and apoptosis of human liver cancer cells. METHODS: Liver cancer cell line HepG2 was cultured and treated with troglitazone. Cell proliferation was detected by 3-(4-,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay; apoptosis was detected by flow cytometry and terminal deoxynucleotidyl transferase- mediated nick end labeling of DNA fragmentation sites (TUNEL) assay; and apoptosis-related protein was detected by immunocytochemistry and Western blotting. RESULTS: Troglitazone inhibited growth and induced apoptosis of HepG2 cells in a dose-dependent manner, and induced activation of caspase-3 expression. Troglitazone not only drove apoptosis-inhibiting factor survivin to translocate incompletely from the nucleus to the cytoplasm, but also inhibited expression of survivin, while it did not affect expression of apoptosis-promoting factor Bax. CONCLUSION: PPARγ ligands inhibit growth and induce apoptosis of liver cancer cells, and may have applications for the prevention and treatment of liver cancer.

Peroxisome proliferator-activated receptor-γ is essential in the pathogenesis of gastric carcinoma

AIM:To investigate whether peroxisome proliferator-activated receptor γ (PPAR-γ) is expressed in human gastric carcinoma and whether PPAR-γ is a potential target for gastric carcinoma therapy.METHODS: PPAR-γ protein in gastric carcinoma was examined by immunohistochemistry. In the gastric carcinoma cell line MGC803, PPAR-γ, survivin, Skp2 and p27 protein and mRNA were examined by Western blotting and real-time reverse transcription-polymerase chain reaction, respectively; proliferation was examined by MTT; apoptosis was examined by chromatin staining with Hoechst 33342 and fluorescence activated cell sorting (FACS). and cell cycle was examined by FACS; the knockdown of PPAR-γ was done by RNA interference.RESULTS: A high level of expression of PPAR-γ was observed in human gastric carcinoma and in a human gastric carcinoma cell line MGC803. The PPAR-γ agonist 15-deoxy-12,14-prostaglandin J2 (15d-PGJ2) inhibited growth, and induced apoptosis and G1/G0 cell cycle arrest in MGC803 cells in a concentration-dependent and time-dependent manner. The effect of 15d-PGJ2 on MGC803 cells was not reversed by the selective and irreversible antagonist GW9662 for PPAR-γ. Furthermore, survivin and Skp2 expression were decreased, whereasp27 expression was enhanced following 15d-PGJ2 treatment in a dose-dependent manner in MGC803 cells. Interestingly, we also found that small interfering RNA for PPAR-γ inhibited growth and induced apoptosis in MGC803 cells. The inhibition of PPAR-γ function may be a potentially important and novel modality for treatment and prevention of gastric carcinoma.CONCLUSION: A PPAR-γ agonist inhibited growth of human gastric carcinoma MGC803 cells by inducing apoptosis and G1/G0 cell cycle arrest with the involvement of survivin, Skp2 and p27 and not via PPAR-γ.

EFFECT OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ACTIVATORS ON TUMOR NECROSIS FACTOR-αEXPRESSION IN NEONATAL RAT CARDIAC MYOCYTES

Objective To investigate the effect of peroxisome proliferator-activated receptor-α(PPARα) and PPARγactivators on tumor necrosis factor-α(TNFα) expression in neonatal rat cardiac myocytes. Methods Primary cultures of cardiac myocytes from 1- to 3-day-old Wistar rats were prepared, and myocytes were ex-posed to lipopolysaccharide (LPS) and varying concentrations of PPARαor PPARγactivator (fenofibrate or pioglitazone).RT-PCR and ELISA were used to measure TNFα, PPARα, and PPARγexpression in cultured cardiac myocytes. Transient tr-ansfection of TNFαpromoter with or without nuclear factor-kappaB (NF-κB) binding site to cardiac myocytes was performed. Results Pretreatment of cardiac myocytes with fenofibrate or pioglitazone inhibited LPS-induced TNFαmRNA and protein expression in a dose-dependent manner. However, no significant changes were observed on PPARαor PPARγmRNA expression when cardiac myocytes were pretreated with fenofibrate or pioglitazone. Proportional suppression of TNFαpromoter activity was observed when myocytes was transiently transfected with whole length of TNFαpromoter (-721/+17) after being stimulated with LPS and fenofibrate or pioglitazone, whereas no change of promoter activity was observed with transfection of TNFαreporter construct in deletion of NF-κB binding site (-182/+17). Conclusions PPARαand PPARγactivators may inhibit cardiac TNFαexpression but not accompanied by change of PPARαor PPARγmRNA expression. Therefore PPARαand PPARγactivators appear to play a role in anti-inflammation. The mechanism may partly be involved in suppression of the NF-κB pathway.

Role of peroxisome proliferator-activated receptors gene polymorphisms in type 2 diabetes and metabolic syndrome

Metabolic syndrome(MetS) and type 2 diabetes mellitus(T2DM) are the serious public health problems worldwide.Moreover,it is estimated that MetS patients have about five-fold greater risk of the T2 DM development compared with people without the syndrome.Peroxisome proliferator-activated receptors are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of MetS and T2 DM.All three members of the peroxisome proliferator-activated receptor(PPAR) nuclear receptor subfamily,PPARα,PPARp/5 and PPARγ are critical in regulating insulin sensitivity,adipogenesis,lipid metabolism,and blood pressure.Recently,more and more studies indicated that the gene polymorphism of PPARs,such as Leu^(162)Val and Val^(227)Ala of PPARα,+294T> C of PPARβ/δ,Pro^(12)Ala and C1431 T of PPARγ,are significantly associated with the onset and progressing of MetS and T2 DM in different population worldwide.Furthermore,a large body of evidence demonstrated that the glucose metabolism and lipid metabolism were influenced by gene-gene interaction among PPARs genes.However,given the complexity pathogenesis of metabolic disease,it is unlikely that genetic variation of a single locus would provide an adequate explanation of inter-individual differences which results in diverse clinical syndromes.Thus,gene-gene interactions and gene-environment interactions associated with T2 DM and MetS need future comprehensive studies.