PPARdelta Research Articles

Intratumoral Polymorphism of Peroxisome Proliferator-Activated Receptor Delta-87 T>C in Colorectal Cancer.

Peroxisome proliferator activated receptor delta (PPARD) is a nuclear receptor transcription factor whose single nucleotide polymorphism (SNP), especially PPARD-87 T>C (rs2016520), may play an important role in expression regulation of PPARD. But its expression patterns as well as contribution in colorectal cancer (CRC) are still controversial. In this study, whether the intratumoral heterogeneity of polymorphism of PPARD-87 T>C (rs2016520) existed and its influence in CRC were investigated. Tumor masses from primary CRC patients were collected during the operation of tumorectomy, specimens at the different sites of the same tumor mass were sampled and stored individually. The SNP of PPARD-87 T>C was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the expression of PPARD in vivo was observed by immunohistochemistry. The correlation of PPARD -87 T>C intratumoral polymorphism and the clinicopathological parameters of patients was analyzed statistically. Tumor samples were collected from 106 CRC patients (70 males and 36 females) with an average age of 61.04±13.67 years. A total number of 808 samples (7.60±1.60 per patient) were mainly harvested at peripheral superficial (n=376), central superficial (n=163), invasive front (n=112) and mesenteric cancer foci (n=42) of tumor tissues as well as cancerous adjacent mucosa (n=104). PCR-RFLP analysis showed that T/T (n=460, 56.9%) and T/C (n=334, 41.3%) were the main genotypes of -87 T>C among these samples. Furthermore, intratumoral genotype of -87 T>C was homogeneous in 90 patients and heterogeneous in other 16 patients. The intratumoral heterogeneity was related to patients' age (P=0.016), tumor location (P=0.011) and the grade of differentiation (P=0.022). For patients with intratumoral heterogeneity, immunochemistry showed the expressions of PPARD were not influenced by T/T or T/C genotypes. Intratumoral heterogeneity of PPARD-87 T>C wildly existed in CRC, and associated with patients' age, tumor location and differentiation. However, the immunochemistry assay revealed that there's no significant link between heterogeneity and expression of PPARD.

Peroxisome Proliferator Activated Receptor (PPAR) Delta Genetic Polymorphism in Saudi Normal Population

Background: Peroxisome proliferator-activated receptors (PPARs) are transcription factors that belong to the superfamily of nuclear hormone receptors. Three PPARs members, PPAR-alpha, PPAR- delta and PPAR gamma, have been characterized. PPAR-delta in humans is encoded by the PPARD gene and has been shown to possess a role in regulating fatty acid catabolism and energy homeostasis. Several polymorphisms have been identified in PPARD as potential functional variants. PPARD +294T > C polymorphism was shown to modify serum lipid concentrations in some ethnic groups. Aim: The current study aimed to screen the presence of the PPARD polymorphism in the Saudi population. Method: Blood samples were collected from normal individuals. Genomic DNA was extracted from peripheral blood monnuclear cells and the partial gene of the PPARD was amplified by polymerase chain reaction and subjected to gel electrophoresis. PPARD rs2016520 polymorphism was analyzed by polymerase chain reaction–restriction fragment length polymorphism. Results: The frequencies of CC, CT, and TT genotypes in normal Saudi population were 9.09%, 14.2% and 76.6%, respectively. Conclusion: The Saudi nationals seems to have low frequency of the PPARD +294T > C polymorphisms. Limitations: Relatively small sample size, serum lipid levels were not determined.

Corrigendum to: Intratumoral polymorphism of peroxisome proliferator-activated receptor delta -87 T>C in colorectal cancer

Corrigendum to: Intratumoral polymorphism of peroxisome proliferator-activated receptor delta -87 T>C in colorectal cancer

Siamese neem flower extract suppresses cholesterol absorption by interfering NPC1L1 and micellar property in vitro and in intestinal Caco-2 cells.

Siamese neem (Azadirachta indica A. Juss var. siamensis Valeton) (A. indica) leaf extract, a traditional ayurvedic medicine, has been reported to exhibit antipyretic, antibacterial, antidyslipidemic, and antihyperglycemia effects. This study investigated the mechanism of hypocholesterolemic effect of methanolic extract of Siamese neem flowers in in vitro studies and in Caco-2 cells. Pancreatic cholesterol esterase and 3-hydroxy 3-methylglutaryl-CoA (HMG-CoA) reductase activities were assessed. Cholesterol micelle formation was prepared for in vitro cholesterol physicochemical property analyses, micelle size and solubility, and transport of cholesterol into the Caco-2 cells. The expression of niemann-pick C1 like 1 (NPC1L1), and its major regulator, peroxisome proliferator-activated receptor δ (PPARδ), were determined by western blot and real time polymerase chain reaction, respectively. A. indica flower extract inhibited pancreatic cholesterol esterase activity and increased cholesterol micelles size. Uptake of cholesterol into Caco-2 cells was inhibited by A. indica flower extract in a dose-dependent manner. In addition, A. indica extract inhibited HMG-CoA reductase activity, resulting in low level of intracellular cholesterol accumulation, together with increased cytosolic NPC1L1 protein expression and decreased PPARδ gene expression. In conclusion, A. indica flower extract has cholesterol-lowering effects by inhibiting intestinal cholesterol absorption, interfering micellar cholesterol formation, and attenuating cholesterol synthesis. As such, A. indica flower extract has potential for developing into nutraceutical product for prevention of hypocholesterolemia.

6-Gingerol Normalizes the Expression of Biomarkers Related to Hypertension via PPARδ in HUVECs, HEK293, and Differentiated 3T3-L1 Cells.

Hypertension is a disease with a high prevalence and high mortality rates worldwide. In addition, various factors, such as genetic predisposition, lifestyle factors, and the abnormality of organs related to blood pressure, are involved in the development of hypertension. However, at present, there are few available drugs for hypertension that do not induce side effects. Although the therapeutic effects of ginger on hypertension are well established, the precise mechanism has not been elucidated. Therefore, this study was designed to evaluate the antihypertensive mechanism of 6-gingerol, one of the main ingredients of ginger, and to assist in the development of new drugs for hypertension without side effects. The antihypertensive effects and mechanism of 6-gingerol were identified through reverse transcription polymerase chain reaction (RT-PCR), western blotting, and immunocytochemical staining for biomarkers involved in hypertension in human umbilical vein endothelial cells (HUVECs), human embryonal kidney cells (HEK293 cells), and mouse preadipocytes (3T3-L1 cells). The lipid accumulation in differentiated 3T3-L1 cells was evaluated by using Oil Red O staining. 6- Gingerol increased the level of phosphorylated endothelial nitric oxide synthase (eNOS) protein but decreased that of vascular cell adhesion protein 1 (VCAM1) and tumor necrosis factor alpha (TNFα) in HUVECs. In HEK293 cells, the expression of the epithelial sodium channel (ENaC) protein was reduced by 6-gingerol. Lipid accumulation was attenuated by 6-gingerol treatment in differentiated 3T3-L1 cells. These effects were regulated via peroxisome proliferator-activated receptor delta (PPARδ). 6-Gingerol ameliorated the expression of biomarkers involved in the development of hypertension through PPARδ in HUVECs, HEK293, and differentiated 3T3-L1 cells.

Peroxisome Proliferator Activated Receptor-Delta Controls Fat Oxidation in Alloreactive T Cells

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a curative treatment for high-risk leukemia and multiple non-malignant hematologic disorders. However, the routine use of alloHSCT remains limited by acute graft-versus-host disease (GVHD), where activated donor T cells attack and destroy host tissues in the skin, gastrointestinal tract, and liver. We have previously shown that GVHD-causing T cells increase fat oxidation compared to both syngeneic and naive T cells. To explore this adaptation mechanistically, we studied the role of the transcription factor Peroxisome Proliferator Activated Receptor delta (PPAR-δ) in alloreactive donor T cells during the initiation of GVHD. By day 7 post-transplant, alloreactive T cells up-regulated PPAR-δ >5-fold compared to pre-transplant naive T cells (p<0.0001, Figure 1A). Furthermore, PPAR-δ was necessary for maximally severe GVHD, as major-MHC mismatched B6xDBA2 F1 mice receiving donor T cells deficient in exon 4 of PPAR-δ (PPAR-δ KO) survived longer than mice receiving wildtype (WT) T cells (p<0.007, Figure 1B).We next investigated the mechanism underlying this observed decrease in GVHD severity. As a transcription factor, PPAR-δ controls expression of multiple genes involved in fat transport and oxidation. To determine its role in alloreactive cells, RNA was collected from CD4 and CD8 T cells on day 7 post-transplant and levels of 8 known PPAR-δ targets quantitated by RT-PCR. These 8 targets were selected from a longer list of genes known to be up-regulated in alloreactive cells. Transcript levels of both carnitine palmitoyl transferase-1a (CPT-1a) and CD36 decreased in PPAR-δ KO CD8 T cells (Figure 2A), with decreases in CD36 protein levels confirmed by immunoblot (Figure 2B). Interestingly, changes in CPT-1a and CD36 did not occur in PPAR-δ KO CD4 T cells. To assess the functional consequence of these changes, day 7 WT versus PPAR-δ KO CD8 T cells were plated with 3H-palmitate and fat oxidation measured ex vivo. Consistent with a decrease in expression of genes involved in fat transport and mitochondrial fat import, fat oxidation decreased by >75% in PPAR-δ KO CD8 cells (Figure 2C). However, despite these decreases, the number of PPAR-δ KO CD8 T cells recovered on day 7 post-transplant was equivalent to WT T cells (Figure 3A, left panel). In contrast, PPAR-δ KO CD4 T cell numbers decreased by 30% on day 7, despite equivalent levels of CD36 and CPT1a (Figure 3A, right panel).Finally, we addressed whether pharmacologic inhibition of PPAR-δ might also effectively mitigate GVHD. Administration of the PPAR-δ inhibitor GSK3787 on days 3-6 post-transplant substantially decreased the number of donor T cell recovered on day 7 (Figure 3B), with PPAR-δ impairment corroborated by a decrease in CPT1a gene transcription. However, instead of improving recipient health, GSK3787 treatment instead worsened weight loss and increased rates of post-transplant morbidity and mortality. From these data, we conclude that PPAR-δ is necessary in alloreactive T cells to cause maximally severe GVHD and that mechanistically, an absence of PPAR-δ impairs fat oxidation in CD8 T cells without impacting CD8 T cell numbers. In contrast, PPAR-δ deficiency decreases the number of CD4 T cells post-transplant, but does so without impacting CPT1a or CD36 levels, highlighting clear differences in metabolic reprogramming between CD4 and CD8 alloreactive cells. Finally, our data suggest that systemic inhibition of PPAR-δ post-transplant is not feasible given a sharp increase in toxicity. Future work will elucidate the mechanism of PPAR-δ in CD4 T cells, define the additional metabolic adaptations of CD8 cells which lack PPAR-δ, and determine if similar changes occur in human T cells. Together, these studies will test whether cellular inhibition of PPAR-δ represents a clinically-relevant, future therapy for GVHD. DisclosuresNo relevant conflicts of interest to declare.

PPARβ/δ-agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes.

Astrocytes are the gatekeepers of neuronal energy supply. In neurodegenerative diseases, bioenergetics demand increases and becomes reliant upon fatty acid oxidation as a source of energy. Defective fatty acid oxidation and mitochondrial dysfunctions correlate with hippocampal neurodegeneration and memory deficits in Alzheimer's disease (AD), but it is unclear whether energy metabolism can be targeted to prevent or treat the disease. Here we show for the first time an impairment in fatty acid oxidation in human astrocytes derived from induced pluripotent stem cells of AD patients. The impairment was corrected by treatment with a synthetic peroxisome proliferator activated receptor delta (PPARβ/δ) agonist GW0742 which acts to regulate an array of genes governing cellular metabolism. GW0742 enhanced the expression of CPT1a, the gene encoding for a rate-limiting enzyme of fatty acid oxidation. Similarly, treatment of a mouse model of AD, the APP/PS1-mice, with GW0742 increased the expression of Cpt1a and concomitantly reversed memory deficits in a fear conditioning test. Although the GW0742-treated mice did not show altered astrocytic glial fibrillary acidic protein-immunoreactivity or reduction in amyloid beta (Aβ) load, GW0742 treatment increased hippocampal neurogenesis and enhanced neuronal differentiation of neuronal progenitor cells. Furthermore, GW0742 prevented Aβ-induced impairment of long-term potentiation in hippocampal slices. Collectively, these data suggest that PPARβ/δ-agonism alleviates AD related deficits through increasing fatty acid oxidation in astrocytes and improves cognition in a transgenic mouse model of AD.

Analysis of the PPARD gene expression level changes in football players in response to the training cycle

The PPARD gene codes protein that belongs to the peroxisome proliferator-activated receptor (PPAR) family engaged in a variety of biological processes, including lipid metabolism in muscle cells. In this study, we assess the relationship between PPARD gene expression lipid metabolism parameters and the variation of the PPARD gene expression before (T1) and after 12 hours of training (T2) sessions in a group of football players. Peripheral blood lymphocytes were obtained from 22 football players (17.5±0.7 years, 178±0.7 cm, 68.05±9.18 kg). The PPARD gene expression, analyzed by quantitative polymerase chain reaction (qPCR), was significantly higher after T2 (p = 0.0006). Moreover, at the end of the training cycle, there was a significant decrease in relative fat tissue (FAT) (%) (p = 0.01) and absolute FAT (kg) (p = 0.01). A negative correlation was observed between absolute FAT (kg) and PPARD gene expression level in T2 (p = 0.03). The levels of cholesterol and triglyceride (TG) fractions were not significantly different (p >0.05) before and after training. No significant relationship between PPARD expression and cholesterol or TG levels was found. We found that physical training affects PPARD expression. Moreover, the negative correlation between PPARD expression and absolute FAT (kg) level may be indicative of the contribution of PPARD in metabolic adaptation to increased lipid uptake that can be used to control the body composition of athletes.

The Role of PPAR-δ in Metabolism, Inflammation, and Cancer: Many Characters of a Critical Transcription Factor.

Peroxisome proliferator-activated receptor-delta (PPAR-δ), one of three members of the PPAR group in the nuclear receptor superfamily, is a ligand-activated transcription factor. PPAR-δ regulates important cellular metabolic functions that contribute to maintaining energy balance. PPAR-δ is especially important in regulating fatty acid uptake, transport, and β-oxidation as well as insulin secretion and sensitivity. These salutary PPAR-δ functions in normal cells are thought to protect against metabolic-syndrome-related diseases, such as obesity, dyslipidemia, insulin resistance/type 2 diabetes, hepatosteatosis, and atherosclerosis. Given the high clinical burden these diseases pose, highly selective synthetic activating ligands of PPAR-δ were developed as potential preventive/therapeutic agents. Some of these compounds showed some efficacy in clinical trials focused on metabolic-syndrome-related conditions. However, the clinical development of PPAR-δ agonists was halted because various lines of evidence demonstrated that cancer cells upregulated PPAR-δ expression/activity as a defense mechanism against nutritional deprivation and energy stresses, improving their survival and promoting cancer progression. This review discusses the complex relationship between PPAR-δ in health and disease and highlights our current knowledge regarding the different roles that PPAR-δ plays in metabolism, inflammation, and cancer.

Synthesis of a unique dimethyl thiazoline containing intermediate of novel peroxisome proliferator-activated receptors(PPAR)δ agonists

Peroxisome proliferator-activated receptor delta (PPARδ) is considered as a promising biological target for the development of new drugs to treat metabolic syndrome including hyperlipidemia. In this study, a simple and efficient method for the preparation of a unique dimethyl thiazoline containing intermediate (13) of new PPARδ agonists as GW501516 analogue is described. The intermediate 13 was readily obtained by coupling reaction of 4-(chloromethyl)-5,5-dimethyl-2-(4-(trifluoromethyl)phenyl)-4,5-dihydrothiazole (11) with 4-mercapto-2-methylphenol (12) in the presence of tetrabutylammonium hydrogensulfate (TBAHS) and Cs2CO3 in DMF at 80 °C for 1 h. This unique intermediate could be useful for the synthesis of various novel PPARδ agonists to understand the structural and biological significance of PPARδ.

A genome-wide detection of selection signatures in conserved and commercial pig breeds maintained in Poland

BackgroundIdentification of selection signatures can provide a direct insight into the mechanism of artificial selection and allow further disclosure of the candidate genes related to the animals’ phenotypic variation. Domestication and subsequent long-time selection have resulted in extensive phenotypic changes in domestic pigs, involving a number of traits, like behavior, body composition, disease resistance, reproduction and coat color. In this study, based on genotypes obtained from PorcineSNP60 Illumina assay we attempt to detect both diversifying and within-breed selection signatures in 530 pigs belonging to four breeds: Polish Landrace, Puławska, Złotnicka White and Złotnicka Spotted, of which the last three are a subject of conservative breeding and substantially represent the native populations.ResultsA two largely complementary statistical methods were used for signatures detection, including: pairwise FST and relative extended haplotype homozygosity (REHH) test. Breed-specific diversifying selection signals included several genes involved in processes connected with fertility, growth and metabolism which are potentially responsible for different phenotypes of the studied breeds. The diversifying selection signals also comprised PPARD gene that was previously found to have a large effect on the shape of the external ear in pigs or two genes encoding neuropeptide Y receptors (Y2 and Y5) involved in fat deposition and stress response which are important features differentiating the studied breeds. REHH statistics allowed detecting several within-breed selection signatures overlapping with genes connected with a range of functions including, among others: metabolic pathways, immune system response or implantation and development of the embryo.ConclusionsThe study provides many potential candidate genes with implication for traits selected in the individual breeds and gives strong basis for further studies aiming at identification of sources of variation among the studied pig breeds.

The PPARδ agonist GW0742 restores neuroimmune function by regulating Tim-3 and Th17/Treg-related signaling in the BTBR autistic mouse model

Autism spectrum disorders (ASD) are neurodevelopmental disorders that are characterized by repetitive behaviors, and impairments in communication and social interaction. Studies have shown that activation of peroxisome proliferator-activated receptor-delta (PPARδ) causes anti-inflammatory effects in animal models of neuroinflammatory diseases. We investigated the possible anti-inflammatory effect of a PPARδ agonist, GW0742 in the BTBR T+ Itpr3tf/J (BTBR) mouse model of autism. BTBR and C57BL/6 (B6) mice were treated orally with GW0742 (30 mg/kg, p.o., once daily) for 7 days. Effect of GW0742 treatment on repetitive behavior, marble burying, and thermal sensitivity response was assessed on day 8. We further examined the effect of GW0742 treatment on immunological parameters in splenocytes using flow cytometry (CD4+TIM-3+, IL-17A+TIM-3+, IL-17A+CD4+, RORγT+TIM-3+, RORγT+CD4+, Stat3+TIM-3+, Foxp3+TIM-3+, Foxp3+CD4+, and IFN-γ+CD4+). We also explored the effects of GW0742 on mRNA and protein expression of TIM-3, IL-17A, RORγT, Stat3, IFN-γ, Foxp3, and IL-10 in the brain tissue using RT-PCR and western blot analyses. GW0742 treatment substantially decreased repetitive behaviors, and lowered thermal sensitivity response in BTBR mice. GW0742 attenuated the expression of inflammatory markers such as IL-17A, RORγT, Stat3, TIM-3, and IFN-γ, while upregulating anti-inflammatory markers such as IL-10/Foxp3 both in the brain and periphery of BTBR mice. In conclusion, this study suggests that GW0742 corrects neurobehavioral dysfunction in BTBR mice which is concurrent with modulation of multiple signaling pathways.

The Effect of Diet on Improved Endurance in Male C57BL/6 Mice.

The consumption of fruits and vegetables appears to help with maintaining an adequate level of exercise and improves endurance. However, the mechanisms that are involved in this process are not well understood. In the current study, the impact of diets enriched in fruits and vegetables (GrandFusion®) on exercise endurance was examined in a mouse model. GrandFusion (GF) diets increased mitochondrial DNA and enzyme activity, while they also stimulated mitochondrial mRNA synthesis in vivo. GF diets increased both the mRNA expression of factors involved in mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), mitochondrial transcription factor A (Tfam), estrogen-related receptor alpha (ERRα), nuclear respiratory factor 1 (NRF-1), cytochrome c oxidase IV (COXIV) and ATP synthase (ATPsyn). Mice treated with GF diets showed an increase in running endurance, rotarod perseverance and grip strength when compared to controls who were on a regular diet. In addition, GF diets increased the protein expression of phosphorylated AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), PGC-1α and peroxisome proliferator-activated receptor delta (PPAR-δ), which was greater than exercise-related changes. Finally, GF reduced the expression of phosphorylated ribosomal protein S6 kinase 1 (p-S6K1) and decreased autophagy. These results demonstrate that GF diets enhance exercise endurance, which is mediated via mitochondrial biogenesis and function.

Modulation of xenobiotic nuclear receptors in high-fat diet induced non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the western countries. The histological spectrum of NAFLD includes simple steatosis, steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Nuclear receptors are a large group of ligand-dependent transcription factors that sense the environmental and endogenous changes and regulate numerous physiological and pathological processes. Accumulating evidence has suggested that a dysregulation of nuclear receptors in NAFLD may effect on the metabolism of endogenous and exogenous chemicals in the liver. The current study was designed to systematically characterize the time-dependent modulation of nuclear receptors including the peroxisome proliferator-activated receptors (PPARs), the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), the liver X receptor (LXR), and the farnesoid X receptor (FXR) in the progression of NAFLD. Male C57BL/6 mice fed by a high fat diet were used to induce NAFLD. Hepatic steatosis, lobular inflammation, progressive fibrosis, increased hepatocyte DNA synthesis, and liver tumor formation were observed at various time points in our mouse model. During the development of hepatic steatosis (8–16 weeks), PPARα was activated as indicated by its target genes as well as the elevated peroxisomal acyl-CoA oxidase activity. The mRNA level of Pparγ was also upregulated while Pparδ gene expression was significantly reduced during the development of hepatic steatosis. PXR target gene Cyp3a11 was consistently increased 3-4-fold in addition to the increased microsomal Cyp3a enzymatic activity at all stages of NAFLD. In contrast, CAR mediated Cyp2b10 gene expression was found increased only by week 12. LXRα target genes Abcg5 and Abcg8 were significantly elevated during the whole course of NAFLD. The mRNA of Fxr was downregulated at 24 and 32 weeks in high fat diet fed mice, which might correlate with the development of progressive fibrosis at the stage of steatohepatitis. The results of our study provided a systematic evaluation of the changes of nuclear receptors and their downstream chemicalmetabolism and transport enzymes in the progression of NAFLD.

A metabolic interplay coordinated by HLX regulates myeloid differentiation and AML through partly overlapping pathways

The H2.0-like homeobox transcription factor (HLX) regulates hematopoietic differentiation and is overexpressed in Acute Myeloid Leukemia (AML), but the mechanisms underlying these functions remain unclear. We demonstrate here that HLX overexpression leads to a myeloid differentiation block both in zebrafish and human hematopoietic stem and progenitor cells (HSPCs). We show that HLX overexpression leads to downregulation of genes encoding electron transport chain (ETC) components and upregulation of PPARδ gene expression in zebrafish and human HSPCs. HLX overexpression also results in AMPK activation. Pharmacological modulation of PPARδ signaling relieves the HLX-induced myeloid differentiation block and rescues HSPC loss upon HLX knockdown but it has no effect on AML cell lines. In contrast, AMPK inhibition results in reduced viability of AML cell lines, but minimally affects myeloid progenitors. This newly described role of HLX in regulating the metabolic state of hematopoietic cells may have important therapeutic implications.

Alpha-lipoic acid reduces retinal cell death in diabetic mice

Oxidative stress plays an important role in the development of diabetic retinopathy. Here, we examined whether α-lipoic acid (α-LA), a natural antioxidant, attenuated retinal injury in diabetic mice. The α-LA was orally administered to control mice or mice with streptozotocin-induced diabetes. We found that α-LA reduced oxidative stress, decreased and increased retinal 4-hydroxy-2-nonenal and glutathione peroxidase, respectively, and inhibited retinal cell death. Concomitantly, α-LA reversed the decreased activation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase, and increased the levels of peroxisome proliferator-activated receptor delta and sirtuin3 in diabetic mouse retinas, similar to results shown after metformin treatment of retinal pigment epithelial cells (RPE) exposed to high glucose. Moreover, α-LA lowered the levels of O-linked β-N-acetylglucosamine transferase (OGT) and thioredoxin-interacting protein (TXNIP) in diabetic retinas that were more pronounced after metformin treatment of RPE cells. Importantly, α-LA lowered interactions between AMPK and OGT as shown by co-immunoprecipitation analyses, and this was accompanied by less cell death as measured by double immunofluorescence staining by terminal deoxynucleotide transferase-mediated dUTP nick-end labelling and OGT or TXNIP in retinal ganglion cells. Consistently, α-LA lowered the levels of cleaved poly(ADP-ribose) polymerase and pro-apoptotic marker cleaved caspase-3 in diabetic retinas. Our results indicated that α-LA reduced retinal cell death partly through AMPK activation or OGT inhibition in diabetic mice.

Associations between hypertension and the peroxisome proliferator-activated receptor-\u03b4 (PPARD) gene rs7770619 C>T polymorphism in a Korean population

BackgroundOxidative stress is associated with the increased risk of hypertension (HTN). This cross-sectional study is aimed to identify the association between the peroxisome proliferator-activated receptor-δ (PPARD) polymorphism and plasma malondialdehyde (MDA), an oxidative stress marker which is related to HTN development, and to determine whether PPARD gene is a candidate gene for HTN.ResultsOne thousand seven hundred ninety-three individuals with normal blood pressure (BP) and HTN were included in this cross-sectional study. The Korean Chip was used to obtain genotype data. Through the analysis, the ten most strongly associated single-nucleotide polymorphisms (SNPs) were nominated for an MDA-related SNP. Among them, the rs7770619 polymorphism was identified in the PPARD gene. The CT genotype of the PPARD rs7770619 C>T polymorphism was associated with a lower risk of HTN before and after adjustments for age, sex, body mass index, smoking, and drinking. Significant associations were observed between plasma MDA and the PPARD rs7770619 C>T polymorphism and between systolic BP and the PPARD rs7770619 SNP in the controls. The CT controls showed significantly lower systolic BP and plasma MDA than the CC controls. Additionally, in both controls and HTN patients, the CT subjects showed significantly lower serum glucose and higher adiponectin levels than the CC subjects. Furthermore, the CT subjects showed significantly higher serum free fatty acid levels than the CC subjects among the HTN patients.ConclusionThis is a new finding that the PPARD rs7770619 C>T SNP is a novel candidate variant for HTN based on the association between PPARD and plasma MDA in a Korean population.

Serum Angiopoietin-like peptide 4 levels in patients with hepatic steatosis

ObjectivesAngiopoietin-like peptide 4 (ANGPTL-4) plays an important role in lipid metabolism by inhibiting the enzyme lipoprotein lipase. This effect of ANGPTL-4 results in suppression of the release of plasma triglyceride-derived fatty acids. Increase in fatty acid levels entering to the liver and abnormalities in their secretion is one of the main mechanisms in pathogenesis of hepatic steatosis. In this study, we aimed to investigate the role of ANGPTL-4 in pathogenesis of hepatic steatosis by determining its levels in patients with fatty liver disease. MethodsTotally 51 patients (age: 37.9 ± 9.9 years, M/F) diagnosed with grade 2–3 hepatic steatosis with ultrasound and 30 healthy volunteers (age: 34.8 ± 9.5 years, M/F) were included in the study. In both groups, routine biochemical tests including fasting blood glucose, fasting insulin levels, triglyceride, total cholesterol, LDL- cholesterol, HDL-cholesterol, AST, ALT, ALP, GGT levels were measured together with the ANGPTL-4 levels. In determination of ANGPTL-4 levels, ELISA was performed. ResultsWhen compared with the control group, ANGPTL-4 levels were determined to be decreased in patients with hepatic steatosis (369 ± 243 vs 303 ± 286 ng/mL, p = 0.014). There was a negative weak correlation observed between ANGPTL-4 and triglyceride levels (r = −0.246, p = 0.027). Among all groups, when patients with and without insulin resistance were compared; ANGPTL-4 levels were determined to be similar. While fasting blood glucose levels were similar between 2 groups; fasting insulin and triglyceride levels were determined to be increased in hepatic steatosis group (Insulin 17.7 ± 12 vs 7.4 ± 3.3 µIU/mL, p < 0.001, triglyceride 158 ± 46.4 vs 118 ± 59.8 mg/dL p < 0.001). ConclusionsWe have determined lower serum ANGPTL-4 levels in patients with hepatic steatosis. ANGPTL-4 that is regulating LPL activity plays an important role in fatty liver disease pathogenesis via free fatty acid metabolism and peroxisome proliferator-activated receptor-delta (PPAR-δ). We believe that the results of this study would elucidate the investigations about the mechanism of fatty liver disease development and treatments targeting ANGPTL-4.

Physical training improves thermogenesis and insulin pathway, and induces remodeling in white and brown adipose tissues.

Physical training (PT) has been considered as a treatment in metabolic syndrome (MS), since it induces thermogenic activity in brown (BAT) and white (WAT) adipose tissues. We evaluated the therapeutic effect of PT on activity of WAT and BAT in rats with MS induced by high-fat diet (30% lard) for 13weeks and submitted, for the last 6weeks, to swimming or kept sedentary (SED) rats. MS-SED rats compared to control diet (CT-SED) rats showed low physical fitness and high levels of glucose, insulin, homeostasis evaluation of insulin resistance (HOMA-IR), homeostasis evaluation of the functional capacity of β-cells (HOMA-β), and blood pressure. The gastrocnemius muscle decreased in peroxisome proliferator-activated receptor gamma coactivator 1-alpha and beta (PGC-1α, PGC-1β), and uncoupled protein 2 and 3 (UCP2 and UCP3) expressions. Both WAT and BAT increased in the adipocyte area and decreased in blood vessels and fibroblast numbers. WAT increased in expression of pro-inflammatory adipokines and decreased in anti-inflammatory adipokine and adiponectin. WAT and gastrocnemius showed impairment in the insulin signaling pathway. In response to PT, MS rats showed increased physical fitness and restoration of certain biometric and biochemical parameters and blood pressure. PT also induced thermogenic modulations in skeletal muscle, WAT and BAT, and also improved the insulin signaling pathway. Collectively, PT was effective in treating MS by inducing improvement in physical fitness and interchangeable effects between skeletal muscle, WAT and BAT, suggesting a development of brown-like adipocyte cells.

PPARD rs7770619 polymorphism in a Korean population: Association with plasma malondialdehyde and impaired fasting glucose or newly diagnosed type 2 diabetes.

Both the peroxisome proliferator-activated receptor delta gene ( PPARD) and malondialdehyde plasma concentrations may play a role in impaired glucose metabolism. The aim of this work was to determine whether PPARD is a candidate gene for impaired fasting glucose or type 2 diabetes and whether a particular genetic variant shows association with plasma malondialdehyde levels. Among the 10 single-nucleotide polymorphisms that were most strongly associated with malondialdehyde, the rs7770619 polymorphism in PPARD was analysed in 1798 subjects with normal fasting glucose, impaired fasting glucose and newly diagnosed type 2 diabetes. Our data demonstrate that the CT genotype of the rs7770619 is associated with a lower risk of impaired fasting glucose or type 2 diabetes together with lower plasma levels of malondialdehyde in both groups ( p < 0.05). Glucose levels and the rs7770619 are significantly associated in individuals with normal fasting glucose, and a trend towards an association between glucose levels and rs7770619 is also observed in individuals with impaired fasting glucose or type 2 diabetes. In conclusion, PPARD rs7770619 is a novel candidate variant for impaired fasting glucose and type 2 diabetes and shows association with malondialdehyde levels. Future work is required to understand the mechanisms for these associations and the clinical implications of our findings.