Peroxisome Proliferator-activated Receptor Gamma Protein Research Articles

The Mechanism of the Anti-Obesity Effects of a Standardized Brassica juncea Extract in 3T3-L1 Preadipocytes and High-Fat Diet-Induced Obese C57BL/6J Mice.

Obesity is a global health concern. Recent research has suggested that the development of anti-obesity ingredients and functional foods should focus on natural products without side effects. We examined the effectiveness and underlying mechanisms of Brassica juncea extract (BJE) in combating obesity via experiments conducted in both in vitro and in vivo obesity models. In in vitro experiments conducted in a controlled environment, the application of BJE demonstrated the ability to suppress the accumulation of lipids induced by MDI in 3T3-L1 adipocytes. Additionally, it downregulated adipogenic-related proteins peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer-binding protein-α (C/EBP-α), adipocyte protein 2 (aP2), and lipid synthesis-related protein acetyl-CoA carboxylase (ACC). It also upregulated the heat generation protein peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and fatty acid oxidation protein carnitine palmitoyltransferase-1 (CPT-1). The oral administration of BJE decreased body weight, alleviated liver damage, and inhibited the accumulation of lipids in mice with diet-induced obesity resulting from a high-fat diet. The inhibition of lipid accumulation by BJE in vivo was associated with a decreased expression of adipogenic and lipid synthesis proteins and an increased expression of heat generation and fatty acid oxidation proteins. BJE administration improved obesity by decreasing adipogenesis and activating heat generation and fatty acid oxidation in 3T3-L1 cells and in HFD-induced obese C57BL/6J mice. These results suggest that BJE shows potential as a natural method for preventing metabolic diseases associated with obesity.

Functionally conserved PPARG exonic circRNAs enhance intramuscular fat deposition by regulating PPARG and HSL

Circular RNAs (circRNA) are a kind of endogenous biological macromolecules that play significant roles in many biological processes, including adipogenesis, a precisely orchestrated process that is mediated by a large number of factors. Among them, peroxisome proliferator-activated receptor gamma (PPARG), is undoubtedly the most important regulator of adipocyte development in all types of adipose tissue. The formation of intramuscular fat (IMF), is a key factor that influences the meat quality in livestock animals. PPARG has been demonstrated to show a positive correlation with IMF deposition although the regulatory mechanism involved is not known. This study demonstrates that PPARG mediates IMF deposition by producing multiple exonic circRNAs (circPPARGs). Three circPPARGs promote adipogenic differentiation and inhibit the proliferation of intramuscular preadipocytes and these effects are conserved across several species including buffaloes, cattle and mice. Notably, circPPARG1 interacts with PPARG protein to inhibit the transcription of hormone sensitive lipase (HSL) involved in lipolysis. In addition, the positive effects of circPPARG1 on IMF deposition were identified in mice in vivo. Thus, PPARG drives IMF deposition, not only through the common transcription factor pathway, but also by producing circRNAs. This study provides new insights into our understanding of the regulatory mechanisms of PPARG in IMF deposition.

The obesogenic side of Genistein.

Genistein (GN) has been highly recommended for its medicinal properties like anticancer, antidiabetic, antihyperlipidemic, antiviral, and antioxidant activities among others. Recently, scientists realized that Genistein is an endocrine disruptor. It is an obesogen that interferes with the endocrine system causing obesity through many mechanisms like inducing adipocyte differentiation, lipid accumulation, and transformation of some stem cells into adipocytes (bone marrow mesenchymal stem cells for example) in vitro. Animal studies show that GN upregulates genes associated with adipogenesis like CCAAT/enhancer binding protein alpha (Cebpα), CCAAT/enhancer binding protein beta (Cebpβ), and PPARγ. In silico studies reveal a strong binding affinity for estrogen receptors. All these findings were contingent on concentration and tissues. It is beyond dispute that obesity is one of the most frustrating medical conditions under the sun. The pathophysiology of this disease was first attributed to a high-calorie diet and lack of physical activity. However, studies proved that these two factors are not enough to account for obesity in both children and adults. This mini review highlights how Genistein interaction with the peroxisome proliferator-activated receptor gamma protein can cause obesity.

Identification of antidiabetic inhibitors from Allophylus villosus and Mycetia sinensis by targeting α-glucosidase and PPAR-γ: In-vitro, in-vivo, and computational evidence

Diabetes mellitus (DM) is a metabolic disorder arising from insulin deficiency and defectiveness of the insulin receptor functioning on transcription factor where the body loses control to regulate glucose metabolism in β-cells, pancreatic and liver tissues to homeostat glucose level. Mainstream medicines used for DM are incapable of restoring normal glucose homeostasis and have side effects where medicinal plant-derived medicine administrations have been claimed to cure diabetes or at least alleviate the significant symptoms and progression of the disease by the traditional practitioners. This study focused on screening phytocompounds and their pharmacological effects on anti-hyperglycemia on Swiss Albino mice of n-hexane, ethyl acetate, and ethanol extract of both plants Mycetia sinensis and Allophylus villosus as well as the in-silico investigations. Qualitative screening of phytochemicals and total phenolic and flavonoid content estimation were performed significantly in vitro analysis. FTIR and GC–MS analysis précised the functional groups and phytochemical investigations where FTIR scanned 14, 23 & 17 peaks in n-hexane, ethyl acetate, and ethanol extracts of Mycetia sinensis whereas the n-hexane, ethyl acetate, and ethanol extracts of Allophylus villosus scanned 11 peaks, 18 peaks, and 29 peaks, respectively. In GC–MS, 24 chemicals were identified in Mycetia sinensis extracts, whereas 19 were identified in Allophylus villosus extracts. Moreover, both plants' ethyl acetate and ethanol fractioned extracts were reported significantly (p < 0.05) with concentrations of 250 mg and 500 mg on mice for oral glucose tolerance test, serum creatinine test and serum alkaline phosphatase test. In In silico study, a molecular docking study was done on these 43 phytocompounds identified from Mycetia sinensis and Allophylus villosus to identify their binding affinity to the target Alpha Glucosidase (AG) and Peroxisome proliferator-activated receptor gamma protein (PPARG). Therefore, ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis, quantum mechanics-based DFT (density-functional theory), and molecular dynamics simulation were done to assess the effectiveness of the selected phytocompounds. According to the results, phytocompounds such as 2,4-Dit-butyl phenyl 5-hydroxypentanoate and Diazo acetic acid (1S,2S,5R)-2-isopropyl-5-methylcyclohexyl obtained from Mycetia sinensis and Allophylus villosus extract possess excellent antidiabetic activities.

Cross-talk between PPARγ, NF-κB, and p38 MAPK signaling mediates the ameliorating effects of bergenin against the iron overload-induced hepatotoxicity

Hepatotoxicity is a serious health problem that associates the iron overload diseases such as thalassemia and sickle cell anemia. Induction of oxidative tissue injury and inflammation largely contributes to the iron-induced hepatotoxicity. The current study investigated the hepatoprotective potential of bergenin against the iron overload-associated hepatotoxicity. Male Wistar rats were treated with 30 mg/kg iron-dextran every other day over a ten-day period to establish an iron overload model. Bergenin was given in 80 mg/kg/day over the ten-day experimental period. Liver and blood specimens were then collected and subjected to various biochemical, histopathological, and molecular analyses. The results indicated that bergenin significantly decreased hepatic iron content and improved the hepatocellular integrity as demonstrated by reduced activity of the intracellular liver enzymes in the sera of the iron-intoxicated rats and alleviation of the iron-induced histopathological anomalies. Additionally, it alleviated the iron-induced oxidative tissue injury and improved the antioxidant potential of the liver tissue as reflected by decreased DNA oxidative damage and lipid peroxidation along with improved activity of the antioxidant enzymes. Equally important, bergenin attenuated the iron-evoked inflammation as indicated by down-regulation of the tumor necrosis factor alpha, interleukin-1 beta, myeloperoxidase, and cyclooxygenase-2. Mechanistically, bergenin suppressed the iron-induced nuclear translocation of the inflammatory transcription factor nuclear factor kappa B and phosphorylation of the inflammatory protein p38 mitogen-activated protein kinase. Interestingly, bergenin enhanced expression of the antioxidant and anti-inflammatory protein peroxisome proliferator-activated receptor gamma in the iron-intoxicated rats. Collectively, the presented study highlights the attenuating activity of bergenin on the iron-evoked hepatocellular injury and inflammation that is potentially mediated through targeting p38 mitogen-activated protein kinase and nuclear factor kappa B signaling as well as peroxisome proliferator-activated receptor gamma protein expression.

Network Pharmacology Study to Reveal the Potentiality of a Methanol Extract of Caesalpinia sappan L. Wood against Type-2 Diabetes Mellitus.

Caesalpinia sappan L. (CS) is widely used to treat diabetic complications in south-east Asia, specifically in traditional Chinese medicine. This study intends to explain the molecular mechanism of how chemical constituents of CS interrelate with different signaling pathways and receptors involved in T2DM. GC-MS was employed to identify the chemical compounds from the methanol extract of CS wood (MECSW). Lipinski’s rule of five was applied, and 33 bioactive constituents have been screened from the CS extract. After that, 124 common targets and 26 compounds associated with T2DM were identified by mining several public databases. Protein–protein interactions and compound-target network were constructed using the STRING database and Cytoscape tool. Protein–protein interactions were identified in 121 interconnected nodes active in T2DM and peroxisome proliferator-activated receptor gamma (PPARG) as key target receptors. Furthermore, pathway compound target (PCT) analysis using the merger algorithm plugin of Cytoscape revealed 121 nodes from common T2DM targets, 33 nodes from MECSW compounds and 9 nodes of the KEGG pathway. Moreover, network topology analysis determined “Fisetin tetramethyl ether” as the key chemical compound. The DAVID online tool determined seven signaling receptors, among which PPARG was found most significant in T2DM progression. Gene ontology and KEGG pathway analysis implied the involvement of nine pathways, and the peroxisome proliferator-activated receptor (PPAR) pathway was selected as the hub signaling pathway. Finally, molecular docking and quantum chemistry analysis confirmed the strong binding affinity and reactive chemical nature of fisetin tetramethyl ether with target receptors exceeding that of the conventional drug (metformin), PPARs agonist (rosiglitazone) and co-crystallized ligands, indicating that fisetin could be a potential drug of choice in T2DM management. This study depicts the interrelationship of the bioactive compounds of MECSW with the T2DM-associated signaling pathways and target receptors. It also proposes a more pharmaceutically effective substance, fisetin tetramethyl ether, over the standard drug that activates PPARG protein in the PPAR signaling pathway of T2DM.

Oolong tea extract alleviates weight gain in high-fat diet-induced obese rats by regulating lipid metabolism and modulating gut microbiota.

Obesity is a serious global health issue, and the societal interventions during the COVID-19 pandemic may have perturbed energy homeostasis, which affects the condition of obesity. Tea is a traditional beverage in Asia and has been shown to provide many beneficial health effects. Oolong tea is semifermented, with its chemical composition comprising features of green (unfermented) and black (fermented) tea. Although green tea has anti-obesity properties, studies on the anti-obesity ability of oolong tea are still scarce. In this study, we analyzed the chemical composition of oolong tea extract (OTE) and investigated the effects of OTE on high-fat diet-induced obese rats. OTE contained more (-)-epigallocatechin-3-gallate, (-)-epigallocatechin, and (-)-gallocatechin-3-gallate than theaflavins and theasinensins. Rats fed with a high-fat diet (HFD) and treated with 0.5% OTE exhibited significantly reduced body weight and visceral fat weight compared with the HFD-only group. OTE also decreased adipocyte size, lipogenesis-related protein sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN) protein expression and increased thermogenesis-related protein peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and uncoupling protein 1 (UCP1) protein expression in epididymal adipose tissue compared with the HFD group. Moreover, the OTE groups had a significantly higher abundance of Candidatus arthromitus and Hydrogenoanaerobacterium and a lower abundance of Ruminococcus1, Oscillibacter, and Odoribacter compared with the HFD group. All these results show that OTE can alleviate weight gain by regulating lipid metabolism and modulating the distribution of the gut microbiota to decrease lipid accumulation in adipose tissue.

Lipid Inhibitory Effect of (-)-loliolide Isolated from Sargassum horneri in 3T3-L1 Adipocytes: Inhibitory Mechanism of Adipose-Specific Proteins.

Sargassum horneri (S. horneri) is a well-known brown seaweed widely distributed worldwide. Several biological activities of S. horneri have been reported. However, its effects on lipid metabolism and the underlying mechanisms remain elusive. In the present study, we examined the inhibitory effect of the active compound “(−)-loliolide ((6S,7aR)-6-hydroxy-4,4,7a-trimethyl-5,6,7,7a-tetrahydro-1-benzofuran-2(4H)-one (HTT))” from S. horneri extract on lipid accumulation in differentiated adipocytes. MTT assays demonstrated that (−)-loliolide is not toxic to 3T3-L1 adipocytes in a range of concentrations. (−)-loliolide significantly reduced intracellular lipid accumulation in the differentiated phase of 3T3-L1 adipocytes as shown by Oil Red O staining. Western blot analysis revealed that (−)-loliolide increased the expression of lipolytic protein phospho-hormone-sensitive lipase (p-HSL) and thermogenic protein peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1). Additionally, (−)-loliolide decreased expression of adipogenic and lipogenic proteins, including sterol regulatory element-binding protein-1 (SREBP-1), peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer-binding protein-α (C/EBP-α), and fatty acid-binding protein 4 (FABP4) in 3T3-L1 adipocytes. These results indicate that (−)-loliolide from S. horneri could suppress lipid accumulation via regulation of antiadipogenic and prolipolytic mechanisms in 3T3-L1 cells. Considering the multifunctional effect of (−)-loliolide, it can be useful as a lipid-lowering agent in the management of patients who suffer from obesity.

The Effects of C3G and D3G Anthocyanin-Rich Black Soybean on Energy Metabolism in Beige-like Adipocytes.

Various mechanisms of obesity prevention have been identified; however, the roles of brown or beige fat as regulators of the energy balance are unclear. The effects of anthocyanin-rich black soybean, Glycine max (L.) Merr., testa (ABS) extracts on the energy balance were investigated by comparing beige-like adipocytes (BLA) and white adipocytes (WAT). ABS extracts reduced peroxisome proliferator-activated receptor gamma protein expression and triglyceride accumulation in WAT and BLA without inducing nuclear damage. The biomarkers of fat degradation (phospho-AMPKα and ATGL) or glycerol secretion in the medium and β-oxidation of fatty acids (CPT2) in the ABS-treated BLA were increased compared to those in WAT. ABS extracts significantly increased the expression of thermogenesis markers (UCP1 and CIDEA) and biomarkers related to mitochondrial activation (cytochrome c and NRF1) in BLA. In the primary cell culture of brown adipocytes (BAT) from rats fed ABS, the expression levels of PGC1-α, cytochrome c, and UCP1 proteins were increased compared to those in BAT from nonfed rats. A reduction in the NAD/NADH ratio was consistently associated with an increase in the oxygen consumption rate and basal/maximal respiration rate in ABS-treated BLA. Anthocyanins promote beiging in the body, contribute to the prevention of obesity, and are potentially useful functional materials.

Isolation, identification, expression and subcellular localization of PPARG gene in buffalo mammary gland.

Peroxisome proliferator-activated receptor gamma (PPARG), as a member of the nuclear receptor superfamily, plays an important role in adipocyte differentiation and regulation of lipid and glucose metabolism. In this study, the transcripts of PPARG gene were isolated and identified in buffalo mammary gland. The results showed that two types of transcripts (PPARG1 and PPARG2) of PPARG gene produced by alternative 5' end use were expressed in buffalo mammary gland, and each of them had four different alternative splicing variants. The PPARG1 includes PPARG1a, PPARG1b, PPARG1c and PPARG1d, while the PPARG2 contains PPARG2a, PPARG2b, PPARG2c and PPARG2d. Among them, only PPARG1a, PPARG2a and PPARG2d can encode complete functional proteins with three complete functional domains, and the rest encode truncated proteins with incomplete functional domains. All the eight variants of PPARG protein do not contain transmembrane regions and signal peptides, but their conserved domain, secondary and tertiary structure and subcellular localization were different. Subcellular localization confirmed that the main transcripts PPARG1a and PPARG2a played a functional role in the nucleus, which was consistent with the results by in silico prediction. RT-qPCR analysis of buffalo mammary tissue showed that the mRNA expression levels of PPARG1 and PPARG2 in lactation were higher than those in non-lactation, and the expression levels of transcripts PPARG2d and PPARG1b+PPARG2b in lactating stage were also higher than those in non-lactating stage, but the mRNA abundance of transcripts PPARG1c, PPARG1d and PPARG2c in non-lactating period was higher than that in lactating period. The results of this study suggest that PPARG1 and PPARG2 may play important role in buffalo milk fat synthesis, and the eight alternative splicing variants found here are likely to be related to the post-transcriptional regulation of lactation.

Pyruvate dehydrogenase kinase 1 interferes with glucose metabolism reprogramming and mitochondrial quality control to aggravate stress damage in cancer.

Pyruvate dehydrogenase kinase 1 (PDK1) is a key factor in the connection between glycolysis and the tricarboxylic acid cycle. Restoring the mitochondrial OXPHOS function by inhibiting glycolysis through targeting PDK1 has become a hot spot for tumor therapy. However, the specific mechanism by which metabolic changes affect mitochondrial function remains unclear. Recent studies have found that mitochondrial quality control such as mitochondrial protein homeostasis plays an important role in maintaining mitochondrial function. Here, we focused on PDK1 and explored the specific mechanism by which metabolic changes affect mitochondrial OXPHOS function. We showed that glucose metabolism in HepG2 and HepG3B cells switched from anaerobic glycolysis to the mitochondrial tricarboxylic acid cycle under different concentrations of dichloroacetate (DCA) or short hairpin PDK1. After DCA treatment or knockdown of PDK1, the mitochondrial morphology was gradually condensed and exhibited shorter and more fragmented filaments. Additionally, expression of the mitochondrial autophagy proteins parkin and PTEN-induced kinase was down-regulated, and the biosynthetic protein peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) and its regulated complex I, III, IV, and V protein were down-regulated. This indicated that PDK1 inhibition affected the level of mitochondrial quality control. Analysis of mitochondrial function revealed significantly increased mitochondrial reactive oxygen species and decreased membrane potential. Therefore, glucose metabolism reprogramming by PDK1 inhibition could induce mitochondrial quality control disorders to aggravate mitochondrial stress damage.

Peroxisome Proliferator Activated Receptor Gamma Sensitizes Non-small Cell Lung Carcinoma to Gamma Irradiation Induced Apoptosis.

The nuclear receptors known as peroxisome proliferator activated receptor gamma (PPARG) are lipid-activated transcription factors that have emerged as key regulators of inflammation. PPARG ligands have been shown to have an anti-proliferative effect on a variety of cancers. These ligands can induce apoptosis via TP53 (Tumor protein p53) or ERK1/2 (Extracellular signal-regulated kinases 1/2) (EPHB2) pathways. However, the exact mechanism is not known. PPAR, a type II nuclear hormone receptor deserves attention as a selective target for radiotherapy. Our study examines the potential of selective agonism of PPARG for radiation therapy in non-small cell lung carcinoma (NSCLC). We found that the overexpression of PPARG protein as well as its induction using the agonist, rosiglitazone was able to stimulate radiation-induced cell death in otherwise radio resistant NSCLC A549 cell line. This cell death was apoptotic and was found to be BAX (BCL2 associated X) mediated. The treatment also inhibited radiation-induced AKT (Protein Kinase B) phosphorylation. Interestingly, the ionising radiation (IR) induced apoptosis was found to be inversely related to TP53 levels. A relatively significant increase in the levels of radiation induced apoptosis was observed in H1299 cells (TP53 null) under PPARG overexpression condition further supporting the inverse relationship between apoptosis and TP53 levels. The combination of PPARG agonist and radiation was able to induce apoptosis at a radiation dose at which A549 and H1299 are radioresistant, thus confirming the potential of the combinatorial strategy. Taken together, PPARG agonism was found to invigorate the radiosensitising effect and hence its use in combination with radiotherapy is expected to enhance sensitivity in otherwise resistant cancer types.

Peroxisome proliferator activated receptor gamma in human placenta may mediate the adverse effects of phthalates exposure in pregnancy

Peroxisome-proliferator activated receptor gamma (PPARG) in placenta play an important role in pregnancy. Our previous study showed that it mediated the effects of phthalates on placental mRNA expression of estrogen synthetases in rats. To assess the effects of phthalate exposure on PPARG placental expression, and the contribution of PPARG to the effects of phthalates in human. 207 healthy pregnant women were recruited and their cord blood and placenta were collected upon delivery. Three phthalates, estrogens in cord blood and protein expression of PPARG in placenta were measured. Linear regression were used to analyze the relationship between phthalates exposure, PPARG expression and hormones. Phthalate levels in cord blood were positively associated with PPARG protein expression in placenta (p<0.05), whereas estrogens in cord blood were negatively associated with phthalate levels and PPARG expression (p<0.05). This study shows that PPARG in placenta may mediate the adverse effects of phthalates on pregnancy in human.

Anti-adipogenic activity of Carduus crispus and its constituent apigenin in 3T3-L1 adipocytes by downregulating PPARγ and C/EBPα

Carduus crispus, native to Europe and Asia, is a traditional herbal medicine used for treating inflammatory disorders in Korea. Obesity is characterized by a state of chronic inflammation with increased inflammatory markers along with the expression and release of inflammation-related adipokines. Most anti-obesity drugs have been developed based on this concept. Our research for anti-obesity agents derived from C. crispus utilized the 3T3-L1 cell line. The methanol extract was initially screened and exhibited significant inhibition of adipogenesis in 3T3-L1 adipocytes. Among five liquid–liquid partition fractions, the ethyl acetate (EA) fraction showed the most potent suppressive effect compared with hexane, chloroform, n-butanol, and water. The EA fraction was considered for further study because of the presence of abundant polyphenols, including flavonoids. To isolate the active components from the EA fraction, elution–extrusion countercurrent chromatography was used. Among the seven fractions from the EA layer, fraction 6 inhibited lipid accumulation as well as CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma protein expression levels. The active component apigenin (fraction 6) was confirmed using high-performance liquid chromatography, electrospray ionization mass spectrometry, and one-dimensional nuclear magnetic resonance spectroscopy. The present data suggest that apigenin is one of the main bioactive compounds from C. crispus for inhibiting adipogenesis in 3T3-L1 adipocytes via the activation of AMP-activated protein kinase.

Involvement of resveratrol in crosstalk between adipokine adiponectin and hepatokine fetuin-A in vivo and in vitro

Metabolic homeostasis is maintained by the coordinated regulation of several physiological processes and organ crosstalk. Especially, the interaction between adipose tissue and liver is critical for the regulation of glucose and lipid metabolism. This study investigated the involvement of resveratrol (RSV) in the crosstalk between adipokine adiponectin and hepatokine fetuin-A. Adipocytes-hepatocytes co-culture system and a high-fat (HF) diet-induced obesity (DIO) mouse model were utilized. Protein levels of adiponectin and fetuin-A were analyzed in adipocytes and hepatocytes with the knockdown of adiponectin and fetuin-A, respectively. After six weeks of the HF diet treatment, RSV was delivered via an osmotic pump for four weeks. The experimental groups were lean control fed with a standard diet, HF diet-induced obese control and HF_RSV (8 mg/kg/day). After 4 weeks of each treatment, blood and tissues were collected, and the levels of adiponectin and fetuin-A were analyzed. RNA interference during co-culture of adipocytes and hepatocytes demonstrated the existence of crosstalk between adiponectin and fetuin-A. The four-week RSV treatment resulted in increased serum adiponectin and decreased serum fetuin-A in diet-induced obesity mice. The serum levels of adiponectin and fetuin-A were inversely related. In epididymal fat depots, RSV increased adiponectin, peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, sirtuin1 and AMP-activated protein kinase (AMPK). RSV lowered fetuin-A and NF-κB, and increased liver AMPK. These results demonstrate the crosstalk between adiponectin and fetuin-A, and suggest that RSV may be involved in adipose tissue and liver crosstalk through the interaction between adiponectin and fetuin-A.

SUMOylation and Ubiquitylation Circuitry Controls Pregnane X Receptor Biology in Hepatocytes.

Several nuclear receptor (NR) superfamily members are known to be the molecular target of either the small ubiquitin-related modifier (SUMO) or ubiquitin-signaling pathways. However, little is currently known regarding how these two post-translational modifications interact to control NR biology. We show that SUMO and ubiquitin circuitry coordinately modifies the pregnane X receptor (PXR, NR1I2) to play a key role in regulating PXR protein stability, transactivation capacity, and transcriptional repression. The SUMOylation and ubiquitylation of PXR is increased in a ligand- and tumor necrosis factor alpha -: dependent manner in hepatocytes. The SUMO-E3 ligase enzymes protein inhibitor of activated signal transducer and activator of transcription-1 (STAT1) STAT-1 (PIAS1) and protein inhibitor of activated STAT Y (PIASy) drive high levels of PXR SUMOylation. Expression of protein inhibitor of activated stat 1 selectively increases SUMO(3)ylation as well as PXR-mediated induction of cytochrome P450, family 3, subfamily A and the xenobiotic response. The PIASy-mediated SUMO(1)ylation imparts a transcriptionally repressive function by ameliorating interaction of PXR with coactivator protein peroxisome proliferator-activated receptor gamma coactivator-1-alpha. The SUMO modification of PXR is effectively antagonized by the SUMO protease sentrin protease (SENP) 2, whereas SENP3 and SENP6 proteases are highly active in the removal of SUMO2/3 chains. The PIASy-mediated SUMO(1)ylation of PXR inhibits ubiquitin-mediated degradation of this important liver-enriched NR by the 26S proteasome. Our data reveal a working model that delineates the interactive role that these two post-translational modifications play in reconciling PXR-mediated gene activation of the xenobiotic response versus transcriptional repression of the proinflammatory response in hepatocytes. Taken together, our data reveal that the SUMOylation and ubiquitylation of the PXR interface in a fundamental manner directs its biologic function in the liver in response to xenobiotic or inflammatory stress.

In Vivo Chronic and In Vitro Acute Effects of Di(2-Ethylhexyl) Phthalate on Pseudopregnant Rabbit Corpora Lutea: Possible Involvement of Peroxisome Proliferator-Activated Receptor Gamma1

The in vivo chronic and in vitro acute effects of di(2-ethylhexyl) phthalate (DEHP) on the reproductive function of peroxisome proliferator-activated receptor gamma (PPARG) were studied in rabbit corpora lutea (CL) at early stage (Day 4), midstage (Day 9), and late stage (Day 13) of pseudopregnancy. The rabbits were in vivo treated with DEHP for 15 days before induction of pseudopregnancy. Immunohistochemistry provided evidence for the presence of PPARG, prostaglandin endoperoxide synthase 1 (PTGS1), PTGS2, prostaglandin E2-9-ketoreductase (PGE2-9-K), and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) in all the luteal cells during pseudopregnancy. DEHP decreased progesterone plasma levels and CL production in all the luteal stages and PPARG protein and gene expressions in early and mid-CL. DEHP in vivo treatment reduced PTGS2 protein expression at the late stage and that of PGE2-9-K at all the stages, whereas PTGS1 and 3beta-HSD were not affected. In in vitro cultured CL, DEHP alone, the PPARG antagonist T0070907 alone, or DEHP plus T0070907 diminished progesterone production and 3beta-HSD activity and increased PGF2alpha and PTGS2 in early and mid-CL, whereas DEHP plus the PPARG agonist 15d-PGJ2 did not affect these hormones and enzymes. All the in vitro treatments did not affect PGE2 secretion as well as PTGS1 and PGE2-9-K enzymatic activities in all the luteal stages. These results provided evidence that DEHP favors functional luteolysis of pseudopregnant rabbit CL, with a mechanism that seems to involve PPARG expression down-regulation, an increase of PTGS2 activity and prostaglandin F2alpha secretion, 3beta-HSD down-regulation, and decrease in progesterone.

Telmisartan protects against microvascular dysfunction during myocardial ischemia/reperfusion injury by activation of peroxisome proliferator-activated receptor gamma

BackgroundWe investigated the potential of telmisartan to improve microvascular dysfunction induced by myocardial ischemia/reperfusion (I/R) injury by activating the peroxisome proliferator-activated receptor gamma (PPARG) pathway.MethodsForty-eight male rabbits were randomly allocated into sham-operated, I/R, GW9662, telmisartan, telmisartan–GW9662, or candesartan groups. Rabbits were anesthetized, and the left anterior descending coronary artery (LAD) was ligated for 60 minutes. Following reperfusion for 6 hours, angiotensin II content of the heart was determined using radioimmunoassay. Myocardial neutrophil accumulation and microvessel cross-sectional area were examined histologically. Myocardial capillaries were examined with transmission electron microscopy. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the myocardium were measured using enzyme-linked immunosorbent assay. Western blot was utilized for investigating the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and PPARG.ResultsAngiotensin II concentration was significantly increased in all treatment groups compared with the sham-operated group (P < 0.05, all). Accumulation of polymorphonuclear neutrophils was significantly lower, while microvessel cross-sectional area was significantly higher in the telmisartan, telmisartan-GW9662, and candesartan groups compared with the I/R group (P < 0.05). ICAM-1 and VCAM-1 levels were also significantly lower, and correlated with lower NF-κB expression in these groups. The effects were the most significant in the telmisartan group compared with the telmisartan–GW9662 and candesartan groups. Telmisartan significantly increased PPARG protein expression compared with all other groups (P < 0.05, all).ConclusionsExcept for the typical effects of angiotensin II-receptor blocker, telmisartan improved microvascular dysfunction during myocardial I/R injury via the PPARG pathway.

Deficiency of caveolin-1 in Apcmin/+ mice promotes colorectal tumorigenesis

Caveolin-1 (Cav1), a scaffold protein of membrane caveolae and coactivator of peroxisome proliferator-activated receptor gamma (PPARg), inhibits oncogenic signaling through Ras and wingless. However, the in vivo role of Cav1 in colorectal cancer (CRC) remained unknown. To test whether loss of Cav1 accelerates tumorigenesis, we generated a novel mouse model of CRC by crossing C57BL/6 Apc(min/+) with B6129 Cav1 knockout (Cav1-/-) mice. Apc(min/+) Cav1-/- mice developed large, microinvasive and vascularized intraepithelial adenocarcinomas in the distal colon and rectum with higher incidence than Apc(min/+) Cav1+/- and Apc(min/+) Cav1+/+ littermates. Intratumoral gene signatures related to Ras and wingless signaling were elevated, nuclear localization of PPARg protein and expression of PPARg-target genes were reduced independently of Cav1. The PPARg-agonist rosiglitazone prevented tumor formation in mice irrespectively of the Cav1 status and upregulated expression of the Ras-inhibitory protein docking protein-1. Thus, codeficiency of Cav1 and adenomatous polyposis coli facilitated formation of CRC, and activation of PPARg may offer novel strategies for treatment of CRC.

Fibroblast growth factor 21: from pharmacology to physiology

Fibroblast growth factor 21 (FGF21) is an atypical member of the FGF family that functions as an endocrine hormone. Pharmacologic studies show that FGF21 has broad metabolic actions in obese rodents and primates that include enhancing insulin sensitivity, decreasing triglyceride concentrations, and causing weight loss. In lean rodents, FGF21 expression is strongly induced in liver by prolonged fasting through a mechanism that involves the nuclear receptor peroxisome proliferator-activated receptor alpha. FGF21, in turn, induces the transcriptional coactivator protein peroxisome proliferator-activated receptor gamma coactivator protein 1alpha and stimulates hepatic gluconeogenesis, fatty acid oxidation, and ketogenesis. FGF21 also blocks somatic growth and sensitizes mice to a hibernation-like state of torpor. Thus, FGF21 plays a key role in eliciting and coordinating the adaptive starvation response. Interestingly, FGF21 expression is induced in white adipose tissue by peroxisome proliferator-activated receptor gamma, which suggests that it also regulates metabolism in the fed state. This article highlights recent advances in our understanding of FGF21's pharmacologic and physiologic actions.