PPAR Pathway Research Articles

Role of PPAR Pathway in Atrial Fibrillation Associated with Heart Valvular Disease: Transcriptomics and Proteomics in the Human Atrial Tissue

ObjectiveAtrial fibrillation (AF) is one of the most common cardiac arrhythmias. Previous studies have shown that electrical, contractile, and structural remodeling play the key role in the onset and maintenance of AF. Heart valvular disease (HVD) is associated with an increased risk of thromboembolic events, mainly in patients with AF. However, the molecular mechanism of AF in HVD remains unrevealed, although there was an attempt to discover the plasma biomarkers in HVD.MethodsHuman atrial tissues from patients with HVD in persistent AF preoperatively for at least 6 months or remaining sinus rhythm (as control) undergoing heart valve replacement surgery were studied by combined transcriptomics and proteomics. Owing to the fact that there are maximal 8 Isobaric tags in proteomics analysis by iTRAQ technology, 8 tissue samples were allocated, including left atrial tissues from 3 AF patients (AFLA) and right atrial tissues (3 AFRA and 2 SRRA) from 5 patients. The analysis of transcriptomics and proteomics were from the same samples. Big data obtained from omics study were analyzed by bioinformatics tools. The fold changes of >1.2 (or <0.8) and P value < 0.05 were considered as significant.ResultHierarchical clustering analysis revealed that the genomic expressions of three groups have differences in transcriptomics. Pairwise comparison was performed and differentially expressed genes were identified, including 193 genes up‐regulated and 279 genes down‐regulated. Heat map from differentially expressed proteins in proteomics analysis indicates that there are significant differences in patients with or without AF and between the left and right atrium. Based on Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, we found that the expression of genes and proteins associated with PPARα, β/δ, γ was altered in omics study in AF patients. Genes/proteins, such as FATCD36, SCD‐1, FABP, ADIPO, APOA1, APOA2, FATP, FADS2, ACBP, CPT‐1, aP2, CAP, and etc., are included in the PPAR pathway. These genes/proteins may be developed as potential biomarkers for disease pathogenesis and progress in AF.ConclusionOur study provides an integrative analysis of transcriptomics and proteomics in human atrial tissues of AF‐associated HVD patients and reveals that PPAR signaling pathway plays an important role in pathogenesis of AF. Some of differential proteins may become biomarkers and provide new diagnostic and therapeutic methods for AF in the future.Support or Funding InformationThis work was supported by the National Natural Science Foundation of China [81870288 & 81870227]; the Non‐profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2019XK310001& 2018TX31002]; Tianjin Science and Technology Committee[18PTZWHZ00060];Binhai New Area Health Bureau (2018BWKZ005)

Adiponectin and Cognitive Decline.

Adiponectin (ADPN) is a plasma protein secreted by adipose tissue showing pleiotropic effects with anti-diabetic, anti-atherogenic, and anti-inflammatory properties. Initially, it was thought that the main role was only the metabolism control. Later, ADPN receptors were also found in the central nervous system (CNS). In fact, the receptors AdipoR1 and AdipoR2 are expressed in various areas of the brain, including the hypothalamus, hippocampus, and cortex. While AdipoR1 regulates insulin sensitivity through the activation of the AMP-activated protein kinase (AMPK) pathway, AdipoR2 stimulates the neural plasticity through the activation of the peroxisome proliferator-activated receptor alpha (PPARα) pathway that inhibits inflammation and oxidative stress. Overall, based on its central and peripheral actions, ADPN appears to have neuroprotective effects by reducing inflammatory markers, such as C-reactive protein (PCR), interleukin 6 (IL6), and Tumor Necrosis Factor a (TNFa). Conversely, high levels of inflammatory cascade factors appear to inhibit the production of ADPN, suggesting bidirectional modulation. In addition, ADPN appears to have insulin-sensitizing action. It is known that a reduction in insulin signaling is associated with cognitive impairment. Based on this, it is of great interest to investigate the mechanism of restoration of the insulin signal in the brain as an action of ADPN, because it is useful for testing a possible pharmacological treatment for the improvement of cognitive decline. Anyway, if ADPN regulates neuronal functioning and cognitive performances by the glycemic metabolic system remains poorly explored. Moreover, although the mechanism is still unclear, women compared to men have a doubled risk of developing cognitive decline. Several studies have also supported that during the menopausal transition, the estrogen reduction can adversely affect the brain, in particular, verbal memory and verbal fluency. During the postmenopausal period, in obese and insulin-resistant individuals, ADPN serum levels are significantly reduced. Our recent study has evaluated the relationship between plasma ADPN levels and cognitive performances in menopausal women. Thus, the aim of this review is to summarize both the mechanisms and the effects of ADPN in the central nervous system and the relationship between plasma ADPN levels and cognitive performances, also in menopausal women.

The acute toxic effects of hexavalent chromium on the liver of marine medaka (Oryzias melastigma)

Chromium is toxic to marine animals and can cause damage to many of their organs, including the liver. To test the toxicity of chromium on marine organisms, we exposed the liver of the marine medaka (Oryzias melastigma) with hexavalent chromium [Cr(VI)]. Our results show that Cr enrichment in the liver demonstrates a positive correlation to the exposure concentration. With the increase of Cr(VI) concentration, pathological changes including nuclear migration, cell vacuolization, blurred intercellular gap, nuclear condensation, become noticeable. To further study changes in gene expression in the liver after Cr(VI) exposure, we used RNA-seq to compare expression profiles before and after Cr(VI) exposure. After acute Cr(VI) exposure (2.61 mg/l) for 96 h, 5862 transcripts significantly changed. It is the first time that the PPAR pathway was found to respond sensitively to Cr(VI) exposure in fish. Finally, combined with other published study, we found that there may be some difference between Cr(VI) toxicity in seawater fish and freshwater fish, due to degree of oxidative stress, distribution patterns and detailed Cr(VI) toxicological mechanisms. Not only does our study explore the mechanisms of Cr(VI) toxicity on the livers of marine medaka, it also points out different Cr(VI) toxicity levels and potential mechanisms between seawater fish and freshwater fish.

Adaptation of extracellular matrix to massive small bowel resection in mice

BackgroundExtracellular matrix (ECM) affects cell behavior, and vice versa. How ECM changes after small bowel resection (SBR) to support adaptive cellular processes has not been described. Here we characterize changes in ECM following SBR and integrate this with concomitant transcriptional perturbations. MethodsA 50% proximal SBR or sham surgery was performed on mice. On postoperative day 7, ileal tissue was sequentially depleted of protein components to generate an ECM-enriched fraction. ECM was analyzed for protein composition using mass spectrometry with subsequent Ingenuity Pathway Analysis (IPA) to identify predicted pathways and upstream regulators. qPCR and RNA-sequencing (RNA-Seq) were performed to corroborate these predicted pathways. Results3034 proteins were differentially regulated between sham and SBR, of which 95 were significant (P < 0.05). IPA analysis predicted PPARα agonism to be an upstream regulator of the observed proteomic changes (P < 0.001). qPCR and RNA-Seq with KEGG analysis confirmed significant engagement of the PPAR pathway (P < 0.05). ConclusionTranscriptional signatures of adapting bowel predict subsequent ECM changes after SBR. How ECM communicates with surrounding cells to drive adaptation and vice versa merits further investigation. Our findings thus far suggest ECM supports tissue hyperplasia and altered metabolic demand following SBR.Level of evidence

MicroRNA expression profiling of caudal fin cell of C. auratus gibelio upon cyprinid herpesvirus 2 infection

As a member of the genus Cyprinivirus in the family Alloherpesviridae, Cyprinid herpesvirus 2 (CyHV-2) has caused great economic loss in the aquaculture industry, mainly in C. auratus gibelio and goldfish. However, the molecular mechanisms underlying the pathogenicity of CyHV-2 remain elusive. In this study, high-throughput sequencing technology was employed to explore the miRNA expression profiles of C. auratus gibelio (GiCF) caudal fin cells in response to Cyprinid Herpesvirus-2 (CyHV-2) infection. A total of 631 novel miRNAs and 409 known miRNAs were identified. The expression levels of 7 miRNAs were found as significantly modulated (5 down-regulation and 2 up-regulation; P < 0.01, |logFC|>1, TPM>10) in CyHV-2 infected cells. 7 miRNA and their potential mRNA targets were validated by Real-time PCR (qRT-PCR), respectively. Targets prediction and functional analysis of these 7 miRNAs revealed significant enrichment for several signaling pathways, including PPAR, p53 and FoxO pathways. These studies provided more valuable basis for further study on the roles of miRNAs in CyHV-2 replication and pathogenesis.

Pemafibrate, a selective PPARα modulator, and fenofibrate suppress microglial activation through distinct PPARα and SIRT1-dependent pathways

Pemafibrate, a selective peroxisome proliferator-activated receptor (PPAR) α modulator, is a new drug that specifically modulates PPARα conformation and co-activator recruitment, thereby lowers plasma triglycerides with less off-target effects. Classical PPARα ligands such as fenofibrate suppress inflammatory cells including microglia. However, effects of pemafibrate on microglia have never been addressed. Here we show that pemafibrate, like other PPARα ligands, potently suppressed NF-κB phosphorylation and cytokine expression in microglial cells. PPARα knockdown significantly amplified LPS-induced cytokine expression. Pemafibrate-induced suppression of IL-6 expression was reversed by PPARα knockdown. However, suppression by fenofibrate was not reversed by PPARα knockdown but by Sirtuin 1 (SIRT1) knockdown. In conclusion, pemafibrate and fenofibrate similarly suppresses microglial activation but through distinct PPARα and SIRT1-dependet pathways.

Early microRNA indicators of PPARα pathway activation in the liver

MicroRNAs (miRNAs) are short non-coding RNA species that play key roles in post-transcriptional regulation of gene expression. MiRNAs also serve as a promising source of early biomarkers for different environmental exposures and health effects, although there is limited information linking miRNA changes to specific target pathways. In this study, we measured liver miRNAs in male B6C3F1 mice exposed to a known chemical activator of the peroxisome proliferator-activated receptor alpha (PPARα) pathway, di(2-ethylhexyl) phthalate (DEHP), for 7 and 28 days at concentrations of 0, 750, 1500, 3000, or 6000 ppm in feed. At the highest dose tested, DEHP altered 61 miRNAs after 7 days and 171 miRNAs after 28 days of exposure, with 48 overlapping miRNAs between timepoints. Analysis of these 48 common miRNAs indicated enrichment in PPARα–related targets and other pathways related to liver injury and cancer. Four of the 10 miRNAs exhibiting a clear dose trend were linked to the PPARα pathway: mmu-miRs-125a-5p, -182−5p, -20a−5p, and -378a−3p. mmu-miRs-182−5p and -378a−3p were subsequently measured using digital drop PCR across a dose range for DEHP and two related phthalates with weaker PPARα activity, di-n-octyl phthalate and n-butyl benzyl phthalate, following 7-day exposures. Analysis of mmu-miRs-182−5p and -378a−3p by transcriptional benchmark dose analysis correctly identified DEHP as having the greatest potency. However, benchmark dose estimates for DEHP based on these miRNAs (average 163; range 126−202 mg/kg-day) were higher on average than values for PPARα target genes (average 74; range 29−183 mg/kg-day). These findings identify putative miRNA biomarkers of PPARα pathway activity and suggest that early miRNA changes may be used to stratify chemical potency.

Lactobacillus plantarum KFY04 prevents obesity in mice through the PPAR pathway and alleviates oxidative damage and inflammation.

In this study, lactic acid bacterium, Lactobacillus plantarum KFY04, was isolated from Xinjiang yogurt, and it was used to intervene in obese mice maintained on a 45% fat diet, and we compared its effects to those of a commercial strain, LDSB, and l-carnitine. The results showed that the LP-KFY04 intervention mice gained weight more slowly and had lower liver, epididymal adipose, and perirenal adipose tissue indices when compared to the other high-fat groups. Moreover, the LP-KFY04 can reduce the formation of fat vacuoles in the liver, while also reducing adipocyte differentiation and volume, and LP-KFY04 groups had the lowest liver and serum AST, ALT, TG, and TC levels and lowest serum LDL-C and highest HDL-C levels among the groups maintained on a high-fat diet. LP-KFY04 was also shown to mitigate obesity-associated oxidative damage and inflammatory responses. Additionally, quantitative real-time PCR and western blot analysis examining liver and adipose tissue expression of PPAR-α, CYP7A1, CPT1, and LPL showed an increased expression in the LP-KFY04 groups while decreased expression levels of PPAR-γ and C/EBPα relative to the other high-fat diet groups. These results show that of the different interventions, LP-KFY04 was the most effective at mitigating the effects of obesity than LDSB and l-carnitine. The results confirmed that LP-KEY04 has better anti-obesity, anti-oxidative, and anti-inflammatory effects than current fermentation strains. It indicates LP-KFY04 is a fermentation strain with potential practical value and high functionality, and it shows that a fermentation strain should not only have good fermentation performance, but, more importantly, it must provide more functionality on the basis of fermentation.

Distinct cardiac energy metabolism and oxidative stress adaptations between obese and non-obese type 2 diabetes mellitus.

Background: Little is known about the pathophysiological diversity of myocardial injury in type 2 diabetes mellitus (T2DM), but analyzing these differences is important for the accurate diagnosis and precise treatment of diabetic cardiomyopathy. This study aimed to elucidate the key cardiac pathophysiological differences in myocardial injury between obese and non-obese T2DM from mice to humans.Methods: Obese and non-obese T2DM mouse models were successfully constructed and observed until systolic dysfunction occurred. Changes in cardiac structure, function, energy metabolism and oxidative stress were assessed by biochemical and pathological tests, echocardiography, free fatty acids (FFAs) uptake fluorescence imaging, transmission electron microscopy, etc. Key molecule changes were screened and verified by RNA sequencing, quantitative real-time polymerase chain reaction and western blotting. Further, 28 human heart samples of healthy population and T2DM patients were collected to observe the cardiac remodeling, energy metabolism and oxidative stress adaptations as measured by pathological and immunohistochemistry tests.Results: Obese T2DM mice exhibited more severe cardiac structure remodeling and earlier systolic dysfunction than non-obese mice. Moreover, obese T2DM mice exhibited severe and persistent myocardial lipotoxicity, mainly manifested by increased FFAs uptake, accumulation of lipid droplets and glycogen, accompanied by continuous activation of the peroxisome proliferator activated receptor alpha (PPARα) pathway and phosphorylated glycogen synthase kinase 3 beta (p-GSK-3β), and sustained inhibition of glucose transport protein 4 (GLUT4) and adipose triglyceride lipase (ATGL), whereas non-obese mice showed no myocardial lipotoxicity characteristics at systolic dysfunction stage, accompanied by the restored PPARα pathway and GLUT4, sustained inhibition of p-GSK-3β and activation of ATGL. Additionally, both obese and non-obese T2DM mice showed significant accumulation of reactive oxygen species (ROS) when systolic dysfunction occurred, but the NF-E2-related factor 2 (Nrf2) pathway was significantly activated in obese mice, while was significantly inhibited in non-obese mice. Furthermore, the key differences found in animals were reliably verified in human samples.Conclusion: Myocardial injury in obese and non-obese T2DM may represent two different types of complications. Obese T2DM individuals, compared to non-obese individuals, are more prone to develop cardiac systolic dysfunction due to severe and persistent myocardial lipotoxicity. Additionally, anti-oxidative dysfunction may be a key factor leading to myocardial injury in non-obese T2DM.

Sijunzi, Lizhong, and Fuzilizhong Decoction Alleviate Nonalcoholic Fatty Liver Disease through Activation of PPAR Pathway.

Objective Sijunzi, Lizhong, and Fuzilizhong decoction were traditional Chinese classic formulations, which are widely used in clinical treatment, and the underlying mechanism is unclear. In this study, we aim to investigate the molecular mechanisms underlying the protective effects of Sijunzi, Lizhong, and Fuzilizhong on nonalcoholic fatty liver disease (NAFLD). Methods Male Wistar rats were fed a high-fat diet for four weeks to induce NAFLD and were thereafter administered Sijunzi (8 g/kg/d), Lizhong (10 g/kg/d), or Fuzilizhong (10 g/kg/d) by gavage for four weeks. Hepatic damage, lipid accumulation, inflammation, autophagy, and peroxisome proliferator-activated receptor-α signaling were evaluated. Results The high-fat diet-fed rats showed typical symptoms of NAFLD, including elevated levels of hepatic damage indicators, increased hepatic lipid deposition and fibrosis, severe liver inflammation, and prominent autophagy. Upon administration of Sijunzi, Lizhong, and Fuzilizhong, liver health was improved remarkably, along with ameliorated symptoms of NAFLD. In addition, NAFLD-suppressed peroxisome proliferator-activated receptor-α signaling was reactivated after treatment with the three types of decoctions. Conclusions The results collectively signify the effective therapeutic and protective functions of Sijunzi, Lizhong, and Fuzilizhong against NAFLD and demonstrate the potential of Chinese herbal medication in mitigating the symptoms of liver diseases. Novelty of the Work. Traditional Chinese herbal medicine has been used for centuries to treat various diseases, but the molecular mechanisms of individual ingredients have rarely been studied. The novelty of our work lies in elucidating the specific signaling pathways involved in the control of NAFLD using three common Chinese herbal decoctions. We suggest that natural herbal formulations can be effective therapeutic agents to combat against NAFLD.

Thrombospondin-I is a critical modulator in non-alcoholic steatohepatitis (NASH).

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by dysregulated lipid metabolism and chronic inflammation ultimately resulting in fibrosis. Untreated, NAFLD may progress to non-alcoholic steatohepatitis (NASH), cirrhosis and death. However, currently there are no FDA approved therapies that treat NAFLD/NASH. Thrombospondin-I (TSP-1) is a large glycoprotein in the extracellular matrix that regulates numerous cellular pathways including transforming growth factor beta 1 (TGF-β1) activation, angiogenesis, inflammation and cellular adhesion. Increased expression of TSP-1 has been reported in various liver diseases; however, its role in NAFLD/NASH is not well understood. We first examined TSP-1 modulation in hepatic stellate cell activation, a critical initiating step in hepatic fibrosis. Knockdown or inhibition of TSP-1 attenuated HSC activation measured by alpha smooth muscle actin (α-SMA) and Collagen I expression. To investigate the impact of TSP-1 modulation in context of NAFLD/NASH, we examined the effect of TSP-1 deficiency in the choline deficient L-amino acid defined high fat diet (CDAHFD) model of NASH in mice by assessing total body and liver weight, serum liver enzyme levels, serum lipid levels, liver steatosis, liver fibrosis and liver gene expression in wild type (WT) and TSP-1 null mice. CDAHFD fed mice, regardless of genotype, developed phenotypes of NASH, including significant increase in liver weight and liver enzymes, steatosis and fibrosis. However, in comparison to WT, CDAHFD-fed TSP-1 deficient mice were protected against numerous NASH phenotypes. TSP-1 null mice exhibited a decrease in serum lipid levels, inflammation markers and hepatic fibrosis. RNA-seq based transcriptomic profiles from the liver of CDAHFD fed mice determined that both WT and TSP-1 null mice exhibited similar gene expression signatures following CDAHFD, similar to biophysical and histological assessment comparison. Comparison of transcriptomic profiles based on genotype suggested that peroxisome proliferator activated receptor alpha (PPARα) pathway and amino acid metabolism pathways are differentially expressed in TSP-1 null mice. Activation of PPARα pathway was supported by observed decrease in serum lipid levels. Our findings provide important insights into the role of TSP-1 in context of NAFLD/NASH and TSP-1 may be a target of interest to develop anti-fibrotic therapeutics for NAFLD/NASH.

Down-regulation of LncRNA CRNDE aggravates kidney injury via increasing MiR-181a-5p in sepsis

Long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) is reported to be linked to inflammation and cell apoptosis. However its role in sepsis induced kidney injury remains unclear. This study aims to explore the possible mechanism of CRNDE in kidney injury induced by sepsis. In vivo urine-derived sepsis (US) rat model and in vitro LPS-induced HK-2 and HEK293 cells were established. Kidney function was measured in rats from different groups. Relative levels of tumor necrosis factor-α (TNF-α) and interleukin-1β(IL-1β) in kidney tissue were detected via Enzyme-linked immune sorbent assay (ELISA). Then we up- or down-regulated CRNDE and miRNA-181a-5p expression in the cells. The biological influence of CRNDE and miR-181a-5p on cells was studied using CCK-8 assay and Annexin V assay. Interaction between CRNDE and miR-181a-5p was determined by bioinformatics analysis, RT-PCR, and dual luciferase reporter assay. Peroxisome proliferator-activated receptor-α (PPARα) and cell apoptosis related molecules were detected by western blot. We demonstrated that CRNDE was markedly down-regulated while miR-181a-5p was significantly up-regulated in sepsis models. CRNDE interacted with miR-181a-5p, and negatively regulated its expression level. CRNDE knockdown in rats increased the urea nitrogen and serum creatinine in plasma. Knockdown of CRNDE or transfection of miR-181a-5p significantly inhibited proliferation and promoted apoptosis of HK-2 and HEK293 cells, while overexpression of CRNDE and transfection of miR-181a-5p inhibitors had opposite effects. For mechanism, miR-181a-5p directly targeted the 3′ untranslated region of PPARα, and depressed its protein level, and PPARα was regulated indirectly by CRNDE. We concluded that CRNDE protected renal cell from sepsis-induced injury via miR-181a-5p/PPARα pathway.

Effect of okra fruit powder supplementation on metabolic syndrome and gut microbiota diversity in high fat diet-induced obese mice.

This study aimed to explore a novel strategy for dietary okra fruit powder (OFP) consumption on attenuation of non-alcohol fatty liver damage, lipid metabolic disorder and gut microbiota dysbiosis and associated mechanisms in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed a normal diet and HFD feeds supplemented with or without OFP (2.5%, 5% and 10%, n=10) for 12weeks. The results showed that supplementation of OFP caused strong inhibition on HFD-caused high blood glucose, body weight gain and liver fat accumulation, as well as dyslipidemia involved in a dose-dependent modulation of hepatic FAS and CD36 expressions of obese mice. The hepatic LXR-α energy metabolism and PPAR-α pathway were also doubly activated by OFP to alleviate lipogenesis, obesity and metabolic syndrome. Malonaldehyde production was effectively antagonized, and glutathione peroxidase and superoxide dismutase activities were elevated by OFP supplementation in HFD-fed mice. OFP also significantly improved colonic SCFAs (acetic acid, propionic acid and butyrate acid) formation, especially for butyrate production via increasing the proportion of selected butyrate-producing bacteria. OFP also dramatically modified the gut microbial species at the family level with suppressing an increase in Proteobacteria, Actinobacteria and F/B ratio, and the decrease in Bacteroidetes caused by HFD. These findings support that dietary OFP consumption is a novel strategy to prevent obesity, metabolic syndrome and gut microbiota imbalance.

SIRT5 inhibits bovine preadipocyte differentiation and lipid deposition by activating AMPK and repressing MAPK signal pathways

SIRT5 (sirtuin 5) is located in the mitochondria and plays an important role in biological processes such as maintaining the balance of lipid metabolism and promoting fatty acid oxidation mobilization. In this study, the bovine preadipocyte differentiation and obese mouse models were constructed; combined with transcriptome sequencing (RNA-seq) and morphological identification, the regulatory and molecular mechanisms underlying the effects of SIRT5 on bovine preadipocyte differentiation and lipid metabolism were studied. The results reveal that during the differentiation of preadipocytes, SIRT5 inhibited the expression of key genes that promote lipid formation and differentiation in fatty acid biosynthesis and PPAR pathways. SIRT5 significantly activated the adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) pathway and repressed the mitogen-activated protein kinase (MAPK) pathway. Eventually, SIRT5 significantly inhibited the differentiation of bovine preadipocytes and simultaneously inhibited lipid synthesis and lipid deposition in adipocytes. The verification experiments performed using obese mice also yielded consistent results in vivo.

Abstract A135: Discovery of BGS1954, a covalent small molecule ligand of FABP5 using IMTACTM platform

Abstract Fatty acid-binding protein-5 (FABP5) or epidermal FABP belongs to a low molecular weight lipid binding protein family. FABP5 is involved in binding, storing, and transporting hydrophobic ligands to the proper cellar compartment. Recent studies have suggested that FABP5 play important roles in regulation of gene expression associated with with cell growth and differentiation. FABP5 expression level was closely related to malignency in several types of cancers. The functions of FABP5 in modulation of cellular signaling have been studies and suggested that FABP5 is involved in EGFR, NFkB and PPAR pathways. Using IMTACTM (Isobaric Mass Tagged Affinity Characterization) to screen small molecule library in live cancer cells, ligands covalently bound to FABP5 were identified. Our initial characterization of compounds showed that they specifically bind to FABP5 and inhibit cancer cell growth. These FABP5-specific covalent small molecule ligands will provide a valuable pharmacological tool to dissect FABP5 functions and shed light on the therapeutic potential of targeting FABP5 for the treatment of cancer and metabolic disorders. Citation Format: Hang Chen, Heather Ha, Robert Stanley, Cindy Huang, Qian Cai, Irene Yuan, Ping Cao. Discovery of BGS1954, a covalent small molecule ligand of FABP5 using IMTACTM platform [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A135. doi:10.1158/1535-7163.TARG-19-A135

Distinct molecular etiologies of male and female hepatocellular carcinoma

BackgroundSex-differences in cancer occurrence and mortality are evident across tumor types; men exhibit higher rates of incidence and often poorer responses to treatment. Targeted approaches to the treatment of tumors that account for these sex-differences require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality, but previous studies have failed to explore the sex-specific dysregulation of gene expression in HCC.MethodsHere, we characterize the sex-shared and sex-specific regulatory changes in HCC tumors in the TCGA LIHC cohort using combined and sex-stratified differential expression and eQTL analyses.ResultsBy using a sex-specific differential expression analysis of tumor and tumor-adjacent samples, we uncovered etiologically relevant genes and pathways differentiating male and female HCC. While both sexes exhibited activation of pathways related to apoptosis and cell cycle, males and females differed in the activation of several signaling pathways, with females showing PPAR pathway enrichment while males showed PI3K, PI3K/AKT, FGFR, EGFR, NGF, GF1R, Rap1, DAP12, and IL-2 signaling pathway enrichment. Using eQTL analyses, we discovered germline variants with differential effects on tumor gene expression between the sexes. 24.3% of the discovered eQTLs exhibit differential effects between the sexes, illustrating the substantial role of sex in modifying the effects of eQTLs in HCC. The genes that showed sex-specific dysregulation in tumors and those that harbored a sex-specific eQTL converge in clinically relevant pathways, suggesting that the molecular etiologies of male and female HCC are partially driven by differential genetic effects on gene expression.ConclusionsSex-stratified analyses detect sex-specific molecular etiologies of HCC. Overall, our results provide new insight into the role of inherited genetic regulation of transcription in modulating sex-differences in HCC etiology and provide a framework for future studies on sex-biased cancers.

Berberine (BBR) Attenuated Palmitic Acid (PA)-Induced Lipotoxicity in Human HK-2 Cells by Promoting Peroxisome Proliferator-Activated Receptor α (PPAR-α).

BackgroundBerberine (BBR), a natural alkaloid isolated from Coptis chinensis, has frequently been reported as an antidiabetic reagent, partly due to its lipid-lowering activity. Evidence suggests that BBR ameliorates palmitate-induced lipid deposition and apoptosis in renal tubular epithelial cells (TECs), which tracks in tandem with the enhancement of peroxisome proliferator-activated receptor a (PPAR-a). The study aim was to investigate the roles of BBR in renal lipotoxicity in vitro, and investigate whether PPAR-a was the underlying mechanism.Material/MethodsHuman TECs (HK-2 cells) were injured with palmitic acid (PA), and then treated with BBR, BBR+PPAR-a inhibitor (GW6471), and PA+PPAR-a agonist (fenofibrate). Endoplasmic reticulum (ER) stress was assessed by measuring the expression of prospective evaluation of radial keratotomy (PERK), C/EBP-homologous protein (CHOP), and 78 kDa glucose-regulated protein (GRP78). Lipid metabolism was assessed by determining lipid anabolism-associated genes, including fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and lipoprotein lipase (LPL), as well as lipid catabolism-associated gene, including carnitine palmitoyl transferase 1 (CPT1). Inflammatory response of HK-2 cells was evaluated by measuring interleukin (IL)-6 and tumor necrosis factor (TNF)-a. Cell apoptosis and protein levels of cleaved-caspase-3 were evaluated.ResultsPA downregulated PPAR-a and induced server lipotoxicity in HK-2 cells by ER stress, increasing lipid deposition, and elevating inflammatory response of HK-2 cells accompanied with inducting cell apoptosis and cleaved-caspase-3, which were obviously reversed by additional treatment of BBR or PPAR-a agonist. However, the protective effect of BBR in PA-induced lipotoxicity in HK-2 cells was significantly ameliorated by PPAR-a inhibitor.ConclusionsBBR attenuated PA-induced lipotoxicity via the PPAR-a pathway.

Role of adiponectin and its target receptors to control deposition of fat in obesity related disorders

BackgroundAdiponectin is a protein hormone secreted by adipocytes. AimThe aim of present review is to enlist them all, and mention their significance in obesity, which helps researchers in drug discovery and future medicine. Material and methodsThe last 20 years data has been searched and studied to mention their current role in obesity treatment and ailments of disease. Results and conclusionAdiponectin exert its action through receptors AdipoR1, AdipoR2, T-cadherin. In muscle AdipoR1 is exhibit, while in liver AdipoR2 is mainly exhibit. AMPK and PPARα pathway in liver and skeletal muscle are magnified by adiponectin. Adiponectin show many function like expand fatty acids oxidation, control glucose level and manage receptor activity. Circulating level of adiponectin is lower in case of obesity, insulin resistance and other metabolic disorder. In this review we will focus on role of adiponectin and its receptors in metabolic disorder obesity.

Ginsenoside Rb3 regulates energy metabolism and apoptosis in cardiomyocytes via activating PPARα pathway

Heart failure (HF) leads to an increase in morbidity and mortality globally. Disorders of energy metabolism and apoptosis of cardiomyocytes are critically involved in the progression of HF. Ginsenoside Rb3 (G-Rb3) is a natural product derived from ginseng that has cardio-protective effect. The pharmacological mechanism of G-Rb3 in the treatment of HF remains to be clarified. In this study, we aimed to explore the regulative effects of G-Rb3 on fatty acids oxidation and apoptosis by in vivo and in vitro studies. Myocardial infarction (MI)-induced HF mice model and a cellular H9C2 injury model was induced by oxygen-glucose deprivation/reperfusion (OGD/R) stimulation. The results showed that G-Rb3 could protect heart functions in MI-induced HF model. G-Rb3 treatment up-regulated expressions of key enzymes involved in β-oxidation of fatty acids, including carnitine palmitoyltransterase-1α (CPT-1α), acyl-CoA dehydrogenase long chain (ACADL) and the major mitochondrial deacetylase enzyme sirtuin 3 (SIRT3). The upstream transcriptional regulator, peroxisome proliferator-activated receptor α (PPARα), was also up-regulated by G-Rb3 treatment. In vitro study demonstrated that G-Rb3 could protect mitochondrial membrane integrity and exert anti-apoptotic effects, in addition to regulating fatty acids oxidation. Impressively, after cells were co-treated with PPARα inhibitor, the regulative effects of G-Rb3 on energy metabolism and apoptosis were abrogated. Our study suggests that G-Rb3 is a promising agent and PPARα is potential target in the management of HF.

Effect of subacute and prenatal DINCH plasticizer exposure on rat dams and male offspring hepatic function: The role of PPAR-α

Plasticizers are compounds added to plastics to modify their physical proprieties. The most well-known class of plasticizers, the phthalates, has been shown to possess antiandrogenic and tumor promoting activities. 1,2-Cyclohexane dicarboxylic acid diisononyl ester (DINCH) was approved for use in food contact containers in 2006 and has been used as a replacement for phthalates in toys and children products. However, we reported previously that the DINCH metabolite MINCH acts on primary rat adipocytes through the peroxisome proliferator activated receptor (PPAR)-α pathway in a manner similar to phthalates. Evidence from our studies, as well as from the current bibliography on DINCH, suggests that the liver might be one of its target organs. In the present study, we collected tissues from dams exposed subacutely and progeny at postnatal day (PND) 3 and 60 exposed in utero to DINCH (1, 10 and 100 mg/kg bw/day). Exposure to DINCH drastically affected liver gene expression in all 3 age groups tested and in particular at the dose of 1 mg/kg bw/day. The PPAR-α pathway along with other metabolic and DNA replication pathways were affected by DINCH. Modifications in PPAR-α and superoxide dismutase (SOD)-1 protein levels were observed in dams at PND21, as well as male progeny at PND3 and 60. No sign of fibrosis or direct liver toxicity was observed after 8 days of stimulus with low doses of DINCH. This study provides evidence that DINCH is not a biologically inert molecule in the rat, and in the liver its actions are mediated, at least in part, by PPAR-α.