PPARGEpigenetic Deregulation and Its Role in Colorectal Tumorigenesis

Peroxisome proliferator-activated receptor gamma (PPARγ) plays critical roles in lipid storage, glucose metabolism, energy homeostasis, adipocyte differentiation, inflammation, and cancer. Its function in colon carcinogenesis has largely been debated; accumulating evidence, however, supports a role as tumor suppressor through modulation of crucial pathways in cell differentiation, apoptosis, and metastatic dissemination. Epigenetics adds a further layer of complexity to gene regulation in several biological processes. In cancer, the relationship with epigenetic modifications has provided important insights into the underlying molecular mechanisms. These studies have highlighted how epigenetic modifications influencePPARGgene expression in colorectal tumorigenesis. In this paper, we take a comprehensive look at the current understanding of the relationship between PPARγand cancer development. The role that epigenetic mechanisms play is also addressed disclosing novel crosstalks betweenPPARGsignaling and the epigenetic machinery and suggesting how this dysregulation may contribute to colon cancer development.

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Peroxisome Proliferator-Activated Receptor Alpha Target Genes

PPAR Research ◽

10.1155/2010/612089 ◽

2010 ◽

Vol 2010 ◽

pp. 1-20 ◽

Cited By ~ 377

Author(s):

Maryam Rakhshandehroo ◽

Bianca Knoch ◽

Michael Müller ◽

Sander Kersten

Keyword(s):

Energy Homeostasis ◽

Target Genes ◽

Biological Function ◽

Molecular Target ◽

Peroxisome Proliferator ◽

Biological Processes ◽

Nutrient Metabolism ◽

Peroxisome Proliferator Activated Receptor ◽

Receptor Alpha

The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARαserves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARαbinds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARαgoverns biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARαis directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARαin lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARαtarget genes. The emphasis is on gene regulation by PPARαin liver although many of the results likely apply to other organs and tissues as well.

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RT-PCR analysis of corticotroph-associated genes expression in carcinoid tumours in the ectopic-ACTH syndrome

Acta Endocrinologica ◽

10.1530/eje.1.02077 ◽

2006 ◽

Vol 154 (1) ◽

pp. 159-166 ◽

Cited By ~ 12

Author(s):

M Messager ◽

C Carrière ◽

X Bertagna ◽

Y de Keyzer

Keyword(s):

Transcription Factor ◽

Molecular Mechanisms ◽

Ectopic Acth Syndrome ◽

Pcr Analysis ◽

Peroxisome Proliferator ◽

Rt Pcr ◽

Ectopic Acth ◽

Peroxisome Proliferator Activated Receptor ◽

Carcinoid Tumours ◽

Transcription Factor Genes

Objective: ACTH is frequently produced in non-pituitary tumours, leading to the ectopic-ACTH syndrome, but the molecular mechanisms of its expression remain obscure. This study was aimed at understanding the transcription mechanisms of the ACTH-precursor gene in carcinoid tumours of the lung or thymus. Design: Transcripts coding for a series of corticotroph-associated transcription factor genes were detected, together with markers of the corticotroph phenotype. We studied a series of 41 carcinoid tumours including 15 with proven ectopic-ACTH syndrome. Methods: Specific RT-PCR reactions were designed for each gene including alternatively spliced isoforms. Results: The markers of the corticotroph phenotype were detected in all ACTH-positive tumours. Expression of the Tpit and Pitx1 genes were not restricted to ACTH-positive tumours but were also detected in many ACTH-negative carcinoids. Only a subset of ACTH-negative tumours expressed NAK-1/Nur77, and NeuroD1 expression was detected in <50% of the tumours regardless of their secretory status. The glucocorticoid receptor alpha was detected in every tumour in contrast to its beta isoform detectable in a few tumours only. Chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1) and peroxisome proliferator-activated receptor (PPAR) γ2 were expressed in 50% of the tumours of each group whereas PPARγ1 was expressed in almost every tumour. Conclusions: ACTH-positive carcinoids do not share a characteristic expression pattern of the corticotroph-associated transcription factor genes, suggesting that the transcriptional mechanisms of the ACTH-precursor gene differ from those in normal pituitary corticotrophs. Expression of Tpit and Pitx1 genes in most carcinoids suggests that some aspects of the pituitary corticotroph phenotype may belong to general carcinoid differentiation.

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Growth hormone controls lipolysis by regulation of FSP27 expression

Journal of Endocrinology ◽

10.1530/joe-18-0282 ◽

2018 ◽

Vol 239 (3) ◽

pp. 289-301 ◽

Cited By ~ 13

Author(s):

Rita Sharma ◽

Quyen Luong ◽

Vishva M Sharma ◽

Mitchell Harberson ◽

Brian Harper ◽

...

Keyword(s):

Insulin Resistance ◽

Growth Hormone ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Specific Protein ◽

Negative Regulator ◽

Gamma Activity ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

Growth hormone (GH) has long been known to stimulate lipolysis and insulin resistance; however, the molecular mechanisms underlying these effects are unknown. In the present study, we demonstrate that GH acutely induces lipolysis in cultured adipocytes. This effect is secondary to the reduced expression of a negative regulator of lipolysis, fat-specific protein 27 (FSP27; aka Cidec) at both the mRNA and protein levels. These effects are mimicked in vivo as transgenic overexpression of GH leads to a reduction of FSP27 expression. Mechanistically, we show GH modulation of FSP27 expression is mediated through activation of both MEK/ERK- and STAT5-dependent intracellular signaling. These two molecular pathways interact to differentially manipulate peroxisome proliferator-activated receptor gamma activity (PPARγ) on the FSP27 promoter. Furthermore, overexpression of FSP27 is sufficient to fully suppress GH-induced lipolysis and insulin resistance in cultured adipocytes. Taken together, these data decipher a molecular mechanism by which GH acutely regulates lipolysis and insulin resistance in adipocytes.

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LncRNA LOC102176306 plays important roles in goat testicular development

Reproduction ◽

10.1530/rep-20-0568 ◽

2021 ◽

Vol 161 (5) ◽

pp. 523-537

Author(s):

Shi-Yu An ◽

Zi-Fei Liu ◽

El-Samahy M A ◽

Ming-Tian Deng ◽

Xiao-Xiao Gao ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Proliferation ◽

Molecular Mechanisms ◽

Complex Iii ◽

Testicular Development ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Atp Production ◽

Positive Effects ◽

And Oxidative Stress

Long ncRNAs regulate a complex array of fundamental biological processes, while its molecular regulatory mechanism in Leydig cells (LCs) remains unclear. In the present study, we established the lncRNA LOC102176306/miR-1197-3p/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) regulatory network by bioinformatic prediction, and investigated its roles in goat LCs. We found that lncRNA LOC102176306 could efficiently bind to miR-1197-3p and regulate PPARGC1A expression in goat LCs. Downregulation of lncRNA LOC102176306 significantly supressed testosterone (T) synthesis and ATP production, decreased the activities of antioxidant enzymes and mitochondrial complex I and complex III, caused the loss of mitochondrial membrane potential, and inhibited the proliferation of goat LCs by decreasing PPARGC1A expression, while these effects could be restored by miR-1197-3p inhibitor treatment. In addition, miR-1197-3p mimics treatment significantly alleviated the positive effects of lncRNA LOC102176306 overexpression on T and ATP production, antioxidant capacity and proliferation of goat LCs. Taken together, lncRNA LOC102176306 functioned as a sponge for miR-1197-3p to maintain PPARGC1A expression, thereby affecting the steroidogenesis, cell proliferation and oxidative stress of goat LCs. These findings extend our understanding of the molecular mechanisms of T synthesis, cell proliferation and oxidative stress of LCs.

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Methanol Extract of Mongolian Iris bungei Maxim. Stimulates 3T3-L1 Adipocyte Differentiation

Journal of Nanoscience and Nanotechnology ◽

10.1166/jnn.2021.19160 ◽

2021 ◽

Vol 21 (7) ◽

pp. 3943-3949

Author(s):

Jaegoo Yeon ◽

Sung-Suk Suh ◽

Ui-Joung Youn ◽

Badamtsetseg Bazarragchaa ◽

Ganbold Enebish ◽

...

Keyword(s):

Bacterial Infections ◽

Fatty Acid Synthase ◽

Molecular Mechanisms ◽

Adipocyte Differentiation ◽

Methanol Extract ◽

Regulatory Element ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Peroxisome Proliferator Activated Receptor

Iris bungei Maxim. (IB), which is native to China and Mongolia, is used as a traditional medicine for conditions such as inflammation, cancer, and bacterial infections. However, the effects of Iris bungei Maxim. on adipocyte differentiation have not been studied. In the present study, we first demonstrated the molecular mechanisms underlying the adipogenic activity of the methanol extract of Mongolian I. bungei Maxim. (IB). IB significantly enhanced intracellular lipid accumulation and adipocyte differentiation in 3T3-L1 preadipocytes in a concentration-dependent manner. Moreover, IB markedly stimulated the expression of genes related to adipogenesis such as peroxisome proliferator-activated receptor γ, adiponectin, and aP2. In addition, we also observed that IB induces lipogenic genes such as fatty acid synthase, sterol regulatory element binding protein 1c, stearoyl-CoA desaturase, and acetyl-CoA carboxylase. Interestingly IB regulated adipocyte differentiation in both the early and middle stages. Taken together, these adipogenic and lipogenic effects of IB suggest its efficacy for the prevention and/or treatment of type 2 diabetes.

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Elafibranor interrupts adipose dysfunction-mediated gut and liver injury in mice with alcoholic steatohepatitis

Clinical Science ◽

10.1042/cs20180873 ◽

2019 ◽

Vol 133 (3) ◽

pp. 531-544 ◽

Cited By ~ 9

Author(s):

Tzu-Hao Li ◽

Ying-Ying Yang ◽

Chia-Chang Huang ◽

Chih-Wei Liu ◽

Hung-Cheng Tsai ◽

...

Keyword(s):

Liver Injury ◽

Energy Homeostasis ◽

Intestinal Barrier ◽

Peroxisome Proliferator ◽

Intestinal Epithelial ◽

Peroxisome Proliferator Activated Receptor ◽

Alcoholic Steatohepatitis ◽

Ppar Agonists ◽

Apoptosis And Inflammation ◽

Adipose Dysfunction

Abstract Background: Reversal of alcohol-induced peroxisome proliferator-activated receptor (PPAR) α (PPARα) and PPARδ dysfunction has been reported to decrease the severity of alcoholic steatohepatitis (ASH). Autophagy is essential for cell survival and tissue energy homeostasis. Emerging evidence indicates that alcohol-induced adipose tissue (AT) autophagy dysfunction contributes to injury in the intestine, liver, and AT of ASH. Methods: The effects and mechanisms of dual PPARα/δ agonist elafibranor on autophagy stimulation were investigated using mice with ASH. Results: C57BL/6 mice on ethanol diet showed AT dysfunction, disrupted intestinal barrier, and ASH, which was accompanied by alcohol-mediated decrease in PPARα, PPARδ, and autophagy levels in intestine, liver, and AT. Chronic treatment with elafibranor attenuated AT apoptosis and inflammation by restoration of tissue PPARα, PPARδ, and autophagy levels. In ASH mice, alcohol-induced AT dysfunction along with increased fatty acid (FA) uptake and decreased free FA (FFA) release from AT was inhibited by elafibranor. The improvement of AT autophagy dysfunction by elafibranor alleviated inflammation and apoptosis-mediated intestinal epithelial disruption in ASH mice. Acute elafibranor incubation inhibited ethanol-induced ASH-mice-sera-enhanced autophagy dysfunction, apoptosis, barrier disruption, and intracellular steatosis in Caco-2 cells and primary hepatocytes (PHs). Conclusion: Altogether, these findings demonstrated that the PPARα/δ agonist, elafibranor, decreased the severity of liver injury by restoration of alcohol-suppressed AT autophagy function and by decreasing the release of apoptotic markers, inflammatory cytokines, and FFA, thereby reducing intestinal epithelium disruption and liver inflammation/apoptosis/steatosis in ASH mice. These data suggest that dual PPAR agonists can serve as potential therapeutic agents for the management of ASH.

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

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/6363748 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Jiayao Yang ◽

Dongqing Tao ◽

Wei Ma ◽

Song Liu ◽

Yan Liao ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Peroxisome Proliferator ◽

High Fat ◽

Peroxisome Proliferator Activated Receptor ◽

Nonalcoholic Fatty Liver ◽

Chinese Herbal

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.

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Epigenetic modifications of histones in cancer

Genome Biology ◽

10.1186/s13059-019-1870-5 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 46

Author(s):

Zibo Zhao ◽

Ali Shilatifard

Keyword(s):

Histone Modifications ◽

Functional Significance ◽

Epigenetic Modifications ◽

Cancer Development ◽

Clinical Implications ◽

Biological Processes ◽

Disease Pathogenesis ◽

Different Types ◽

Histone Modifiers ◽

The Many

AbstractThe epigenetic modifications of histones are versatile marks that are intimately connected to development and disease pathogenesis including human cancers. In this review, we will discuss the many different types of histone modifications and the biological processes with which they are involved. Specifically, we review the enzymatic machineries and modifications that are involved in cancer development and progression, and how to apply currently available small molecule inhibitors for histone modifiers as tool compounds to study the functional significance of histone modifications and their clinical implications.

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Association with Coregulators Is the Major Determinant Governing Peroxisome Proliferator-activated Receptor Mobility in Living Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m608172200 ◽

2006 ◽

Vol 282 (7) ◽

pp. 4417-4426 ◽

Cited By ~ 32

Author(s):

Cicerone Tudor ◽

Jérôme N. Feige ◽

Harikishore Pingali ◽

Vidya Bhushan Lohray ◽

Walter Wahli ◽

...

Keyword(s):

Ligand Binding ◽

Molecular Mechanisms ◽

Resonance Energy Transfer ◽

Resonance Energy ◽

Living Cells ◽

Correlation Spectroscopy ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Peroxisome Proliferator Activated Receptors

The nucleus is an extremely dynamic compartment, and protein mobility represents a key factor in transcriptional regulation. We showed in a previous study that the diffusion of peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors regulating major cellular and metabolic functions, is modulated by ligand binding. In this study, we combine fluorescence correlation spectroscopy, dual color fluorescence cross-correlation microscopy, and fluorescence resonance energy transfer to dissect the molecular mechanisms controlling PPAR mobility and transcriptional activity in living cells. First, we bring new evidence that in vivo a high percentage of PPARs and retinoid X receptors is associated even in the absence of ligand. Second, we demonstrate that coregulator recruitment (and not DNA binding) plays a crucial role in receptor mobility, suggesting that transcriptional complexes are formed prior to promoter binding. In addition, association with coactivators in the absence of a ligand in living cells, both through the N-terminal AB domain and the AF-2 function of the ligand binding domain, provides a molecular basis to explain PPAR constitutive activity.

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Peroxisome Proliferator-Activated Receptor γ and PGC-1α in Cancer: Dual Actions as Tumor Promoter and Suppressor

PPAR Research ◽

10.1155/2018/6727421 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 19

Author(s):

Seong-Hoon Yun ◽

Sang-Heum Han ◽

Joo-In Park

Keyword(s):

Metabolic Pathways ◽

Energy Homeostasis ◽

Tumor Promoter ◽

Clinical Implications ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Interacting Protein ◽

Action Mechanisms ◽

Important Regulator

Peroxisome proliferator-activated receptor γ (PPARγ) is part of a nuclear receptor superfamily that regulates gene expression involved in cell differentiation, proliferation, immune/inflammation response, and lipid metabolism. PPARγ coactivator-1α (PGC-1α), initially identified as a PPARγ-interacting protein, is an important regulator of diverse metabolic pathways, such as oxidative metabolism and energy homeostasis. The role of PGC-1α in diabetes, neurodegeneration, and cardiovascular disease is particularly well known. PGC-1α is also now known to play important roles in cancer, independent of the role of PPARγ in cancer. Though many researchers have studied the expression and clinical implications of PPARγ and PGC-1α in cancer, there are still many controversies about the role of PPARγ and PGC-1α in cancer. This review examines and summarizes some recent data on the role and action mechanisms of PPARγ and PGC-1α in cancer, respectively, particularly the recent progress in understanding the role of PPARγ in several cancers since our review was published in 2012.

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