scholarly journals Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators.

1995 ◽  
Vol 15 (6) ◽  
pp. 3012-3022 ◽  
Author(s):  
S S Lee ◽  
T Pineau ◽  
J Drago ◽  
E J Lee ◽  
J W Owens ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Target Genes ◽  
Receptor Gene ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferators ◽  
Targeted Disruption ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cycle Regulation ◽  
Insight Into

To gain insight into the function of peroxisome proliferator-activated receptor (PPAR) isoforms in rodents, we disrupted the ligand-binding domain of the alpha isoform of mouse PPAR (mPPAR alpha) by homologous recombination. Mice homozygous for the mutation lack expression of mPPAR alpha protein and yet are viable and fertile and exhibit no detectable gross phenotypic defects. Remarkably, these animals do not display the peroxisome proliferator pleiotropic response when challenged with the classical peroxisome proliferators, clofibrate and Wy-14,643. Following exposure to these chemicals, hepatomegaly, peroxisome proliferation, and transcriptional-activation of target genes were not observed. These results clearly demonstrate that mPPAR alpha is the major isoform required for mediating the pleiotropic response resulting from the actions of peroxisome proliferators. mPPAR alpha-deficient animals should prove useful to further investigate the role of this receptor in hepatocarcinogenesis, fatty acid metabolism, and cell cycle regulation.

scholarly journals Peroxisome Proliferator-Activated Receptor γ Target Gene Encoding a Novel Angiopoietin-Related Protein Associated with Adipose Differentiation

2000 ◽  
Vol 20 (14) ◽  
pp. 5343-5349 ◽  
Author(s):  
J. Cliff Yoon ◽  
Troy W. Chickering ◽  
Evan D. Rosen ◽  
Barry Dussault ◽  
Yubin Qin ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Time Course ◽  
Target Gene ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Isolation And Characterization ◽  
Adipose Differentiation ◽  
Novel Target

ABSTRACT The nuclear receptor peroxisome proliferator-activated receptor γ regulates adipose differentiation and systemic insulin signaling via ligand-dependent transcriptional activation of target genes. However, the identities of the biologically relevant target genes are largely unknown. Here we describe the isolation and characterization of a novel target gene induced by PPARγ ligands, termed PGAR (for PPARγ angiopoietin related), which encodes a novel member of the angiopoietin family of secreted proteins. The transcriptional induction of PGAR follows a rapid time course typical of immediate-early genes and occurs in the absence of protein synthesis. The expression of PGAR is predominantly localized to adipose tissues and placenta and is consistently elevated in genetic models of obesity. Hormone-dependent adipocyte differentiation coincides with a dramatic early induction of the PGAR transcript. Alterations in nutrition and leptin administration are found to modulate the PGAR expression in vivo. Taken together, these data suggest a possible role for PGAR in the regulation of systemic lipid metabolism or glucose homeostasis.

scholarly journals Characterization of the transactivation domain in the peroxisome-proliferator-activated receptor γ co-activator (PGC-1)

2007 ◽  
Vol 403 (3) ◽  
pp. 511-518 ◽  
Author(s):  
Prabodh Sadana ◽  
Edwards A. Park
Keyword(s):  
Transcriptional Activation ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Transactivation Domain ◽  
Peroxisome Proliferator Activated Receptor ◽  
N Terminus ◽  
Cpt I

The PGC-1s (peroxisome-proliferator-activated receptor γ co-activators) are a family of transcriptional regulators that induce the expression of various metabolic genes. PGC-1 proteins stimulate genes involved in mitochondrial biogenesis, fatty acid oxidation and hepatic gluconeogenesis. Previous studies have demonstrated that the PGC-1α and β isoforms interact with nuclear receptors through the conserved LXXLL (leucine-X-X-leucine-leucine) motifs. In the present study, we have investigated the mechanisms by which these PGC-1 isoforms stimulate gene expression. We have determined that the N-terminus of PGC-1 is responsible for transcriptional activation. Two conserved peptide motifs were identified in the N-terminus of PGC-1α and β isoforms. These domains were named AD1 and AD2 (activation domain 1 and 2). Deletion of both of these motifs decreased the induction of various PGC-1-regulated genes including the PEPCK (phosphoenolpyruvate carboxykinase) and CPT-I (carnitine palmitoyltransferase-I) genes. It was determined that amino acids containing a negative charge in AD1 and the leucine residues in AD2 were important for the transcriptional induction of the PEPCK and CPT-I genes. Disruption of the AD motifs did not diminish the ability of the PGC-1α protein to associate with the PEPCK or CPT-I genes. In addition, deletion of the AD domains did not eliminate the ability of PGC-1α to interact with the thyroid hormone receptor. The data indicate that the AD1 and AD2 motifs mediate the induction of many PGC-1- responsive genes, but they do not contribute to the recruitment of PGC-1 to target genes.

scholarly journals Peroxisome Proliferator-Activated Receptor Alpha Target Genes

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-20 ◽  
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.

scholarly journals The Role of NF-κB in PPARα-Mediated Hepatocarcinogenesis

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-9 ◽  
Author(s):  
Howard P. Glauert ◽  
Karen Calfee-Mason ◽  
Yixin Li ◽  
Vani Nilakantan ◽  
Michelle L. Twaroski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
The Other ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferators ◽  
Liver Carcinogenesis ◽  
Carcinogenic Activity ◽  
Peroxisome Proliferator Activated Receptor ◽  
Rats And Mice ◽  
Lines Of Evidence

In this review, the role of NF-κB in the induction of hepatocarcinogenesis by peroxisome proliferators is examined. The administration of peroxisome proliferators for more than a three-day period leads to the activation of NF-κB in the livers of rats and mice. On the other hand, peroxisome proliferator activated receptor-α(PPARα) activation in non-hepatic tissues can lead to the inhibition of NF-κB activation. Several lines of evidence support the hypothesis that the activation of NF-κB by peroxisome proliferators in the liver is mediated by oxidative stress. The role of NF-κB in peroxisome proliferator-induced hepatocarcinogenesis has been examined using NF-κB knockout models. Specifically, the induction of cell proliferation and the promotion of liver carcinogenesis are inhibited in mice lacking the p50 subunit of NF-κB. Overall, the activation of NF-κB appears to be important in the carcinogenic activity of peroxisome proliferators.

scholarly journals The Nuclear Hormone Receptor PPARγas a Therapeutic Target in Major Diseases

2010 ◽  
Vol 10 ◽  
pp. 2181-2197 ◽  
Author(s):  
Martina Victoria Schmidt ◽  
Bernhard Brüne ◽  
Andreas von Knethen
Keyword(s):  
Therapeutic Target ◽  
Hormone Receptor ◽  
Target Genes ◽  
Inflammatory Responses ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Sensitizers

The peroxisome proliferator-activated receptor γ (PPARγ) belongs to the nuclear hormone receptor superfamily and regulates gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements (PPREs) in the promoter region of target genes. Originally, PPARγwas identified as being essential for glucose metabolism. Thus, synthetic PPARγagonists, the thiazolidinediones (TZDs), are used in type 2 diabetes therapy as insulin sensitizers. More recent evidence implied an important role for the nuclear hormone receptor PPARγin controlling various diseases based on its anti-inflammatory, cell cycle arresting, and proapoptotic properties. In this regard, expression of PPARγis not restricted to adipocytes, but is also found in immune cells, such as B and T lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes. The expression of PPARγin lymphoid organs and its modulation of macrophage inflammatory responses, lymphocyte proliferation, cytokine production, and apoptosis underscore its immune regulating functions. Moreover, PPARγexpression is found in tumor cells, where its activation facilitates antitumorigenic actions. This review provides an overview about the role of PPARγas a possible therapeutic target approaching major, severe diseases, such as sepsis, cancer, and atherosclerosis.

scholarly journals Hepatic Ago2 Regulates PPARα for Oxidative Metabolism Linked to Glycemic Control in Obesity and Post Bariatric Surgery

Endocrinology ◽  
2021 ◽  
Vol 162 (4) ◽  
Author(s):  
Jashdeep Bhattacharjee ◽  
Vishnupriya J Borra ◽  
Esam S B Salem ◽  
Cai Zhang ◽  
Kazutoshi Murakami ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Oxidative Metabolism ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mitochondrial Functions ◽  
Mitochondrial Oxidation ◽  
Main Component

Abstract Argonaute 2 (Ago2) is the main component of the RNA-induced silencing complex. We recently showed that liver-specific Ago2-deficiency in mice (L-Ago2 knockout [KO] mice) enhances mitochondrial oxidation and alleviates obesity-associated pathophysiology. However, the precise mechanisms behind the role of hepatic Ago2 in regulating the mitochondrial oxidation associated with glucose metabolism are still unclear. Here, we show that hepatic Ago2 regulates the function of peroxisome proliferator–activated receptor α (PPARα) for oxidative metabolism. In both genetically and diet-induced severe obese conditions, L-Ago2 KO mice developed obesity and hepatic steatosis but exhibited improved glucose metabolism accompanied by lowered expression levels of pathologic microRNAs (miRNAs), including miR-802, miR-103/107, and miR-152, and enhanced expression of PPARα and its target genes regulating oxidative metabolism in the liver. We then investigated the role of hepatic Ago2 in the outcomes of vertical sleeve gastrectomy (VSG) in which PPARα plays a crucial role in a drastic transcription reprogram associated with improved glycemia post VSG. Whereas VSG reduced body weight and improved fatty liver in wild-type mice, these effects were not observed in hepatic Ago2-deficient mice. Conversely, glucose metabolism was improved in a hepatic Ago2-dependent manner post VSG. Treating Ago2-deficient primary hepatocytes with WY-14643, a PPARα agonist, showed that Ago2-deficiency enhances sensitivity to WY-14643 and increases expression of PPARα target genes and mitochondrial oxidation. Our findings suggest that hepatic Ago2 function is intrinsically associated with PPARα that links Ago2-mediated RNA silencing with mitochondrial functions for oxidation and obesity-associated pathophysiology.

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