Role of the Peroxisome Proliferator Activated Receptors in Hypertension

2021 ◽  
Vol 128 (7) ◽  
pp. 1021-1039 ◽  
Author(s):  
Shi Fang ◽  
M. Christine Livergood ◽  
Pablo Nakagawa ◽  
Jing Wu ◽  
Curt D. Sigmund
Keyword(s):  
Blood Pressure ◽  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Large Family ◽  
Future Research ◽  
Peroxisome Proliferator ◽  
Transcriptional Responses ◽  
Peroxisome Proliferator Activated Receptor ◽  
Arterial Blood

Nuclear receptors represent a large family of ligand-activated transcription factors which sense the physiological environment and make long-term adaptations by mediating changes in gene expression. In this review, we will first discuss the fundamental mechanisms by which nuclear receptors mediate their transcriptional responses. We will focus on the PPAR (peroxisome proliferator-activated receptor) family of adopted orphan receptors paying special attention to PPARγ, the isoform with the most compelling evidence as an important regulator of arterial blood pressure. We will review genetic data showing that rare mutations in PPARγ cause severe hypertension and clinical trial data which show that PPARγ activators have beneficial effects on blood pressure. We will detail the tissue- and cell-specific molecular mechanisms by which PPARs in the brain, kidney, vasculature, and immune system modulate blood pressure and related phenotypes, such as endothelial function. Finally, we will discuss the role of placental PPARs in preeclampsia, a life threatening form of hypertension during pregnancy. We will close with a viewpoint on future research directions and implications for developing novel therapies.

scholarly journals Regulator of G protein signaling 5 is a determinant of gestational hypertension and preeclampsia

2015 ◽  
Vol 7 (290) ◽  
pp. 290ra88-290ra88 ◽  
Author(s):  
Vasyl Holobotovskyy ◽  
Yee Seng Chong ◽  
Jennifer Burchell ◽  
Bo He ◽  
Michael Phillips ◽  
...  
Keyword(s):  
Blood Pressure ◽  
G Protein ◽  
Vascular Function ◽  
Gestational Hypertension ◽  
Peroxisome Proliferator ◽  
Protein Signaling ◽  
Current Standard ◽  
Guanine Nucleotide Binding Protein ◽  
Peroxisome Proliferator Activated Receptor

Preeclampsia is a systemic vascular disorder of pregnancy and is associated with increased sensitivity to angiotensin II (AngII) and hypertension. The cause of preeclampsia remains unknown. We identified the role of regulator of G protein (heterotrimeric guanine nucleotide–binding protein) signaling 5 (RGS5) in blood pressure regulation during pregnancy and preeclampsia. RGS5 expression in human myometrial vessels is markedly suppressed in gestational hypertension and/or preeclampsia. In pregnant RGS5-deficient mice, reduced vascular RGS5 expression causes gestational hypertension by enhancing vascular sensitivity to AngII. Further challenge by increasing AngII results in preeclampsia-like symptoms, namely, more severe hypertension, proteinuria, placental pathology, and reduced birth weight. In pregnant heterozygote null mice, treatment with peroxisome proliferator–activated receptor (PPAR) agonists normalizes vascular function and blood pressure through effects on RGS5. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling. Because preeclampsia is refractory to current standard therapies, our study opens an unrecognized and urgently needed opportunity for treatment of gestational hypertension and preeclampsia.

scholarly journals Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis

2019 ◽  
Vol 295 (4) ◽  
pp. 994-1008 ◽  
Author(s):  
Nancy Magee ◽  
An Zou ◽  
Priyanka Ghosh ◽  
Forkan Ahamed ◽  
Don Delker ◽  
...  
Keyword(s):  
Nonalcoholic Steatohepatitis ◽  
Molecular Mechanisms ◽  
Liver Steatosis ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
Rna Seq ◽  
Hepatic Inflammation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Small Heterodimer Partner

Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease worldwide and is characterized by steatosis, inflammation, and fibrosis. The molecular mechanisms underlying NASH development remain obscure. The nuclear receptor small heterodimer partner (Shp) plays a complex role in lipid metabolism and inflammation. Here, we sought to determine SHP's role in regulating steatosis and inflammation in NASH. Shp deletion in murine hepatocytes (ShpHep−/−) resulted in massive infiltration of macrophages and CD4+ T cells in the liver. ShpHep−/− mice developed reduced steatosis, but surprisingly increased hepatic inflammation and fibrosis after being fed a high-fat, -cholesterol, and -fructose (HFCF) diet. RNA-Seq analysis revealed that pathways involved in inflammation and fibrosis are significantly activated in the liver of ShpHep−/− mice fed a chow diet. After having been fed the HFCF diet, WT mice displayed up-regulated peroxisome proliferator-activated receptor γ (Pparg) signaling in the liver; however, this response was completely abolished in the ShpHep−/− mice. In contrast, livers of ShpHep−/− mice had consistent NF-κB activation. To further characterize the role of Shp specifically in the transition of steatosis to NASH, mice were fed the HFCF diet for 4 weeks, followed by Shp deletion. Surprisingly, Shp deletion after steatosis development exacerbated hepatic inflammation and fibrosis without affecting liver steatosis. Together, our results indicate that, depending on NASH stage, hepatic Shp plays an opposing role in steatosis and inflammation. Mechanistically, Shp deletion in hepatocytes activated NF-κB and impaired Pparg activation, leading to the dissociation of steatosis, inflammation, and fibrosis in NASH development.

scholarly journals Alteration of a Single Amino Acid in Peroxisome Proliferator-Activated Receptor-α (PPARα) Generates a PPARδ Phenotype

2000 ◽  
Vol 14 (5) ◽  
pp. 733-740 ◽  
Author(s):  
Ichiro Takada ◽  
Ruth T. Yu ◽  
H. Eric Xu ◽  
Millard H. Lambert ◽  
Valerie G. Montana ◽  
...  
Keyword(s):  
Amino Acid ◽  
Nuclear Receptors ◽  
Site Directed Mutagenesis ◽  
Single Amino Acid ◽  
Peroxisome Proliferator ◽  
Transcriptional Responses ◽  
Peroxisome Proliferator Activated Receptor ◽  
Single Amino Acid Change ◽  
Close Relationship ◽  
Peroxisome Proliferator Activated Receptors

Abstract Three pharmacologically important nuclear receptors, the peroxisome proliferator-activated receptors (PPARs α,γ , and δ), mediate key transcriptional responses involved in lipid homeostasis. The PPARα and γ subtypes are well conserved from Xenopus to man, but the β/δ subtypes display substantial species variations in both structure and ligand activation profiles. Characterization of the avian cognates revealed a close relationship between chick (c) α and γ subtypes to their mammalian counterparts, whereas the third chicken subtype was intermediate to Xenopus (x) β and mammalian δ, establishing that β and δ are orthologs. Like xPPARβ, cPPARβ responded efficiently to hypolipidemic compounds that fail to activate the human counterpart. This provided the opportunity to address the pharmacological problem as to how drug selectivity is achieved and the more global evolutionary question as to the minimal changes needed to generate a new class of receptor. X-ray crystallography and chimeric analyses combined with site-directed mutagenesis of avian and mammalian cognates revealed that a Met to Val change at residue 417 was sufficient to switch the human and chick phenotype. These results establish that the genetic drive to evolve a novel and functionally selectable receptor can be modulated by a single amino acid change and suggest how nuclear receptors can accommodate natural variation in species physiology.

scholarly journals The Role of PPARγ Ligands in Breast Cancer: From Basic Research to Clinical Studies

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2623
Author(s):  
Giuseppina Augimeri ◽  
Cinzia Giordano ◽  
Luca Gelsomino ◽  
Pierluigi Plastina ◽  
Ines Barone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Basic Research ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Natural And Synthetic

Peroxisome proliferator-activated receptor gamma (PPARγ), belonging to the nuclear receptor superfamily, is a ligand-dependent transcription factor involved in a variety of pathophysiological conditions such as inflammation, metabolic disorders, cardiovascular disease, and cancers. In this latter context, PPARγ is expressed in many tumors including breast cancer, and its function upon binding of ligands has been linked to the tumor development, progression, and metastasis. Over the last decade, much research has focused on the potential of natural agonists for PPARγ including fatty acids and prostanoids that act as weak ligands compared to the strong and synthetic PPARγ agonists such as thiazolidinedione drugs. Both natural and synthetic compounds have been implicated in the negative regulation of breast cancer growth and progression. The aim of the present review is to summarize the role of PPARγ activation in breast cancer focusing on the underlying cellular and molecular mechanisms involved in the regulation of cell proliferation, cell cycle, and cell death, in the modulation of motility and invasion as well as in the cross-talk with other different signaling pathways. Besides, we also provide an overview of the in vivo breast cancer models and clinical studies. The therapeutic effects of natural and synthetic PPARγ ligands, as antineoplastic agents, represent a fascinating and clinically a potential translatable area of research with regards to the battle against cancer.

The Role of Peroxisome Proliferator-Activated Receptor in Addiction: A Novel Drug Target

2021 ◽  
Vol 21 ◽  
Author(s):  
Carla Quiroga ◽  
Juan José Barberena ◽  
Jocelyne Alcaraz-Silva ◽  
Sérgio Machado ◽  
Claudio Imperatori ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Acid Oxidation ◽  
Critical Element ◽  
Peroxisome Proliferator ◽  
Addictive Behaviors ◽  
Health Issues ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Activated Receptors ◽  
Novel Drug

: The peroxisome proliferator activated receptors (PPARs) are a superfamily of well-recognized ligand-binding nuclear receptors comprising three isoforms: PPARα, PPARγ, and PPARβ/δ. In response to endogenous lipid messengers, PPARs trigger the transcription of genes related to a wider spectrum of physiological phenomena, including fatty acid oxidation, inflammation, and adipogenesis among many others. Thus, the importance of PPARs as putative protective therapy in health issues has increased the interest in studying these nuclear receptors, including the management of neurodegenerative disorders, multiple sclerosis, and likely addiction. In recent years, several pieces of evidence from animal models have demonstrated the promising role of PPARs as a critical element for interventions in addictive behaviors by reducing the reinforcing properties of addictive substances such as alcohol. However, there is a lack of data in scope and has so far been unexplored the function of PPARs in additional drugs such as cannabis, opioids, methamphetamine, or cocaine. Similar scenario has been found for the management of binge-type eating disorders. Thus, here we review recent advances in understanding the relevance of the PPAR controlling addiction.

scholarly journals Estrogen-related receptor-γ and peroxisome proliferator-activated receptor-γ coactivator-1α regulate estrogen-related receptor-α gene expression via a conserved multi-hormone response element

2005 ◽  
Vol 34 (2) ◽  
pp. 473-487 ◽  
Author(s):  
D Liu ◽  
Z Zhang ◽  
C T Teng
Keyword(s):  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Peroxisome Proliferator ◽  
Hormone Response ◽  
Core Element ◽  
Response Element ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hormone Response Element ◽  
Estrogen Related Receptor

The expression of estrogen-related receptor-α (ERRα) is stimulated by estrogen in selective tissues. Recently, a correlation between ERRα expression and the induction of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in the liver of fasting animals and in cold-stressed brown-fat tissues and skeletal muscle was shown. To explore the molecular mechanisms of ERRα regulation by diverse signals, the promoter of the human ERRα gene was cloned and characterized. Mutation and deletion analyses revealed that a 53 bp region containing repeated core element AGGTCA motifs of the ERRα gene serves as a multi-hormone response element (MHRE) for several nuclear receptors in transient co-transfection studies of human endometrial carcinoma (HEC-1B) cells. Among the nuclear receptors tested, ERRγ bound to and robustly stimulated the transcription of reporters containing at least two AGGTCA motifs. Ectopic expression of PGC-1α in HEC-1B cells strongly activated the reporter containing the MHRE, presumably via the endogenous nuclear receptor binding to the element. Reducing the endogenous level of ERRγ by small interfering RNA, and increasing the ERRγ level by ectopic expression, substantially decreased and increased respectively the transactivation capability of PGC-1α. The activation function 2 domain of the ERRγ and the L2 and L3 motifs of PGC-1α were essential to transactivate the MHRE. Additionally, PGC-1α increases the amount of endogenous ERRγ bound to the MHRE region as determined by a chromatin immunoprecipitation assay. The present study demonstrates that the MHRE of the ERRα gene is a target for ERRγ transactivation, which is enhanced by PGC-1α.

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