Molecular mechanisms of latent inflammation in metabolic syndrome. Possible role of sirtuins and peroxisome proliferator-activated receptor type γ

2015 ◽  
Vol 80 (10) ◽  
pp. 1217-1226 ◽  
Author(s):  
I. S. Stafeev ◽  
M. Y. Menshikov ◽  
Z. I. Tsokolaeva ◽  
M. V. Shestakova ◽  
Ye. V. Parfyonova
Keyword(s):  
Metabolic Syndrome ◽  
Molecular Mechanisms ◽  
Receptor Type ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

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 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.

scholarly journals Role of Mineralocorticoid Receptor in Adipogenesis and Obesity in Male Mice

Endocrinology ◽  
2019 ◽  
Vol 161 (2) ◽  
Author(s):  
Daniel Ferguson ◽  
Irina Hutson ◽  
Eric Tycksen ◽  
Terri A Pietka ◽  
Kevin Bauerle ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Fat Mass ◽  
Mineralocorticoid Receptor ◽  
Peroxisome Proliferator ◽  
Sequencing Analysis ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Brown Adipose

Abstract Increased visceral adiposity and hyperglycemia, 2 characteristics of metabolic syndrome, are also present in conditions of excess glucocorticoids (GCs). GCs are hormones thought to act primarily via the glucocorticoid receptor (GR). GCs are commonly prescribed for inflammatory disorders, yet their use is limited due to many adverse metabolic side effects. In addition to GR, GCs also bind the mineralocorticoid receptor (MR), but there are many conflicting studies about the exact role of MR in metabolic disease. Using MR knockout mice (MRKO), we find that both white and brown adipose depots form normally when compared with wild-type mice at P5. We created mice with adipocyte-specific deletion of MR (FMRKO) to better understand the role of MR in metabolic dysfunction. Treatment of mice with excess GCs for 4 weeks, via corticosterone in drinking water, induced increased fat mass and glucose intolerance to similar levels in FMRKO and floxed control mice. Separately, when fed a high-fat diet for 16 weeks, FMRKO mice had reduced body weight, fat mass, and hepatic steatosis, relative to floxed control mice. Decreased adiposity likely resulted from increased energy expenditure since food intake was not different. RNA sequencing analysis revealed decreased enrichment of genes associated with adipogenesis in inguinal white adipose of FMRKO mice. Differentiation of mouse embryonic fibroblasts (MEFs) showed modestly impaired adipogenesis in MRKO MEFs compared with wild type, but this was rescued upon the addition of peroxisome proliferator-activated receptor gamma (PPARγ) agonist or PPARγ overexpression. Collectively, these studies provide further evidence supporting the potential value of MR as a therapeutic target for conditions associated with metabolic syndrome.

scholarly journals Preventing type 2 diabetes and cardiovascular disease in metabolic syndrome: the role of PPARα

2007 ◽  
Vol 4 (3_suppl) ◽  
pp. S12-S14 ◽  
Author(s):  
Jorge Plutzky
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Lipid Metabolism ◽  
Drug Target ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Central Target ◽  
The Metabolic Syndrome

The clustering of cardiovascular risk factors associated with the metabolic syndrome and type 2 diabetes suggests central mechanisms may exist that account for the presence of these abnormalities. Likewise, this clustering also suggests that key therapeutic targets may exist that could allow improvements in many of these parameters. Extensive data implicate peroxisome proliferator-activated receptor-alpha (PPARα) as an important transcriptional regulator of lipid metabolism, energy balance and inflammation. PPARα is also an established drug target. Experimental data show that activation of PPARα by agonists such as fenofibrate improves dyslipidaemia, increases cholesterol efflux and limits inflammation. All of these effects would also be predicted to decrease atherosclerotic risk. Evidence from surrogate markers in humans is also supportive of the concept that PPARα may act as a central target capable of influencing a variety of different pathways involved in lipid metabolism. Thus, fenofibrate offers the potential for inducing a co-ordinated PPARα response that may improve dyslipidaemia, repress inflammation and limit atherosclerosis in patients with the metabolic syndrome or type 2 diabetes.

scholarly journals The role of peroxisome proliferator-activated receptor in the treatment of non-alcoholic fatty liver disease

2017 ◽  
Vol 67 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Xin Sun ◽  
Yan Zhang ◽  
Meilin Xie
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Peroxisome Proliferator Activated Receptors ◽  
Alcoholic Fatty Liver Disease

AbstractNon-alcoholic fatty liver disease (NAFLD) has been defined as a spectrum of histological abnormalities and is characterized by significant and excessive accumulation of triglycerides in the hepatocytes in patients without alcohol consumption or other diseases. Current studies are targeting new molecular mechanisms that underlie NAFLD and associated metabolic disorders. Many therapeutic targets have been found and used in clinical studies. Peroxisome proliferator-activated receptors (PPARs) are among the potential targets and have been demonstrated to exert a pivotal role in modulation of NAFLD. Many drugs developed so far are targeted at PPARs. Thus, the aim of this paper is to summarize the roles of PPARs in the treatment of NAFLD.

scholarly journals Peroxisome Proliferator-Activated Receptor-γIs Critical to Cardiac Fibrosis

PPAR Research ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Huang-Jun Liu ◽  
Hai-Han Liao ◽  
Zheng Yang ◽  
Qi-Zhu Tang
Keyword(s):  
Immune Cells ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Receptor Superfamily ◽  
Infarction Heart

Peroxisome proliferator-activated receptor-γ(PPARγ) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily, which plays a central role in regulating lipid and glucose metabolism. However, accumulating evidence demonstrates that PPARγagonists have potential to reduce inflammation, influence the balance of immune cells, suppress oxidative stress, and improve endothelial function, which are all involved in the cellular and molecular mechanisms of cardiac fibrosis. Thus, in this review we discuss the role of PPARγin various cardiovascular conditions associated with cardiac fibrosis, including diabetes mellitus, hypertension, myocardial infarction, heart failure, ischemia/reperfusion injury, atrial fibrillation, and several other cardiovascular disease (CVD) conditions, and summarize the developmental status of PPARγagonists for the clinical management of CVD.

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.

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