Mitochondrial Dysfunction and Oxidative Stress in the Pathogenesis of Metabolic Syndrome
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors, which consists of three members, PPARα, PPARγ and PPARβ/δ. Among them, PPARα is expressed highly in tissues with high fatty acid oxidation (FAO) rates, such as liver, heart, skeletal muscle, brown adipose tissue, and kidney, although it is also universally expressed in other tissues, including the intestine, vascular endothelium, smooth muscle and immune cells78. PPARα is an essential nutritional sensor, which regulates transcription of genes involved in fatty acid (FA) catabolism, lipogenesis and ketone body synthesis, in response to feeding and starvation79. These include genes regulating mitochondrial β-oxidation, FA transport and hepatic glucose production80. Moreover, PPARα also displays anti-inflammatory properties by inhibiting pro-inflammatory and acute phase response (APR) signalling pathways, as evidenced by rodent models of systemic inflammation, atherosclerosis and non-alcoholic steatohepatitis (NASH)81,82.
Derivation and Modeling of Mechanistic Data for Use in Risk Assessment
John C. Lipscomb, Edward V. Ohanian in Toxicokinetics and Risk Assessment, 2016
The discovery of the peroxisome proliferator-activated receptor (PPARα), a ligand-activated transcription factor (67), provides a mechanistic basis for understanding how peroxisome proliferators modulate gene expression. Humans express a functionally active PPARα (68,69) and hypolipidemic fibrates modulate lipid homeostasis in humans through the activation of this receptor (70). Ligand-activated PPARα forms a heterodimer with the retinoid X receptor (RXR) (71) that can bind to peroxisome proliferator response elements (PPREs) in the promoter region of genes induced by these ligands. Factors that may contribute to tissue and species differences in response include tissue dosimetry of the activating ligand, the relative levels of the receptor, the nature of PPREs in targeted genes, crosstalk among nuclear transcription factors for RXR, and levels of coactivators and corepressors of the liganded receptor (72). Species comparisons of the latter two factors have not been reported; however, levels of PPARα mRNA levels were found to be lower in the liver of humans compared to rats or mice (73). The hypothesis that differences in PPARα levels account for species differences in response to PPARα agonists has not been tested (74).
Effects of chemical pollutants on spermatogenesis and implications in male infertility
C. Yan Cheng in Spermatogenesis, 2018
PFCs are classified as peroxisome proliferators. This class of molecules activate ligand-dependent transcription factors of the PPAR family to alter lipid metabolism and cell differentiation.161–164 PPARs belong to the steroid hormone receptor superfamily and are able to interact with steroid receptors to modify the activities of other steroid hormones.165 The identification of PPARs in human testes and developing rat testes suggests PPAR-signaling may play a role in testicular cell differentiation during early development.166 Animal and cell culture studies revealed that an activation of PPARs in the testes was associated with gonadal steroidogenesis,167 spermatogenesis,168 and Sertoli cell metabolism.169 Conversely, inactivation of PPAR-elicited peroxisome β-oxidation in mouse testes was found to negatively affect spermatogenesis and cause male infertility.170 Although various studies had illustrated the involvement of the PPAR-pathways in PFC-elicited intoxication, studies of wild-type and PPAR-α null mice treated with PFOS (3–10 mg·kg−1·day−1) demonstrated PPAR-independent effects on reproductive health.171,172
Novel emerging therapies in atherosclerosis targeting lipid metabolism
Published in Expert Opinion on Investigational Drugs, 2020
Manasvi Gupta, Colin Blumenthal, Subhankar Chatterjee, Dhrubajyoti Bandyopadhyay, Vardhmaan Jain, Carl J Lavie, Salim S. Virani, Kausik K Ray, Wilbert S Aronow, Raktim K Ghosh
Peroxisome proliferator-activated receptor (PPAR) alpha is a nuclear receptor that binds to DNA and regulates gene expression, specifically lipid, and glucose metabolism during energy depravation. Among other things it promotes fatty acid oxidation and ketogenesis during fasting states. Pemafibrate is a selective PPAR modulator (SPPARM) that has been shown to reduce TG levels and elevate HDL-C levels. It is approved in Japan for use in dyslipidemia and is still undergoing phase III trials in the US and Europe. Studies examining its use as monotherapy showed a 30% mean reduction in TGs and a 10–15% mean increase in HDL-C after 12 weeks of treatment. This reduction increased to 50% for TGs with a proportional increase in HDL-C when used as an add-on therapy to statins. Notably, there was also a quantitative increase in LDL-C levels, but when examined qualitatively, the increase was found to be of only medium and large-sized LDL fractions, which may not confer the same increase in risk of ASCVD [31].
PPAR Receptors Expressed from Vectors Containing CMV Promoter Can Enhance Self-Transcription in the Presence of Fatty Acids from CLA-Enriched Egg Yolks—A Novel Method for Studies of PPAR Ligands
Published in Nutrition and Cancer, 2020
Aneta A. Koronowicz, Adam Master, Paula Banks, Ewelina Piasna-Słupecka, Dominik Domagała, Mariola Drozdowska, Teresa Leszczyńska
The main physiological roles of PPAR receptors are regulation of fatty acid metabolism, glucose homeostasis, and inflammation (5). In addition, they play an important role in cell proliferation, differentiation, and survival (6), which aroused the interest in their role in carcinogenesis. However, the available literature is ambiguous in assessing the impact of PPAR isoforms on cancer, suggesting its isomer-, ligand-, or even tissue-specific effect. Moreover, some disparate findings raised the possibility of PPAR receptor-independent effects, including the activity of other receptors binding the same ligands as PPAR (7,8). It has been shown that the administration of synthetic PPAR agonist (troglitazone) resulted in cell G1 phase arrest and inhibited proliferation of pancreatic cancer and hepatoma cells (9,10). However, other studies showed that specific PPAR antagonist—T0070907 and HL005 significantly reduced proliferation and migration of breast cancer cells (11,12), however, the precise mechanism of its action has not yet been fully explained.
The roles of hydrogen sulfide in renal physiology and disease states
Published in Renal Failure, 2022
Jianan Feng, Xiangxue Lu, Han Li, Shixiang Wang
PPARs are a class of ligand–activated nuclear transcription factors that belong to the receptor superfamily. Three subtypes of PPARs, PPAR–α, PPAR–β/δ, and PPAR–γ, have been found. Each PPAR subtype can alleviate metabolic abnormalities under the action of agonists; however, their mechanisms of action are different. For example, activation of PPAR–β/δ can significantly improve BP by increasing NO and serve as a new therapeutic target for hypertension [135,136]. Recent studies have shown that the role of H2S in regulating BP might be related to PPARβ/δ activation. H2S is thought to work with NO in synergy to regulate vascular tone. The specific molecular mechanism may involve H2S–mediated upregulation of PPAR–δ expression, increases in protein kinase B or AMPK phosphorylation, and enhancement of eNOS phosphorylation with a consequent increase in NO production [137,138]. In rats, the use of NOS inhibitors, such as Nx–nitro–l–arginine methyl ester, can cause hypertension, which can be reversed by treatment with NaHS [139]. However, in aortic rings of rats, low concentrations of NaHS (10–100 μM) can downregulate NO production and consequently induce vasoconstriction. In contrast, administration of high doses of NaHS has been reported to directly relax aortic rings [140]. These findings suggest a role of H2S/NO crosstalk in BP regulation. The antihypertensive effect of H2S is also dose dependent, but the specific mechanism needs further study [6].
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