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Environmental Health and Preventive... Jul 2019The plasticizer di(2-ethylhexyl) phthalate (DEHP) has been widely used in the manufacture of polyvinyl chloride-containing products such as medical and consumer goods.... (Review)
Review
The plasticizer di(2-ethylhexyl) phthalate (DEHP) has been widely used in the manufacture of polyvinyl chloride-containing products such as medical and consumer goods. Humans can easily be exposed to it because DEHP is ubiquitous in the environment. Recent research on the adverse effects of DEHP has focused on reproductive and developmental toxicity in rodents and/or humans. DEHP is a representative of the peroxisome proliferators. Therefore, peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways are the expected mode of action of several kinds of DEHP-induced toxicities. In this review, we summarize DEHP kinetics and its mechanisms of carcinogenicity and reproductive and developmental toxicity in relation to PPARα. Additionally, we give an overview of the impacts of science policy on exposure sources.
Topics: Animals; Diethylhexyl Phthalate; Environmental Pollutants; Haplorhini; Humans; Mice; PPAR alpha; Plasticizers; Rats
PubMed: 31279339
DOI: 10.1186/s12199-019-0802-z -
Molecular Metabolism Dec 2023The disease progression of the metabolic syndrome is associated with prolonged hyperlipidemia and insulin resistance, eventually giving rise to impaired insulin...
The disease progression of the metabolic syndrome is associated with prolonged hyperlipidemia and insulin resistance, eventually giving rise to impaired insulin secretion, often concomitant with hypoadiponectinemia. As an adipose tissue derived hormone, adiponectin is beneficial for insulin secretion and β cell health and differentiation. However, the down-stream pathway of adiponectin in the pancreatic islets has not been studied extensively. Here, along with the overall reduction of endocrine pancreatic function in islets from adiponectin KO mice, we examine PPARα and HNF4α as additional down-regulated transcription factors during a prolonged metabolic challenge. To elucidate the function of β cell-specific PPARα and HNF4α expression, we developed doxycycline inducible pancreatic β cell-specific PPARα (β-PPARα) and HNF4α (β-HNF4α) overexpression mice. β-PPARα mice exhibited improved protection from lipotoxicity, but elevated β-oxidative damage in the islets, and also displayed lowered phospholipid levels and impaired glucose-stimulated insulin secretion. β-HNF4α mice showed a more severe phenotype when compared to β-PPARα mice, characterized by lower body weight, small islet mass and impaired insulin secretion. RNA-sequencing of the islets of these models highlights overlapping yet unique roles of β-PPARα and β-HNF4α. Given that β-HNF4α potently induces PPARα expression, we define a novel adiponectin-HNF4α-PPARα cascade. We further analyzed downstream genes consistently regulated by this axis. Among them, the islet amyloid polypeptide (IAPP) gene is an important target and accumulates in adiponectin KO mice. We propose a new mechanism of IAPP aggregation in type 2 diabetes through reduced adiponectin action.
Topics: Animals; Mice; Adiponectin; Diabetes Mellitus, Type 2; Insulin; Insulin-Secreting Cells; PPAR alpha
PubMed: 37806486
DOI: 10.1016/j.molmet.2023.101821 -
International Journal of Cosmetic... Dec 2021Peroxisome proliferator-activated receptor (PPAR) agonists are known to modulate the synthesis of dermal lipids and proteins including collagens. Olive (Olea europaea)...
INTRODUCTION
Peroxisome proliferator-activated receptor (PPAR) agonists are known to modulate the synthesis of dermal lipids and proteins including collagens. Olive (Olea europaea) leaves have been reported to contain PPAR-binding ligands. Collagen IV, a major dermal-epidermal junction (DEJ) protein, degrades with both age and disease. Here, we report the formulation of a novel multi-ligand complex, Linefade, and its effects on collagen IV synthesis.
METHODS
Linefade prepared from the leaves of Olea europaea contains 2% w/w plant extract solids dissolved in a mixture of glyceryl monoricinoleate and dimethyl isosorbide. In silico docking was performed with PPAR-α (PDB ID: 2P54). Linefade was evaluated for PPAR-α-dependent transcription in a luciferase reporter assay system. Cell viability and collagen IV levels in human dermal fibroblast cultures were measured using the MTT method and ELISA assay, respectively. Transcriptome analysis was conducted on a full-thickness reconstituted human skin (EpiDermFT) model. Ex vivo cell viability and collagen IV immunostaining were performed on human skin explants.
RESULTS
In silico docking model of the major constituents (oleanolic acid and glyceryl monoricinoleate) produced a co-binding affinity of -6.7 Kcal/mole. Linefade significantly increased PPAR-α transcriptional activity in CHO cells and collagen IV synthesis in adult human dermal fibroblasts. Transcriptome analysis revealed that 1% Linefade modulated the expression of 280 genes with some related to epidermal differentiation, DEJ, PPAR, Nrf2 and retinoid pathways. An ex vivo human explant study showed that 1% Linefade, delivered via a triglycerides excipient, increased collagen IV levels along the dermal-epidermal junction by 52%.
CONCLUSION
In silico modelling and in vitro and ex vivo analyses confirmed Linefade-mediated activation of PPAR-α and stimulation of collagen IV synthesis.
Topics: Adult; Cells, Cultured; Collagen Type IV; Female; Fibroblasts; Humans; Olea; PPAR alpha; Plant Extracts; Plant Leaves; Skin
PubMed: 34661292
DOI: 10.1111/ics.12742 -
Molecular Metabolism Dec 2022Perfluoroalkyl substances (PFAS) are man-made chemicals with demonstrated endocrine-disrupting properties. Exposure to perfluorooctanoic acid (PFOA) has been linked to...
OBJECTIVE
Perfluoroalkyl substances (PFAS) are man-made chemicals with demonstrated endocrine-disrupting properties. Exposure to perfluorooctanoic acid (PFOA) has been linked to disturbed metabolism via the liver, although the exact mechanism is not clear. Moreover, information on the metabolic effects of the new PFAS alternative GenX is limited. We examined whether exposure to low-dose PFOA and GenX induces metabolic disturbances in mice, including NAFLD, dyslipidemia, and glucose tolerance, and studied the involvement of PPARα.
METHODS
Male C57BL/6J wildtype and PPARα mice were given 0.05 or 0.3 mg/kg body weight/day PFOA, or 0.3 mg/kg body weight/day GenX while being fed a high-fat diet for 20 weeks. Glucose and insulin tolerance tests were performed after 18 and 19 weeks. Plasma metabolite levels were measured next to a detailed assessment of the liver phenotype, including lipid content and RNA sequencing.
RESULTS
Exposure to high-dose PFOA decreased body weight and increased liver weight in wildtype and PPARα mice. High-dose but not low-dose PFOA reduced plasma triglycerides and cholesterol, which for triglycerides was dependent on PPARα. PFOA and GenX increased hepatic triglycerides in a PPARα-dependent manner. RNA sequencing showed that the effects of GenX on hepatic gene expression were entirely dependent on PPARα, while the effects of PFOA were mostly dependent on PPARα. In the absence of PPARα, the involvement of PXR and CAR became more prominent.
CONCLUSION
Overall, we show that long-term and low-dose exposure to PFOA and GenX disrupts hepatic lipid metabolism in mice. Whereas the effects of PFOA are mediated by multiple nuclear receptors, the effects of GenX are entirely mediated by PPARα. Our data underscore the potential of PFAS to disrupt metabolism by altering signaling pathways in the liver.
Topics: Male; Mice; Animals; PPAR alpha; Transcriptome; Mice, Inbred C57BL; Fluorocarbons; Non-alcoholic Fatty Liver Disease; Triglycerides; Glucose; Body Weight
PubMed: 36115532
DOI: 10.1016/j.molmet.2022.101602 -
The Journal of Clinical Investigation Apr 2017The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively.... (Review)
Review
The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. We have also recently reported that these receptors have mutually antagonistic impacts on autophagy, which is induced by PPARα but suppressed by FXR. Secretion of multiple blood proteins is a major drain on liver energy and nutrient resources, and we present preliminary evidence that the liver secretome may be directly suppressed by PPARα, but induced by FXR. Finally, previous studies demonstrated a striking deficiency in bile acid levels in malnourished mice that is consistent with results in malnourished children. We present evidence that hepatic targets of PPARα and FXR are dysregulated in chronic undernutrition. We conclude that PPARα and FXR function coordinately to integrate liver energy balance.
Topics: Animals; Fatty Acids; Gluconeogenesis; Glycolysis; Humans; Lipogenesis; Liver; Malnutrition; Mice; Oxidation-Reduction; PPAR alpha; Receptors, Cytoplasmic and Nuclear
PubMed: 28287408
DOI: 10.1172/JCI88893 -
Proceedings of the National Academy of... Mar 2023Diabetes can result in impaired corneal wound healing. Mitochondrial dysfunction plays an important role in diabetic complications. However, the regulation of...
Diabetes can result in impaired corneal wound healing. Mitochondrial dysfunction plays an important role in diabetic complications. However, the regulation of mitochondria function in the diabetic cornea and its impacts on wound healing remain elusive. The present study aimed to explore the molecular basis for the disturbed mitochondrial metabolism and subsequent wound healing impairment in the diabetic cornea. Seahorse analysis showed that mitochondrial oxidative phosphorylation is a major source of ATP production in human corneal epithelial cells. Live corneal biopsy punches from type 1 and type 2 diabetic mouse models showed impaired mitochondrial functions, correlating with impaired corneal wound healing, compared to nondiabetic controls. To approach the molecular basis for the impaired mitochondrial function, we found that Peroxisome Proliferator-Activated Receptor-α (PPARα) expression was downregulated in diabetic human corneas. Even without diabetes, global knockout mice and corneal epithelium-specific conditional knockout mice showed disturbed mitochondrial function and delayed wound healing in the cornea, similar to that in diabetic corneas. In contrast, fenofibrate, a PPARα agonist, ameliorated mitochondrial dysfunction and enhanced wound healing in the corneas of diabetic mice. Similarly, corneal epithelium-specific transgenic overexpression improved mitochondrial function and enhanced wound healing in the cornea. Furthermore, PPARα agonist ameliorated the mitochondrial dysfunction in primary human corneal epithelial cells exposed to diabetic stressors, which was impeded by siRNA knockdown of , suggesting a PPARα-dependent mechanism. These findings suggest that downregulation of PPARα plays an important role in the impaired mitochondrial function in the corneal epithelium and delayed corneal wound healing in diabetes.
Topics: Mice; Humans; Animals; PPAR alpha; Diabetes Mellitus, Experimental; Cornea; Wound Healing; Mice, Knockout; Mitochondria
PubMed: 36943878
DOI: 10.1073/pnas.2217576120 -
Laboratory Investigation; a Journal of... Jan 2023Atrial fibrillation (AF) is a main risk factor for cerebrovascular diseases but lacks precision therapy. Adipose triglyceride lipase (ATGL) is a key enzyme involved in...
Atrial fibrillation (AF) is a main risk factor for cerebrovascular diseases but lacks precision therapy. Adipose triglyceride lipase (ATGL) is a key enzyme involved in the intracellular degradation of triacylglycerol and plays an important role in lipid and energy metabolism. However, the role of ATGL in the regulation of AF remains unclear. In this study, AF was induced by infusion of angiotensin II (Ang II, 2000 ng/kg/min) for 3 weeks in male ATGL knockout (KO) mice and age-matched C57BL/6 wild-type mice. The atrial volume was measured by echocardiography. Atrial fibrosis, inflammatory cells, and superoxide production were detected by histologic examinations. The results showed that ATGL expression was significantly downregulated in the atrial tissue of the Ang II-infused mice. Moreover, Ang II-induced increase in the inducibility and duration of AF, atrial dilation, fibrosis, inflammation, and oxidative stress in wild-type mice were markedly accelerated in ATGL KO mice; however, these effects were dramatically reversed in the ATGL KO mice administered with peroxisome proliferator-activated receptor (PPAR)-α agonist clofibric acid. Mechanistically, Ang II downregulated ATGL expression and inhibited PPAR-α activity, activated multiple signaling pathways (inhibiting kappa B kinase α/β-nuclear factor-κB, nicotinamide adenine dinucleotide phosphate oxidase, and transforming growth factor-β1/SMAD2/3) and reducing Kv1.5, Cx40, and Cx43 expression, thereby contributing to atrial structural and electrical remodeling and subsequent AF. In summary, our results indicate that ATGL KO enhances AF inducibility, possibly through inhibiting PPAR-α activation and suggest that activating ATGL might be a new therapeutic option for treating hypertensive AF.
Topics: Animals; Male; Mice; Angiotensin II; Atrial Fibrillation; Fibrosis; Lipase; Mice, Inbred C57BL; Mice, Knockout; PPAR alpha; Acyltransferases
PubMed: 36748188
DOI: 10.1016/j.labinv.2022.100004 -
Journal of Assisted Reproduction and... Jun 2023Granulosa cell (GC) proliferation and apoptosis are critical events of the ovum energy supply, which lead to follicular growth retardation or atresia, and various...
miR-4433a-3p promotes granulosa cell apoptosis by targeting peroxisome proliferator-activated receptor alpha and inducing immune cell infiltration in polycystic ovarian syndrome.
BACKGROUND
Granulosa cell (GC) proliferation and apoptosis are critical events of the ovum energy supply, which lead to follicular growth retardation or atresia, and various ovulatory obstacles, eventually resulting in the development of ovarian disorders such as polycystic ovarian syndrome (PCOS). Apoptosis and dysregulated miRNA expression in GCs are manifestations of PCOS. miR-4433a-3p has been reported to be involved in apoptosis. However, there is no study reporting the roles of miR-4433a-3p in GC apoptosis and PCOS progression.
METHODS
miR-4433a-3p and peroxisome proliferator-activated receptor alpha (PPAR-α) levels in GCs of PCOS patients or in tissues of a PCOS rat model were examined by quantitative polymerase chain reaction and immunohistochemistry. Bioinformatics analyses and luciferase assays were used to examine the association between miR-4433a-3p and PPAR-α, as well as PPAR-α and immune cell infiltration, in PCOS patients.
RESULTS
miR-4433a-3p expression in GCs of PCOS patients was increased. miR-4433a-3p overexpression inhibited the growth of the human granulosa-like tumor cell line (KGN) and promoted apoptosis, while co-treatment with PPAR-α and miR-4433a-3p mimic rescued miR-4433a-3p-induced apoptosis. PPAR-α was a direct target of miR-4433a-3p and its expression was decreased in PCOS patients. PPAR-α expression was also positively correlated with the infiltration of activated CD4 T cells, eosinophils, B cells, gamma delta T cells, macrophages, and mast cells, but negatively correlated with the infiltration of activated CD8 T cells, CD56 bright natural killer cells, immature dendritic cells, monocytes, plasmacytoid dendritic cells, neutrophils, and type 1 T helper cells in PCOS patients.
CONCLUSION
The miR-4433a-3p/PPAR-α/immune cell infiltration axis may function as a novel cascade to alter GC apoptosis in PCOS.
Topics: Female; Humans; Rats; Animals; PPAR alpha; Polycystic Ovary Syndrome; Granulosa Cells; CD8-Positive T-Lymphocytes; MicroRNAs; Apoptosis; Cell Proliferation
PubMed: 37204637
DOI: 10.1007/s10815-023-02815-x -
The Kaohsiung Journal of Medical... Jul 2012Phthalates--substances used in the manufacture of plastics--are considered as possible human carcinogens and tumor-promoting agents. The worldwide annual production of... (Review)
Review
Phthalates--substances used in the manufacture of plastics--are considered as possible human carcinogens and tumor-promoting agents. The worldwide annual production of plastics surpassed 300 million tons in 2010. Plastics are an indispensable material in modern society, and many products manufactured from plastics are a boon to public health; however, plastics also pose health risks. Animal studies have indicated that phthalates are carcinogenic, but human epidemiological data confirming this carcinogenicity in humans are limited. The activation of peroxisome proliferator-activated receptor α (PPARα), which has been observed in rodent carcinogenesis, has not been observed in humans. Here, we review the hypothesis that the aryl hydrocarbon receptor (AhR) and its downstream signaling cascade promote phthalate-induced tumorigenesis.
Topics: Animals; Carcinogens; Cell Transformation, Neoplastic; Environmental Exposure; Humans; PPAR alpha; Phthalic Acids; Receptors, Aryl Hydrocarbon
PubMed: 22871597
DOI: 10.1016/j.kjms.2012.05.006 -
Biological & Pharmaceutical Bulletin 2021Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor-type transcription factors that consist of three subtypes (α, γ, and β/δ) with distinct...
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor-type transcription factors that consist of three subtypes (α, γ, and β/δ) with distinct functions and PPAR dual/pan agonists are expected to be the next generation of drugs for metabolic diseases. Saroglitazar is the first clinically approved PPARα/γ dual agonist for treatment of diabetic dyslipidemia and is currently in clinical trials to treat non-alcoholic fatty liver disease (NAFLD); however, the structural information of its interaction with PPARα/γ remains unknown. We recently revealed the high-resolution co-crystal structure of saroglitazar and the PPARα-ligand binding domain (LBD) through X-ray crystallography, and in this study, we report the structure of saroglitazar and the PPARγ-LBD. Saroglitazar was located at the center of "Y"-shaped PPARγ-ligand-binding pocket (LBP), just as it was in the respective region of PPARα-LBP. Its carboxylic acid was attached to four amino acids (Ser289/His323/His449/Thr473), which contributes to the stabilization of Activating Function-2 helix 12, and its phenylpyrrole moiety was rotated 121.8 degrees in PPARγ-LBD from that in PPARα-LBD to interact with Phe264. PPARδ-LBD has the consensus four amino acids (Thr253/His287/His413/Tyr437) towards the carboxylic acids of its ligands, but it seems to lack sufficient space to accept saroglitazar because of the steric hindrance between the Trp228 or Arg248 residue of PPARδ-LBD and its methylthiophenyl moiety. Accordingly, in a coactivator recruitment assay, saroglitazar activated PPARα-LBD and PPARγ-LBD but not PPARδ-LBD, whereas glycine substitution of either Trp228, Arg248, or both of PPARδ-LBD conferred saroglitazar concentration-dependent activation. Our findings may be valuable in the molecular design of PPARα/γ dual or PPARα/γ/δ pan agonists.
Topics: Binding Sites; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Hypolipidemic Agents; Lipid Metabolism; Non-alcoholic Fatty Liver Disease; PPAR alpha; PPAR gamma; Phenylpropionates; Protein Domains; Pyrroles; Recombinant Proteins
PubMed: 34471049
DOI: 10.1248/bpb.b21-00232