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      Association of Peroxisome Proliferator-Activated Receptors (PPARs) with Diabetic Retinopathy in Human and Animal Models: Analysis of the Literature and Genome Browsers

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          Abstract

          Diabetic retinopathy (DR) is a condition that develops after long-lasting and poorly handled diabetes and is presently the main reason for blindness among elderly and youth. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in carbohydrate and fatty-acid metabolism and have also been associated with DR. Three PPAR isoforms are known: PPARG, PPARA, and PPARD. In the present study, we retrieved articles reporting associations between PPARs and DR from PubMed database and compiled the data in two catalogues, for human and animal models. Extracted data was then complemented with additional relevant genomic information. Seven retrieved articles reported testing an association between PPARs with DR in human. Four of them concluded association of PPARG and PPARA with DR in European and Asian populations, having a protective role on DR development. One study reported pathogenic role of PPARG, while two articles reported no association between PPARG and DR among Indian and Chinese populations. Six retrieved articles reported testing of involvement of PPARG and PPARA in DR in animal models, including mouse and rat. The review includes case-control studies, meta-analysis, expression studies, animal models, and cell line studies. Despite a large number of documented sequence variants of the PPAR genes available in genome browsers, researchers usually focus on a small set of previously reported variants. Data extraction from Ensembl genome browser revealed several sequence variants with predicted deleterious effect on protein function which present candidates for further experimental validation. Results of the present analysis will enable more holistic approach for understanding of PPARs in DR development. Additionally, developed catalogues present a baseline for standardized reporting of PPAR-phenotype association in upcoming studies.

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          Most cited references28

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          A critical role for the peroxisome proliferator-activated receptor   (PPAR ) in the cellular fasting response: The PPAR -null mouse as a model of fatty acid oxidation disorders

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            Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation.

            Peroxisome proliferator activated receptor-gamma (PPAR gamma) is a nuclear receptor that regulates adipocyte differentiation, and possibly lipid metabolism and insulin sensitivity. As such, PPAR gamma is a promising candidate gene for several human disorders including obesity and type 2 diabetes mellitus. Screening for mutations in the entire coding region of the PPAR gamma gene (both gamma 1 and gamma 2 isoforms) was performed with DNA of 26 diabetic Caucasians with or without obesity. Two base substitutions were identified: a silent mutation at nucleotide 1431 (CACHis-->CATHis) and a missense mutation (CCGPro-->GCGAla) at codon 12 of PPAR gamma 2. The allele frequency of the Pro12Ala PPAR gamma 2 variant was 0.12 in Caucasian Americans, 0.10 in Mexican Americans, 0.08 in Samoans, 0.03 in African Americans, 0.02 in Nauruans, and 0.01 in Chinese. We conclude that the Pro12Ala PPAR gamma 2 gene variant is present in diverse populations. Further studies of the Pro12Ala variant will determine its relevance to obesity, insulin resistance, and type 2 diabetes.
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              Pathogenic role of diabetes-induced PPAR-α down-regulation in microvascular dysfunction.

              Two independent clinical studies have reported that fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, has robust therapeutic effects on microvascular complications of diabetes, including diabetic retinopathy (DR) in type 2 diabetic patients. However, the expression and function of PPARα in the retina are unclear. Here, we demonstrated that PPARα is expressed in multiple cell types in the retina. In both type 1 and type 2 diabetes models, expression of PPARα, but not PPARβ/δ or PPARγ, was significantly down-regulated in the retina. Furthermore, high-glucose medium was sufficient to down-regulate PPARα expression in cultured retinal cells. To further investigate the role of PPARα in DR, diabetes was induced in PPARα knockout (KO) mice and wild-type (WT) mice. Diabetic PPARα KO mice developed more severe DR, as shown by retinal vascular leakage, leukostasis, pericyte loss, capillary degeneration, and over-expression of inflammatory factors, compared with diabetic WT mice. In addition, overexpression of PPARα in the retina of diabetic rats significantly alleviated diabetes-induced retinal vascular leakage and retinal inflammation. Furthermore, PPARα overexpression inhibited endothelial cell migration and proliferation. These findings revealed that diabetes-induced down-regulation of PPARα plays an important role in DR. Up-regulation or activation of PPARα may represent a novel therapeutic strategy for DR.
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                Author and article information

                Contributors
                Journal
                PPAR Res
                PPAR Res
                PPAR
                PPAR Research
                Hindawi
                1687-4757
                1687-4765
                2020
                3 March 2020
                : 2020
                : 1783564
                Affiliations
                1University of Ljubljana, Biotechnical Faculty, Department of Animal Science, Slovenia
                2University of Ljubljana, Faculty of Medicine, Institute of Histology and Embryology, Slovenia
                3Eye Hospital, University Medical Center Ljubljana, Ljubljana, Slovenia
                4University of Ljubljana, Faculty of Medicine, Slovenia
                Author notes

                Academic Editor: John P. Vanden Heuvel

                Author information
                https://orcid.org/0000-0002-8427-4513
                https://orcid.org/0000-0002-0465-1762
                Article
                10.1155/2020/1783564
                7072119
                32190036
                14057579-f25b-4486-b0e5-19e24560d6b6
                Copyright © 2020 Špela Tajnšek et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 May 2019
                : 3 November 2019
                : 7 February 2020
                Funding
                Funded by: Javna Agencija za Raziskovalno Dejavnost RS
                Award ID: P4-0220
                Categories
                Review Article

                Biochemistry
                Biochemistry

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