title: PPARγ activation attenuates glycated-serum induced pancreatic beta-cell dysfunction through enhancing Pdx1 and Mafa protein stability.
abstract: Pancreatic-duodenal homeobox-1 (Pdx1) and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (Mafa) play important roles in sustaining the pancreatic beta-cell differentiation phenotype. Peroxisome proliferator-activated receptor-γ (PPARγ) is also a regulator of cell differentiation. Our previous study revealed that glycated serum (GS) causes beta-cell dedifferentiation by down-regulating beta-cell specific genes, such as insulin and Pdx1. Here, we show that GS enhanced the cellular accumulation of ubiquitin-conjugated proteins, including Pdx1 and Mafa, in pancreatic beta-cells. Pharmacologic inhibition of proteolytic activity restored the protein levels of Pdx1 and Mafa, whereas inhibition of de novo protein synthesis accelerated their degradation. These findings suggest that both Pdx1 and Mafa are regulated at the post-transcriptional level. We further show that activation of PPARγ could restore GS-induced reduction of Pdx1 and Mafa protein levels, leading to improved insulin secretion and synthesis. Moreover, ectopic expression of Bcl-xl, a mitochondrial regulator, also restored Pdx1 and Mafa protein levels, linking mitochondrial function to Pdx1 and Mafa stability. Taken together, our results identify a key role of PPARγ in regulating pancreatic beta-cell function by improving the stability of Pdx1 and Mafa proteins.
authors: The Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
authors: Yunxia
authors: Y
authors: Zhu
authors: Ai
authors: A
authors: Ma
authors: Hongxiu
authors: H
authors: Zhang
authors: Chaojun
authors: C
authors: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D006031:Glycosylation; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044967:Serum / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D015534:Trans-Activators / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D000077288:Troglitazone; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D002839:Chromans; D018398:Homeodomain Proteins; D007328:Insulin; C094696:Klrg1 protein, rat; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D015534:Trans-Activators; D025801:Ubiquitin; C084010:pancreatic and duodenal homeobox 1 protein; D000077288:Troglitazone; D011188:Potassium