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GLP-1-Induced AMPK Activation Inhibits PARP-1 and Promotes LXR-Mediated ABCA1 Expression to Protect Pancreatic β-Cells Against Cholesterol-Induced Toxicity Through Cholesterol Efflux
T2DM (Type 2 diabetes) is a complex, chronic disease characterized as insulin resistance and islet β-cell dysfunction. Bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) surgery and laparoscopic sleeve gastrectomy (LSG) have become part of a critical treatment regimen in the treatment of ob...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292745/ https://www.ncbi.nlm.nih.gov/pubmed/34307343 http://dx.doi.org/10.3389/fcell.2021.646113 |
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author | Li, Rao Sun, Xulong Li, Pengzhou Li, Weizheng Zhao, Lei Zhu, Liyong Zhu, Shaihong |
author_facet | Li, Rao Sun, Xulong Li, Pengzhou Li, Weizheng Zhao, Lei Zhu, Liyong Zhu, Shaihong |
author_sort | Li, Rao |
collection | PubMed |
description | T2DM (Type 2 diabetes) is a complex, chronic disease characterized as insulin resistance and islet β-cell dysfunction. Bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) surgery and laparoscopic sleeve gastrectomy (LSG) have become part of a critical treatment regimen in the treatment of obesity and T2DM. Moreover, GLP-1 increase following bariatric surgery has been regarded as a significant event in bariatric surgery-induced remission of T2DM. In this study, a high concentration cholesterol-induced lipotoxicity was observed in INS-1 cells, including inhibited cell viability and insulin secretion. Enhanced cell apoptosis and inhibited cholesterol efflux from INS-1 cells; meanwhile, ABCA1 protein level was decreased by cholesterol stimulation. Cholesterol-induced toxicity and ABCA1 downregulation were attenuated by GLP-1 agonist EX-4. GLP-1 induced AMPK phosphorylation during the protection against cholesterol-induced toxicity. Under cholesterol stimulation, GLP-1-induced AMPK activation inhibited PARP-1 activity, therefore attenuating cholesterol-induced toxicity in INS-1 cells. In INS-1 cells, PARP-1 directly interacted with LXR, leading to the poly(ADP-ribosyl)ation of LXRα and downregulation of LXR-mediated ABCA1 expression. In the STZ-induced T2DM model in rats, RYGB surgery or EX-4 treatment improved the glucose metabolism and lipid metabolism in rats through GLP-1 inhibition of PARP-1 activity. In conclusion, GLP-1 inhibits PARP-1 to protect islet β cell function against cholesterol-induced toxicity in vitro and in vivo through enhancing cholesterol efflux. GLP-1-induced AMPK and LXR-mediated ABCA1 expression are involved in GLP-1 protective effects. |
format | Online Article Text |
id | pubmed-8292745 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82927452021-07-22 GLP-1-Induced AMPK Activation Inhibits PARP-1 and Promotes LXR-Mediated ABCA1 Expression to Protect Pancreatic β-Cells Against Cholesterol-Induced Toxicity Through Cholesterol Efflux Li, Rao Sun, Xulong Li, Pengzhou Li, Weizheng Zhao, Lei Zhu, Liyong Zhu, Shaihong Front Cell Dev Biol Cell and Developmental Biology T2DM (Type 2 diabetes) is a complex, chronic disease characterized as insulin resistance and islet β-cell dysfunction. Bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) surgery and laparoscopic sleeve gastrectomy (LSG) have become part of a critical treatment regimen in the treatment of obesity and T2DM. Moreover, GLP-1 increase following bariatric surgery has been regarded as a significant event in bariatric surgery-induced remission of T2DM. In this study, a high concentration cholesterol-induced lipotoxicity was observed in INS-1 cells, including inhibited cell viability and insulin secretion. Enhanced cell apoptosis and inhibited cholesterol efflux from INS-1 cells; meanwhile, ABCA1 protein level was decreased by cholesterol stimulation. Cholesterol-induced toxicity and ABCA1 downregulation were attenuated by GLP-1 agonist EX-4. GLP-1 induced AMPK phosphorylation during the protection against cholesterol-induced toxicity. Under cholesterol stimulation, GLP-1-induced AMPK activation inhibited PARP-1 activity, therefore attenuating cholesterol-induced toxicity in INS-1 cells. In INS-1 cells, PARP-1 directly interacted with LXR, leading to the poly(ADP-ribosyl)ation of LXRα and downregulation of LXR-mediated ABCA1 expression. In the STZ-induced T2DM model in rats, RYGB surgery or EX-4 treatment improved the glucose metabolism and lipid metabolism in rats through GLP-1 inhibition of PARP-1 activity. In conclusion, GLP-1 inhibits PARP-1 to protect islet β cell function against cholesterol-induced toxicity in vitro and in vivo through enhancing cholesterol efflux. GLP-1-induced AMPK and LXR-mediated ABCA1 expression are involved in GLP-1 protective effects. Frontiers Media S.A. 2021-07-07 /pmc/articles/PMC8292745/ /pubmed/34307343 http://dx.doi.org/10.3389/fcell.2021.646113 Text en Copyright © 2021 Li, Sun, Li, Li, Zhao, Zhu and Zhu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Li, Rao Sun, Xulong Li, Pengzhou Li, Weizheng Zhao, Lei Zhu, Liyong Zhu, Shaihong GLP-1-Induced AMPK Activation Inhibits PARP-1 and Promotes LXR-Mediated ABCA1 Expression to Protect Pancreatic β-Cells Against Cholesterol-Induced Toxicity Through Cholesterol Efflux |
title | GLP-1-Induced AMPK Activation Inhibits PARP-1 and Promotes LXR-Mediated ABCA1 Expression to Protect Pancreatic β-Cells Against Cholesterol-Induced Toxicity Through Cholesterol Efflux |
title_full | GLP-1-Induced AMPK Activation Inhibits PARP-1 and Promotes LXR-Mediated ABCA1 Expression to Protect Pancreatic β-Cells Against Cholesterol-Induced Toxicity Through Cholesterol Efflux |
title_fullStr | GLP-1-Induced AMPK Activation Inhibits PARP-1 and Promotes LXR-Mediated ABCA1 Expression to Protect Pancreatic β-Cells Against Cholesterol-Induced Toxicity Through Cholesterol Efflux |
title_full_unstemmed | GLP-1-Induced AMPK Activation Inhibits PARP-1 and Promotes LXR-Mediated ABCA1 Expression to Protect Pancreatic β-Cells Against Cholesterol-Induced Toxicity Through Cholesterol Efflux |
title_short | GLP-1-Induced AMPK Activation Inhibits PARP-1 and Promotes LXR-Mediated ABCA1 Expression to Protect Pancreatic β-Cells Against Cholesterol-Induced Toxicity Through Cholesterol Efflux |
title_sort | glp-1-induced ampk activation inhibits parp-1 and promotes lxr-mediated abca1 expression to protect pancreatic β-cells against cholesterol-induced toxicity through cholesterol efflux |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292745/ https://www.ncbi.nlm.nih.gov/pubmed/34307343 http://dx.doi.org/10.3389/fcell.2021.646113 |
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