Autotaxin signaling facilitates β cell dedifferentiation and dysfunction induced by Sirtuin 3 deficiency
Objective: β cell dedifferentiation may underlie the reversible reduction in pancreatic β cell mass and function in type 2 diabetes (T2D). We previously reported that β cell-specific Sirt3 knockout (Sirt3f/f;Cre/+) mice developed impaired glucose tolerance and glucose-stimulated insulin secretion af...
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-06-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287782200062X |
| _version_ | 1828351078236684288 |
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| author | Huanyi Cao Arthur C.K. Chung Xing Ming Dandan Mao Heung Man Lee Xiaoyun Cao Guy A. Rutter Juliana C.N. Chan Xiao Yu Tian Alice P.S. Kong |
| author_facet | Huanyi Cao Arthur C.K. Chung Xing Ming Dandan Mao Heung Man Lee Xiaoyun Cao Guy A. Rutter Juliana C.N. Chan Xiao Yu Tian Alice P.S. Kong |
| author_sort | Huanyi Cao |
| collection | DOAJ |
| description | Objective: β cell dedifferentiation may underlie the reversible reduction in pancreatic β cell mass and function in type 2 diabetes (T2D). We previously reported that β cell-specific Sirt3 knockout (Sirt3f/f;Cre/+) mice developed impaired glucose tolerance and glucose-stimulated insulin secretion after feeding with high fat diet (HFD). RNA sequencing showed that Sirt3-deficient islets had enhanced expression of Enpp2 (Autotaxin, or ATX), a secreted lysophospholipase which produces lysophosphatidic acid (LPA). Here, we hypothesized that activation of the ATX/LPA pathway contributed to pancreatic β cell dedifferentiation in Sirt3-deficient β cells. Methods: We applied LPA, or lysophosphatidylcoline (LPC), the substrate of ATX for producing LPA, to MIN6 cell line and mouse islets with altered Sirt3 expression to investigate the effect of LPA on β cell dedifferentiation and its underlying mechanisms. To examine the pathological effects of ATX/LPA pathway, we injected the β cell selective adeno-associated virus (AAV-Atx-shRNA) or negative control AAV-scramble in Sirt3f/f and Sirt3f/f;Cre/+ mice followed by 6-week of HFD feeding. Results: In Sirt3f/f;Cre/+ mouse islets and Sirt3 knockdown MIN6 cells, ATX upregulation led to increased LPC with increased production of LPA. The latter not only induced reversible dedifferentiation in MIN6 cells and mouse islets, but also reduced glucose-stimulated insulin secretion from islets. In MIN6 cells, LPA induced phosphorylation of JNK/p38 MAPK which was accompanied by β cell dedifferentiation. The latter was suppressed by inhibitors of LPA receptor, JNK, and p38 MAPK. Importantly, inhibiting ATX in vivo improved insulin secretion and reduced β cell dedifferentiation in HFD-fed Sirt3f/f;Cre/+ mice. Conclusions: Sirt3 prevents β cell dedifferentiation by inhibiting ATX expression and upregulation of LPA. These findings support a long-range signaling effect of Sirt3 which modulates the ATX-LPA pathway to reverse β cell dysfunction associated with glucolipotoxicity. |
| first_indexed | 2024-04-14T01:34:21Z |
| format | Article |
| id | doaj.art-de0dc1c8b0754790a7e2f327beda5247 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-14T01:34:21Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-de0dc1c8b0754790a7e2f327beda52472022-12-22T02:20:02ZengElsevierMolecular Metabolism2212-87782022-06-0160101493Autotaxin signaling facilitates β cell dedifferentiation and dysfunction induced by Sirtuin 3 deficiencyHuanyi Cao0Arthur C.K. Chung1Xing Ming2Dandan Mao3Heung Man Lee4Xiaoyun Cao5Guy A. Rutter6Juliana C.N. Chan7Xiao Yu Tian8Alice P.S. Kong9Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, ChinaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, ChinaSchool of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, ChinaCR-CHUM and Université de Montréal, Montréal, QC, Canada; Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Lee Kong Chian School of Medicine, Nanyang Technological University, SingaporeDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, ChinaSchool of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Co-corresponding author. School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China. Fax: +(852) 2603 5123Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, China; Corresponding author. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China. Fax: +(852) 2637 3852Objective: β cell dedifferentiation may underlie the reversible reduction in pancreatic β cell mass and function in type 2 diabetes (T2D). We previously reported that β cell-specific Sirt3 knockout (Sirt3f/f;Cre/+) mice developed impaired glucose tolerance and glucose-stimulated insulin secretion after feeding with high fat diet (HFD). RNA sequencing showed that Sirt3-deficient islets had enhanced expression of Enpp2 (Autotaxin, or ATX), a secreted lysophospholipase which produces lysophosphatidic acid (LPA). Here, we hypothesized that activation of the ATX/LPA pathway contributed to pancreatic β cell dedifferentiation in Sirt3-deficient β cells. Methods: We applied LPA, or lysophosphatidylcoline (LPC), the substrate of ATX for producing LPA, to MIN6 cell line and mouse islets with altered Sirt3 expression to investigate the effect of LPA on β cell dedifferentiation and its underlying mechanisms. To examine the pathological effects of ATX/LPA pathway, we injected the β cell selective adeno-associated virus (AAV-Atx-shRNA) or negative control AAV-scramble in Sirt3f/f and Sirt3f/f;Cre/+ mice followed by 6-week of HFD feeding. Results: In Sirt3f/f;Cre/+ mouse islets and Sirt3 knockdown MIN6 cells, ATX upregulation led to increased LPC with increased production of LPA. The latter not only induced reversible dedifferentiation in MIN6 cells and mouse islets, but also reduced glucose-stimulated insulin secretion from islets. In MIN6 cells, LPA induced phosphorylation of JNK/p38 MAPK which was accompanied by β cell dedifferentiation. The latter was suppressed by inhibitors of LPA receptor, JNK, and p38 MAPK. Importantly, inhibiting ATX in vivo improved insulin secretion and reduced β cell dedifferentiation in HFD-fed Sirt3f/f;Cre/+ mice. Conclusions: Sirt3 prevents β cell dedifferentiation by inhibiting ATX expression and upregulation of LPA. These findings support a long-range signaling effect of Sirt3 which modulates the ATX-LPA pathway to reverse β cell dysfunction associated with glucolipotoxicity.http://www.sciencedirect.com/science/article/pii/S221287782200062XAutotaxinLysophosphatidic acidβ cell dedifferentiationSirtuin3Mitogen-activated protein kinasesType 2 diabetes |
| spellingShingle | Huanyi Cao Arthur C.K. Chung Xing Ming Dandan Mao Heung Man Lee Xiaoyun Cao Guy A. Rutter Juliana C.N. Chan Xiao Yu Tian Alice P.S. Kong Autotaxin signaling facilitates β cell dedifferentiation and dysfunction induced by Sirtuin 3 deficiency Molecular Metabolism Autotaxin Lysophosphatidic acid β cell dedifferentiation Sirtuin3 Mitogen-activated protein kinases Type 2 diabetes |
| title | Autotaxin signaling facilitates β cell dedifferentiation and dysfunction induced by Sirtuin 3 deficiency |
| title_full | Autotaxin signaling facilitates β cell dedifferentiation and dysfunction induced by Sirtuin 3 deficiency |
| title_fullStr | Autotaxin signaling facilitates β cell dedifferentiation and dysfunction induced by Sirtuin 3 deficiency |
| title_full_unstemmed | Autotaxin signaling facilitates β cell dedifferentiation and dysfunction induced by Sirtuin 3 deficiency |
| title_short | Autotaxin signaling facilitates β cell dedifferentiation and dysfunction induced by Sirtuin 3 deficiency |
| title_sort | autotaxin signaling facilitates β cell dedifferentiation and dysfunction induced by sirtuin 3 deficiency |
| topic | Autotaxin Lysophosphatidic acid β cell dedifferentiation Sirtuin3 Mitogen-activated protein kinases Type 2 diabetes |
| url | http://www.sciencedirect.com/science/article/pii/S221287782200062X |
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