Xue Jiang1,2, Yawen Zhou1,2, Kelvin K L Wu1,2, Zhanrui Chen1,2, Aimin Xu3,4,5, Kenneth K Y Cheng6,7. 1. State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, L8, 21 Sassoon Road, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China. 2. Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China. 3. State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, L8, 21 Sassoon Road, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China. amxu@hku.hk. 4. Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China. amxu@hku.hk. 5. Department of Pharmacology & Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China. amxu@hku.hk. 6. State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, L8, 21 Sassoon Road, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China. dorncky@hku.hk. 7. Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China. dorncky@hku.hk.
Abstract
AIMS/HYPOTHESIS: Beta cell inflammation and demise is a feature of type 1 diabetes. The insulin-sensitising molecule 'adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1' (APPL1), which contains an NH2-terminal Bin/Amphiphysin/Rvs domain, a central pleckstrin homology domain and a COOH-terminal phosphotyrosine-binding domain, has been shown to modulate inflammatory response in various cell types but its role in regulating beta cell mass and inflammation in type 1 diabetes remains unknown. Thus, we investigated whether APPL1 prevents beta cell apoptosis and inflammation in diabetes. METHODS: Appl1-knockout mice and their wild-type littermates, as well as C57BL/6N mice injected with adeno-associated virus encoding APPL1 or green fluorescent protein, were treated with multiple-low-dose streptozotocin (MLDS) to induce experimental type 1 diabetes. Their glucose metabolism and beta cell function were assessed. The effect of APPL1 deficiency on beta cell function upon exposure to a diabetogenic cytokine cocktail (CKS; consisting of TNF-α, IL-1β and IFN-γ) was assessed ex vivo. RESULTS: Expression of APPL1 was significantly reduced in pancreatic islets from mouse models of type 1 diabetes or islets treated with CKS. Hyperglycaemia, beta cell loss and insulitis induced by MLDS were exacerbated by genetic deletion of Appl1 but were alleviated by beta cell-specific overexpression of APPL1. APPL1 preserved beta cell mass by reducing beta cell apoptosis upon treatment with MLDS. Mechanistically, APPL1 deficiency potentiate CKS-induced phosphorylation of NFκB inhibitor, α (IκBα) and subsequent phosphorylation and transcriptional activation of p65, leading to a dramatic induction of NFκB-regulated apoptotic and proinflammatory programs in beta cells. Pharmacological inhibition of NFκB or inducible NO synthase (iNOS) largely abrogate the detrimental effects of APPL1 deficiency on beta cell functions. CONCLUSIONS/ INTERPRETATION: APPL1 negatively regulates inflammation and apoptosis in pancreatic beta cells by dampening the NFκB-iNOS-NO axis, representing a promising target for treating type 1 diabetes.
AIMS/HYPOTHESIS: Beta cell inflammation and demise is a feature of type 1 diabetes. The insulin-sensitising molecule 'adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1' (APPL1), which contains an NH2-terminal Bin/Amphiphysin/Rvs domain, a central pleckstrin homology domain and a COOH-terminal phosphotyrosine-binding domain, has been shown to modulate inflammatory response in various cell types but its role in regulating beta cell mass and inflammation in type 1 diabetes remains unknown. Thus, we investigated whether APPL1 prevents beta cell apoptosis and inflammation in diabetes. METHODS:Appl1-knockout mice and their wild-type littermates, as well as C57BL/6N mice injected with adeno-associated virus encoding APPL1 or green fluorescent protein, were treated with multiple-low-dose streptozotocin (MLDS) to induce experimental type 1 diabetes. Their glucose metabolism and beta cell function were assessed. The effect of APPL1 deficiency on beta cell function upon exposure to a diabetogenic cytokine cocktail (CKS; consisting of TNF-α, IL-1β and IFN-γ) was assessed ex vivo. RESULTS: Expression of APPL1 was significantly reduced in pancreatic islets from mouse models of type 1 diabetes or islets treated with CKS. Hyperglycaemia, beta cell loss and insulitis induced by MLDS were exacerbated by genetic deletion of Appl1 but were alleviated by beta cell-specific overexpression of APPL1. APPL1 preserved beta cell mass by reducing beta cell apoptosis upon treatment with MLDS. Mechanistically, APPL1 deficiency potentiate CKS-induced phosphorylation of NFκB inhibitor, α (IκBα) and subsequent phosphorylation and transcriptional activation of p65, leading to a dramatic induction of NFκB-regulated apoptotic and proinflammatory programs in beta cells. Pharmacological inhibition of NFκB or inducible NO synthase (iNOS) largely abrogate the detrimental effects of APPL1 deficiency on beta cell functions. CONCLUSIONS/ INTERPRETATION:APPL1 negatively regulates inflammation and apoptosis in pancreatic beta cells by dampening the NFκB-iNOS-NO axis, representing a promising target for treating type 1 diabetes.
Authors: G L Tipoe; T M Leung; E Liong; H So; K M Leung; T Y H Lau; W M Tom; M L Fung; S T Fan; A A Nanji Journal: Histol Histopathol Date: 2006-11 Impact factor: 2.303
Authors: Antoinette Moran; Brian Bundy; Dorothy J Becker; Linda A DiMeglio; Stephen E Gitelman; Robin Goland; Carla J Greenbaum; Kevan C Herold; Jennifer B Marks; Philip Raskin; Srinath Sanda; Desmond Schatz; Diane K Wherrett; Darrell M Wilson; Jeffrey P Krischer; Jay S Skyler; Linda Pickersgill; Eelco de Koning; Anette-G Ziegler; Bernhard Böehm; Klaus Badenhoop; Nanette Schloot; Jens Friis Bak; Paolo Pozzilli; Didac Mauricio; Marc Y Donath; Luis Castaño; Ana Wägner; Hans Henrik Lervang; Hans Perrild; Thomas Mandrup-Poulsen Journal: Lancet Date: 2013-04-05 Impact factor: 79.321
Authors: Tahnee Sente; An M Van Berendoncks; Erik Fransen; Christiaan J Vrints; Vicky Y Hoymans Journal: Am J Physiol Heart Circ Physiol Date: 2016-02-26 Impact factor: 4.733
Authors: Kenneth K Y Cheng; Karen S L Lam; Donghai Wu; Yu Wang; Gary Sweeney; Ruby L C Hoo; Jialiang Zhang; Aimin Xu Journal: Proc Natl Acad Sci U S A Date: 2012-05-07 Impact factor: 11.205