Weiling Leng1, Mingxia Wu2, Hang Pan1, Xiaotian Lei1, Liu Chen1, Qinan Wu3, Xinshou Ouyang4, Ziwen Liang1. 1. Department of Endocrinology, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China. 2. Health Management Center, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China. 3. Department of Endocrine Nephropathy, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400038, China. 4. Section of Digestive Diseases, Yale University of Medicine, New Haven, CT, USA.
Abstract
BACKGROUND: Diabetes mellitus (DM) is considered as a risk factor for the progress of liver diseases. After tissue damage, there is the highest amplitude of ubiquitously sterile inflammatory response in the liver, resulting in a major clinical consequence concerning a high prevalence of steatohepatitis in DM patients. This study aimed to investigate the inhibitory efficacy of dapagliflozin (DAPA), a sodium glucose cotransporter-2 (SGLT2) inhibitor, on experimental steatohepatitis with DM. METHODS: DM-steatohepatitis model was established by dual intraperitoneal injection of streptozotocin (STZ) and feeding with the high-fat diet (HFD) in apolipoprotein E-deficient (ApoE-/-) mice (n=40). The mice were concurrently treated with DAPA (1 mg/kg/d) by gavage for 12 weeks. RESULTS: In ApoE-/- mice, dual HFD/STZ dramatically induced hepatic damage and inflammation as compared with HFD alone. DAPA treatment was effective to protect from hepatic damage and inflammation in dual HFD/STZ treated ApoE-/- mice. DAPA also significantly the probability decreased the blood glucose, hepatic lipid accumulation, liver steatosis, and fibrotic response in dual HFD/STZ treated ApoE-/- mice. Further mechanistic investigations indicated that the protection of DAPA on diabetic liver injury was associated with the suppressed production of hepatic reactive oxygen species (ROS) and malondialdehyde (MDA) and the inhibited activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. CONCLUSIONS: These data demonstrate the efficacy of DAPA for protecting liver damage, inflammation and steatosis from experimental steatohepatitis with DM, and indicate a possible involvement of the inhibited activity of ROS-NLRP3 inflammasome. 2019 Annals of Translational Medicine. All rights reserved.
BACKGROUND: Diabetes mellitus (DM) is considered as a risk factor for the progress of liver diseases. After tissue damage, there is the highest amplitude of ubiquitously sterile inflammatory response in the liver, resulting in a major clinical consequence concerning a high prevalence of steatohepatitis in DM patients. This study aimed to investigate the inhibitory efficacy of dapagliflozin (DAPA), a sodium glucose cotransporter-2 (SGLT2) inhibitor, on experimental steatohepatitis with DM. METHODS: DM-steatohepatitis model was established by dual intraperitoneal injection of streptozotocin (STZ) and feeding with the high-fat diet (HFD) in apolipoprotein E-deficient (ApoE-/-) mice (n=40). The mice were concurrently treated with DAPA (1 mg/kg/d) by gavage for 12 weeks. RESULTS: In ApoE-/- mice, dual HFD/STZ dramatically induced hepatic damage and inflammation as compared with HFD alone. DAPA treatment was effective to protect from hepatic damage and inflammation in dual HFD/STZ treated ApoE-/- mice. DAPA also significantly the probability decreased the blood glucose, hepatic lipid accumulation, liver steatosis, and fibrotic response in dual HFD/STZ treated ApoE-/- mice. Further mechanistic investigations indicated that the protection of DAPA on diabetic liver injury was associated with the suppressed production of hepatic reactive oxygen species (ROS) and malondialdehyde (MDA) and the inhibited activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. CONCLUSIONS: These data demonstrate the efficacy of DAPA for protecting liver damage, inflammation and steatosis from experimental steatohepatitis with DM, and indicate a possible involvement of the inhibited activity of ROS-NLRP3 inflammasome. 2019 Annals of Translational Medicine. All rights reserved.
Entities:
Keywords:
Dapagliflozin (DAPA); NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome; reactive oxygen species (ROS); steatohepatitis
Authors: Alexander Wree; Akiko Eguchi; Matthew D McGeough; Carla A Pena; Casey D Johnson; Ali Canbay; Hal M Hoffman; Ariel E Feldstein Journal: Hepatology Date: 2014-01-30 Impact factor: 17.425
Authors: Jakeline Rheinheimer; Bianca M de Souza; Natali S Cardoso; Andrea C Bauer; Daisy Crispim Journal: Metabolism Date: 2017-06-11 Impact factor: 8.694
Authors: Jorge Henao-Mejia; Eran Elinav; Chengcheng Jin; Liming Hao; Wajahat Z Mehal; Till Strowig; Christoph A Thaiss; Andrew L Kau; Stephanie C Eisenbarth; Michael J Jurczak; Joao-Paulo Camporez; Gerald I Shulman; Jeffrey I Gordon; Hal M Hoffman; Richard A Flavell Journal: Nature Date: 2012-02-01 Impact factor: 49.962
Authors: Sandra Feijóo-Bandín; Alana Aragón-Herrera; Manuel Otero-Santiago; Laura Anido-Varela; Sandra Moraña-Fernández; Estefanía Tarazón; Esther Roselló-Lletí; Manuel Portolés; Oreste Gualillo; José Ramón González-Juanatey; Francisca Lago Journal: Int J Mol Sci Date: 2022-05-18 Impact factor: 6.208
Authors: Caitlin Fern Wee; Yao Hao Teo; Yao Neng Teo; Nicholas Lx Syn; Ray Meng See; Shariel Leong; Alicia Swee Yan Yip; Zhi Xian Ong; Chi-Hang Lee; Mark Yan-Yee Chan; Kian-Keong Poh; Ching-Ching Ong; Lynette Ls Teo; Devinder Singh; Benjamin Yq Tan; Leonard Ll Yeo; William Kf Kong; Tiong-Cheng Yeo; Raymond Cc Wong; Ping Chai; Ching-Hui Sia Journal: J Cardiovasc Imaging Date: 2022-07
Authors: Hubert Kolb; Kerstin Kempf; Martin Röhling; Martina Lenzen-Schulte; Nanette C Schloot; Stephan Martin Journal: BMC Med Date: 2021-12-09 Impact factor: 8.775