title: Theophylline-Based KMUP-1 Improves Steatohepatitis via MMP-9/IL-10 and Lipolysis via HSL/p-HSL in Obese Mice.
abstract: KMUP-1 (7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) has been reported to cause hepatic fat loss. However, the action mechanisms of KMUP-1 in obesity-induced steatohepatitis remains unclear. This study elucidated the steatohepatitis via matrix metallopeptidase 9 (MMP-9) and tumor necrosis factor α (TNFα), and related lipolysis via hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) by KMUP-1. KMUP-1 on steatohepatitis-associated HSL/p-HSL/ATGL/MMP-9/TNFα/interleukin-10 (IL-10) and infiltration of M1/M2 macrophages in obese mice were examined. KMUP-1 was administered by oral gavage from weeks 1-14 in high-fat diet (HFD)-supplemented C57BL/6J male mice (protection group) and from weeks 8-14, for 6 weeks, in HFD-induced obese mice (treatment group). Immunohistochemistry (IHC) and hematoxylin and eosin (H&amp;E) staining of tissues, oil globules number and size, infiltration and switching of M1/M2 macrophages were measured to determine the effects on livers. IL-10 and MMP-9 proteins were explored to determine the effects of KMUP-1 on M1/M2 macrophage polarization in HFD-induced steatohepatitis. Long-term administration of KMUP-1 reversed HFD-fed mice increased in body weight, sGOT/sGPT, triglyceride (TG) and glucose. Additionally, KMUP-1 decreased MMP-9 and reactive oxygen species (ROS), and increased HSL/p-HSL and IL-10 in HFD mice livers. In conclusion, KMUP-1, a phosphodiesterase inhibitor (PDEI), was shown to reduce lipid accumulation in liver tissues, suggesting that it could be able to prevent or treat steatohepatitis induced by HFD.
authors.affiliation: Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan. binnan@kmu.edu.tw.
authors.forename: Bin-Nan
authors.initials: BN
authors.lastname: Wu
authors.affiliation: Division of Hepatobiliopancreatic Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan. kkkuo@kmu.edu.tw.
authors.forename: Kung-Kai
authors.initials: KK
authors.lastname: Kuo
authors.affiliation: Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan. sicaja9999@hotmail.com.
authors.forename: Yu-Hsun
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan. a99443@hotmail.com.
authors.forename: Chain-Ting
authors.initials: CT
authors.lastname: Chang
authors.affiliation: Department of Anatomy, School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. hungtu@kmu.edu.tw.
authors.forename: Hung-Tu
authors.initials: HT
authors.lastname: Huang
authors.affiliation: Department of Pathology, School of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan. d750147@kmu.edu.tw.
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
authors.affiliation: Department of Pediatrics, Division of Pediatric Pulmonology and Cardiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan. zenkong@kmu.edu.tw.
authors.forename: Zen-Kong
authors.initials: ZK
authors.lastname: Dai
authors.affiliation: Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan. ingjun@kmu.edu.tw.|Department of Medical Education and Research, Pingtung Christian Hospital, Pingtung 900, Taiwan. ingjun@kmu.edu.tw.
authors.forename: Ing-Jun
authors.initials: IJ
authors.lastname: Chen
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000188:drug therapy*; D016753:Interleukin-10 / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D010880:Piperidines / Q000737:chemistry* / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D002787:Sterol Esterase / Q000378:metabolism*; D013806:Theophylline / Q000737:chemistry*; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014970:Xanthines / Q000737:chemistry* / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D010880:Piperidines; D017382:Reactive Oxygen Species; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D014970:Xanthines; D016753:Interleukin-10; C439304:KMUP 1; D013806:Theophylline; D002787:Sterol Esterase; D020780:Matrix Metalloproteinase 9
keywords: M1/M2 macrophage; adipose triglyceride lipase; fatty liver; hormone sensitive lipase; matrix metallopeptidase 9; tumor necrosis factor α