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Int. J. Mol. Sci. 2016, 17(8), 1345; doi:10.3390/ijms17081345

Theophylline-Based KMUP-1 Improves Steatohepatitis via MMP-9/IL-10 and Lipolysis via HSL/p-HSL in Obese Mice

1
Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
2
Division of Hepatobiliopancreatic Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
3
Department of Anatomy, School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
4
Department of Pathology, School of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
5
Department of Pediatrics, Division of Pediatric Pulmonology and Cardiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
6
Department of Medical Education and Research, Pingtung Christian Hospital, Pingtung 900, Taiwan
*
Author to whom correspondence should be addressed.
Academic Editors: Kathleen Van Craenenbroeck and Masatoshi Maki
Received: 26 June 2016 / Revised: 22 July 2016 / Accepted: 10 August 2016 / Published: 17 August 2016
(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)
View Full-Text   |   Download PDF [11410 KB, uploaded 17 August 2016]   |  

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&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. View Full-Text
Keywords: adipose triglyceride lipase; fatty liver; hormone sensitive lipase; M1/M2 macrophage; matrix metallopeptidase 9; tumor necrosis factor α adipose triglyceride lipase; fatty liver; hormone sensitive lipase; M1/M2 macrophage; matrix metallopeptidase 9; tumor necrosis factor α
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MDPI and ACS Style

Wu, B.-N.; Kuo, K.-K.; Chen, Y.-H.; Chang, C.-T.; Huang, H.-T.; Chai, C.-Y.; Dai, Z.-K.; Chen, I.-J. Theophylline-Based KMUP-1 Improves Steatohepatitis via MMP-9/IL-10 and Lipolysis via HSL/p-HSL in Obese Mice. Int. J. Mol. Sci. 2016, 17, 1345.

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