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&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: Bin-Nan Wu, Kung-Kai Kuo, Yu-Hsun Chen, Chain-Ting Chang, Hung-Tu Huang, Chee-Yin Chai, Zen-Kong Dai, Ing-Jun Chen
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 17 Issue 8 (Aug 17 2016) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 27548140 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Piperidines
• Reactive Oxygen Species
• Triglycerides
• Tumor Necrosis Factor-alpha
• Xanthines
• Interleukin-10
• KMUP 1
• Theophylline
• Sterol Esterase
• Matrix Metalloproteinase 9

Topics

• Adipose Tissue (drug effects, metabolism)
• Animals
• Blood Glucose (drug effects)
• Body Weight (drug effects)
• Diet, High-Fat (adverse effects)
• Fatty Liver (drug therapy)
• Interleukin-10 (metabolism)
• Liver (drug effects, metabolism)
• Macrophages (drug effects, metabolism)
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Obese
• Piperidines (chemistry, therapeutic use)
• Reactive Oxygen Species (metabolism)
• Sterol Esterase (metabolism)
• Theophylline (chemistry)
• Triglycerides (blood)
• Tumor Necrosis Factor-alpha (metabolism)
• Xanthines (chemistry, therapeutic use)