The heparan sulfate mimetic Muparfostat aggravates steatohepatitis in obese mice due to its binding affinity to lipoprotein lipase
文献类型：期刊论文
| 作者 | Zhang, Jia5; Li, Kai5; Sun, Hao-Ran5; Sun, Shao-Kun5; Zhu, Ya-Ting5; Ge, Yu-Ting5; Wu, Yu-Xuan5; Zhou, Qin-Yao5; Li, Guan-Ting5; Chang, Xiao-Ai5 |
| 刊名 | BRITISH JOURNAL OF PHARMACOLOGY
 |
| 出版日期 | 2023-07-01 |
| 卷号 | 180期号:14页码:1803-1818 |
| 关键词 | heparan sulfate mimetic heparanase inhibitor hepatic steatosis lipoprotein lipase obesity |
| DOI | 10.1111/bph.16047 |
| 文献子类 | Article |
| 英文摘要 | Background and PurposeHeparanase is the only confirmed endoglycosidase that cleaves heparan sulfate (HS), a ubiquitous glycosaminoglycan with various essential roles in multiple pathological processes. Thus, the development of heparanase inhibitors has become an attractive strategy for drug discovery, especially in tumour therapy, in which HS mimetics are the most promising compounds. The various biological effects of heparanase also suggest a role for HS mimetics in many non-cancer indications, such as type 1 diabetes. However, the potential benefits of HS mimetics in obesity-related type 2 diabetes have not been elucidated. Experimental ApproachIn this study, we investigated muparfostat (PI-88), a developed HS mimetic currently enrolled in Phase III clinical trials, in obese mouse models and in vitro cultured murine hepatocytes. Key ResultsDaily administration of muparfostat for 4 weeks caused hyperlipidaemia and aggravated hepatic steatosis in obese mice models, but not in lean animals. In cultured hepatocytes, muparfostat did not alter lipid accumulation. Acute tests suggested that muparfostat binds to lipoprotein lipase in competition with HS on vascular endothelial cell surfaces, thereby reducing the degradation of circulating triglycerides by lipoprotein lipase and subsequent uptake of fatty acids into vascular endothelial cells and causing hyperlipidaemia. This hyperlipidaemia aggravates hepatic steatosis and causes liver injury in muparfostat-treated obese mice. Conclusions and ImplicationsThe binding activity of HS mimetics to lipoprotein lipase should be investigated as an additional pharmacological effect during heparanase inhibitor drug discovery. This study also provides novel evidence for an increased risk of drug-induced liver injury in obese individuals. |
| WOS关键词 | INHIBITOR PI-88 ; CONCISE GUIDE ; HEPATOCELLULAR-CARCINOMA ; PHASE-II ; ROLES ; IDENTIFICATION ; ANGIOGENESIS ; METASTASIS ; THERAPY ; PROTEIN |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000935768000001 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309695]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Sun, Peng; Ding, Ying; Han, Xiao |
| 作者单位 | 1.Nanjing Med Univ, Affiliated Hosp 1, Dept Pathol, Nanjing 210029, Peoples R China 2.Nanjing Med Univ, Dept Biochem & Mol Biol, Key Lab Human Funct Genom Jiangsu Prov, Nanjing 211166, Peoples R China; 3.Nanjing Med Univ, Affiliated Hosp 1, Dept Pathol, Nanjing, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China; 5.Nanjing Med Univ, Dept Biochem & Mol Biol, Key Lab Human Funct Genom Jiangsu Prov, Nanjing, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhang, Jia,Li, Kai,Sun, Hao-Ran,et al. The heparan sulfate mimetic Muparfostat aggravates steatohepatitis in obese mice due to its binding affinity to lipoprotein lipase[J]. BRITISH JOURNAL OF PHARMACOLOGY,2023,180(14):1803-1818. |
| APA | Zhang, Jia.,Li, Kai.,Sun, Hao-Ran.,Sun, Shao-Kun.,Zhu, Ya-Ting.,...&Han, Xiao.(2023).The heparan sulfate mimetic Muparfostat aggravates steatohepatitis in obese mice due to its binding affinity to lipoprotein lipase.BRITISH JOURNAL OF PHARMACOLOGY,180(14),1803-1818. |
| MLA | Zhang, Jia,et al."The heparan sulfate mimetic Muparfostat aggravates steatohepatitis in obese mice due to its binding affinity to lipoprotein lipase".BRITISH JOURNAL OF PHARMACOLOGY 180.14(2023):1803-1818. |
入库方式： OAI收割
来源：上海药物研究所
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