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. 2023 Jul;180(14):1803-1818.
doi: 10.1111/bph.16047. Epub 2023 Feb 20.

The heparan sulfate mimetic Muparfostat aggravates steatohepatitis in obese mice due to its binding affinity to lipoprotein lipase

Jia Zhang  1 , Kai Li  1 , Hao-Ran Sun  1 , Shao-Kun Sun  1 , Ya-Ting Zhu  1 , Yu-Ting Ge  1 , Yu-Xuan Wu  1 , Qin-Yao Zhou  1 , Guan-Ting Li  1 , Xiao-Ai Chang  1 , Peng Sun  1   2 , Ying Ding  3 , Xiao Han  1
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Free article

The heparan sulfate mimetic Muparfostat aggravates steatohepatitis in obese mice due to its binding affinity to lipoprotein lipase

Jia Zhang et al. Br J Pharmacol. 2023 Jul.
Free article

Abstract

Background and purpose: Heparanase 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 approach: In 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 results: Daily 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 implications: The 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.

Keywords: heparan sulfate mimetic; heparanase inhibitor; hepatic steatosis; lipoprotein lipase; obesity.

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References

REFERENCES

    1. Alexander, S. P., Cidlowski, J. A., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Davies, J. A., Coons, L., Fuller, P. J., Korach, K. S., & Young, M. J. (2021). THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Nuclear hormone receptors. British Journal of Pharmacology, 178(Suppl 1), S246-S263. https://doi.org/10.1111/bph.15540
    1. Alexander, S. P., Fabbro, D., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., & Southan, C. (2021). THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Enzymes. British Journal of Pharmacology, 178(Suppl 1), S313-S411.
    1. Alexander, S. P., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Buneman, O. P., Cidlowski, J. A., Christopoulos, A., Davenport, A. P., Fabbro, D., Spedding, M., Striessnig, J., Davies, J. A., Ahlers-Dannen, K. E., … Zolghadri, Y. (2021). THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Introduction and other protein targets. British Journal of Pharmacology, 178(Suppl 1), S1-S26. https://doi.org/10.1111/bph.15537
    1. Alexander, S. P. H., Roberts, R. E., Broughton, B. R. S., Sobey, C. G., George, C. H., Stanford, S. C., Cirino, G., Docherty, J. R., Giembycz, M. A., Hoyer, D., Insel, P. A., Izzo, A. A., Ji, Y., MacEwan, D. J., Mangum, J., Wonnacott, S., & Ahluwalia, A. (2018). Goals and practicalities of immunoblotting and immunohistochemistry: A guide for submission to the British Journal of pharmacology. British Journal of Pharmacology, 175, 407-411. https://doi.org/10.1111/bph.14112
    1. Allard, J., Le Guillou, D., Begriche, K., & Fromenty, B. (2019). Drug-induced liver injury in obesity and nonalcoholic fatty liver disease. Advances in Pharmacology, 85, 75-107. https://doi.org/10.1016/bs.apha.2019.01.003

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