Heparanase是唯一一种已确认分解分布广泛对多种病理过程具有重要作用的糖胺聚糖——肝素硫酸（HS）的内源性糖苷酶。因此，开发肝素酶抑制剂已成为一种有吸引力的药物发现策略，特别是在肿瘤治疗方面，其中HS类似物是最有前途的化合物。Heparan酶的各种生物学效应也暗示HS类似物在许多非癌症领域，如1型糖尿病中拥有作用。然而，HS类似物在与肥胖相关的2型糖尿病中的潜在益处尚未阐明。本研究调查了目前正在进行第III期临床试验的已研制HS类似物muparfostat（PI-88）在肥胖小鼠模型和体外培养的小鼠肝细胞中的作用。每天给予muparfostat 4周，可以导致肥胖小鼠模型出现高脂血症和加重的肝脂肪变性，但在瘦小动物中没有发生。在培养的肝细胞中，muparfostat没有改变脂类积累。急性试验表明，muparfostat与血管内皮细胞表面的HS竞争性结合脂蛋白脂酶，从而减少脂蛋白脂酶对周转甘油三酸酯的降解并减少脂肪酸进入血管内皮细胞的摄取，导致高脂血症。这种高脂血症加重了肥胖小鼠的肝脂肪变性并导致肝损伤。应该调查HS类似物与脂蛋白脂酶的结合活性，作为肝素酶抑制剂药物发现期间额外的药理效应。这项研究还提供了肥胖人群药物性肝损伤风险增加的新证据。 ©2023 British Pharmacological Society.

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.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.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.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.© 2023 British Pharmacological Society.