Diacylglycerol acyltransferase 1 (DGAT1) plays a pivotal role in lipid metabolism by catalyzing the committed step in triglyceride (TG) synthesis and has been considered as a potential therapeutic target of multiple metabolic diseases, including dyslipidemia, obesity and type 2 diabetes. Here we report a novel DGAT1 inhibitor, Yhhu2407, which showed a stronger DGAT1 inhibitory activity (IC₅₀ = 18.24 ± 4.72 nM) than LCQ908 (IC₅₀ = 78.24 ± 8.16 nM) in an enzymatic assay and led to a significant reduction in plasma TG after an acute lipid challenge in mice. Pharmacokinetic studies illustrated that Yhhu2407 displayed a low systemic, liver- and intestine-targeted distribution pattern, which is consistent with the preferential tissue expression pattern of DGAT1 and therefore might help to maximize the beneficial pharmacological effects and prevent the occurrence of side effects. Cell-based investigations demonstrated that Yhhu2407 inhibited free fatty acid (FFA)-induced TG accumulation and apolipoprotein B (ApoB)-100 secretion in HepG2 cells. In vivo study also disclosed that Yhhu2407 exerted a beneficial effect on regulating plasma TG and lipoprotein levels in rats, and effectively ameliorated high-fat diet (HFD)-induced dyslipidemia in hamsters. In conclusion, we identified Yhhu2407 as a novel DGAT1 inhibitor with potent efficacy on improving lipid metabolism in rats and HFD-fed hamsters without causing obvious adverse effects.

二酰基甘油酰基转移酶 1 (DGAT1) 通过催化甘油三酯 (TG) 合成中的关键步骤在脂质代谢中发挥关键作用，并被认为是多种代谢疾病的潜在治疗靶点，包括血脂异常、肥胖和 2 型糖尿病。在这里，我们报告了一种新型 DGAT1 抑制剂 Yhhu2407，它显示出比 LCQ908 (IC _{50 ) 更强的 DGAT1 抑制活性 (IC 50}  = 18.24 ± 4.72 nM) = 78.24 ± 8.16 nM)，并导致小鼠急性脂质攻击后血浆 TG 显着降低。药代动力学研究表明，Yhhu2407 表现出较低的全身性、肝脏和肠道靶向分布模式，这与 DGAT1 的优先组织表达模式一致，因此可能有助于最大限度地发挥有益药理作用并防止副作用的发生。基于细胞的研究表明，Yhhu2407 可抑制 HepG2 细胞中游离脂肪酸 (FFA) 诱导的 TG 积累和载脂蛋白 B (ApoB)-100 分泌。体内研究还显示，Yhhu2407 对调节大鼠血浆 TG 和脂蛋白水平具有有益作用，并有效改善高脂饮食 (HFD) 引起的仓鼠血脂异常。综上所述，