Pharmacology, Merck & Co., Inc., Kenilworth, NJ 07033, USA.
Division of Cardio Metabolic Disease, Merck & Co., Inc., Kenilworth, NJ 07033, USA.
Cell Metab. 2018 Jun 5;27(6):1236-1248.e6. doi: 10.1016/j.cmet.2018.04.004. Epub 2018 Apr 26.
Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in triglyceride (TG) synthesis and has been shown to play a role in regulating hepatic very-low-density lipoprotein (VLDL) production in rodents. To explore the potential of DGAT2 as a therapeutic target for the treatment of dyslipidemia, we tested the effects of small-molecule inhibitors and gene silencing both in vitro and in vivo. Consistent with prior reports, chronic inhibition of DGAT2 in a murine model of obesity led to correction of multiple lipid parameters. In contrast, experiments in primary human, rhesus, and cynomolgus hepatocytes demonstrated that selective inhibition of DGAT2 has only a modest effect. Acute and chronic inhibition of DGAT2 in rhesus primates recapitulated the in vitro data yielding no significant effects on production of plasma TG or VLDL apolipoprotein B. These results call into question whether selective inhibition of DGAT2 is sufficient for remediation of dyslipidemia.
二酰基甘油酰基转移酶 2（DGAT2）催化甘油三酯（TG）合成的最后一步，已被证明在调节啮齿动物肝脏极低密度脂蛋白（VLDL）产生方面发挥作用。为了探讨 DGAT2 作为治疗血脂异常的治疗靶点的潜力，我们在体外和体内测试了小分子抑制剂和基因沉默的作用。与先前的报道一致，在肥胖的小鼠模型中慢性抑制 DGAT2 导致多种脂质参数得到纠正。相比之下，在原代人、恒河猴和食蟹猴肝细胞中的实验表明，选择性抑制 DGAT2 只有适度的作用。在恒河猴灵长类动物中进行的 DGAT2 的急性和慢性抑制再现了体外数据，对血浆 TG 或 VLDL 载脂蛋白 B 的产生没有显著影响。这些结果使人怀疑选择性抑制 DGAT2 是否足以纠正血脂异常。
