DS-7250是一种二酰基甘油酰基转移酶1抑制剂，可通过上调脂肪酸合成来增强Zucker肥胖大鼠的肝脂肪变性。,Toxicologic Pathology

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DS-7250是一种二酰基甘油酰基转移酶1抑制剂，可通过上调脂肪酸合成来增强Zucker肥胖大鼠的肝脂肪变性。
Toxicologic Pathology ( IF 1.4 ) Pub Date : 2018-03-29 , DOI: 10.1177/0192623318765909
Kyohei Yasuno ₁ , Kazuyoshi Kumagai ₁ , Takuma Iguchi ₁ , Yoshimi Tsuchiya ₂ , Kiyonori Kai ₁ , Kazuhiko Mori ₁

Affiliation

二酰基甘油酰基转移酶1（DGAT1）催化甘油三酸酯合成的最后一步。由于饲喂高脂饮食（HFD）的Dgat1-/-小鼠对肝脂肪变性有抵抗力，因此DGAT1抑制剂有望具有抗脂肪肝作用。为评估DS-7250的肝功能，向饲喂标准饮食或HFD 14的雄性Fisher 344（F344）和Zucker脂肪（ZF）大鼠口服选择性DGAT1抑制剂，媒介物或10 mg / kg DS-7250或28天。无论采食条件如何，ZF大鼠均表现出轻度肝脂肪变性。与媒介物对照相比，DS-7250在喂食HFD的ZF大鼠中加重了肝脂肪变性。饲喂HFD的F344大鼠未发生肝脂肪变性，其中DS-7250的全身暴露与ZF大鼠相当。在HFD条件下，与F344大鼠相比，ZF大鼠的脂质摄取和脂肪酸合成相关基因的表达更高。与媒介物对照相比，在饲喂HFD的ZF大鼠中，DS-7250上调了涉及新生脂肪形成的关键基因，该关键基因独立于DGAT1引起肝脂肪变性。这些数据表明ZF大鼠由于其遗传特征而更易患肝脂肪变性，而DS-7250则独立于DGAT1加剧了肝脂肪变性。

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DS-7250, a Diacylglycerol Acyltransferase 1 Inhibitor, Enhances Hepatic Steatosis in Zucker Fatty Rats via Upregulation of Fatty Acid Synthesis.

Diacylglycerol acyltransferase 1 (DGAT1) catalyzes the final step in triglyceride synthesis. Since Dgat1-/- mice fed a high-fat diet (HFD) are resistant to hepatic steatosis, DGAT1 inhibitors are expected to have antifatty liver effects. To evaluate the hepatic effects of DS-7250, a selective DGAT1 inhibitor, vehicle or 10 mg/kg of DS-7250 was administered orally to male Fisher 344 (F344) and Zucker fatty (ZF) rats fed a standard diet or HFD for 14 or 28 days. ZF rats showed slight hepatic steatosis regardless of feeding conditions. DS-7250 exacerbated hepatic steatosis in ZF rats fed an HFD compared with the vehicle control. Hepatic steatosis did not occur in F344 rats fed an HFD, in which systemic exposures of DS-7250 were comparable to those in ZF rats. There was a higher expression of genes involved in lipid uptake and fatty acid synthesis in ZF rats compared to F344 rats under HFD conditions. DS-7250 upregulated key genes involved in de novo lipogenesis, which causes hepatic steatosis independently of DGAT1, in ZF rats fed an HFD compared with the vehicle control. These data suggest that ZF rats were more susceptible to hepatic steatosis due to their genetic characteristics and DS-7250 exacerbated hepatic steatosis independently of DGAT1.

更新日期：2019-11-01

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