Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul, 07084, Republic of Korea.
Department of Biochemistry, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea.
Exp Mol Med. 2019 Nov 1;51(11):1-16. doi: 10.1038/s12276-019-0340-1.
The endoplasmic reticulum (ER) is not only important for protein synthesis and folding but is also crucial for lipid synthesis and metabolism. In the current study, we demonstrate an important role of ceramide synthases (CerS) in ER stress and NAFLD progression. Ceramide is important in sphingolipid metabolism, and its acyl chain length is determined by a family of six CerS in mammals. CerS2 generates C22-C24 ceramides, and CerS5 or CerS6 produces C16 ceramide. To gain insight into the role of CerS in NAFLD, we used a high-fat diet (HFD)-induced NAFLD mouse model. Decreased levels of CerS2 and increased levels of CerS6 were observed in the steatotic livers of mice fed a HFD. In vitro experiments with Hep3B cells indicated the protective role of CerS2 and the detrimental role of CerS6 in the ER stress response induced by palmitate treatment. In particular, CerS6 overexpression increased sterol regulatory element-binding protein-1 (SREBP-1) cleavage with decreased levels of INSIG-1, leading to increased lipogenesis. Blocking ER stress abrogated the detrimental effects of CerS6 on palmitate-induced SREBP-1 cleavage. In accordance with the protective role of CerS2 in the palmitate-induced ER stress response, CerS2 knockdown enhanced ER stress and SREBP-1 cleavage, and CerS2 heterozygote livers exhibited a stronger ER stress response and higher triglyceride levels following HFD. Finally, treatment with a low dose of bortezomib increased hepatic CerS2 expression and protected the development of NAFLD following HFD. These results indicate that CerS and its derivatives impact hepatic ER stress and lipogenesis differently and might be therapeutic targets for NAFLD.
内质网（ER）不仅对蛋白质合成和折叠很重要，而且对脂质合成和代谢也至关重要。在目前的研究中，我们证明了神经酰胺合酶（CerS）在内质网应激和非酒精性脂肪性肝病（NAFLD）进展中的重要作用。神经酰胺在鞘脂代谢中很重要，其酰基链长度由哺乳动物中的一组六种 CerS 决定。CerS2 产生 C22-C24 神经酰胺，而 CerS5 或 CerS6 产生 C16 神经酰胺。为了深入了解 CerS 在 NAFLD 中的作用，我们使用了高脂肪饮食（HFD）诱导的 NAFLD 小鼠模型。在喂食 HFD 的脂肪肝小鼠肝脏中，CerS2 的水平降低，CerS6 的水平升高。用棕榈酸处理 Hep3B 细胞的体外实验表明，CerS2 具有保护作用，CerS6 在棕榈酸诱导的内质网应激反应中具有有害作用。特别是，CerS6 过表达增加固醇调节元件结合蛋白-1（SREBP-1）的切割，同时降低 INSIG-1 的水平，导致脂肪生成增加。阻断内质网应激消除了 CerS6 对棕榈酸诱导的 SREBP-1 切割的有害影响。与 CerS2 在棕榈酸诱导的内质网应激反应中的保护作用一致，CerS2 敲低增强了内质网应激和 SREBP-1 的切割，CerS2 杂合子肝脏在喂食 HFD 后表现出更强的内质网应激反应和更高的甘油三酯水平。最后，用低剂量硼替佐米治疗可增加肝 CerS2 的表达，并在喂食 HFD 后保护 NAFLD 的发展。这些结果表明，CerS 及其衍生物对内质网应激和脂肪生成的影响不同，可能是 NAFLD 的治疗靶点。
