Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases

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. Promoting the activity of a protective membrane protein may help limit the development of non-alcoholic fatty liver disease (NAFLD) in obesity. Stress on a key cellular organelle, the endoplasmic reticulum (ER), contributes to NAFLD progression. Woo-Jae Park at Gachon University in Incheon, Joo-Won Park at Ewha Womans University, Seoul, and co-workers across South Korea have uncovered the role of a family of ER membrane proteins called ceramide synthases (CerS) in the regulation of ER stress during disease development. The team found increased levels of CerS6 in the livers of mouse fed a high-fat diet, while CerS2 decreased. The increased C16-ceramide by CerS6 overexpression triggered excess fat formation by increasing ER stress and SREBP-1 cleavage. However, when the team enhanced the expression of CerS2 using an existing chemotherapy drug, mice were protected from developing NAFLD.