Lee Yu Seol, Park Jeong Su, Lee Da Hyun, Lee Dong-Kyu, Kwon Sung Won, Lee Byung-Wan, Bae Soo Han
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, South Korea.
Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
Front Endocrinol (Lausanne). 2018 Sep 21;9:539. doi: 10.3389/fendo.2018.00539. eCollection 2018.
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder closely linked with type II diabetes (T2D). The progression of NAFLD is associated with the induction of lipogenesis through hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. An increase in lipogenesis induces endoplasmic reticulum (ER) stress and accelerates oxidative liver injury in the pathogenesis of NAFLD. Lobeglitazone, one of thiazolidinediones (TZDs), is used as an antidiabetic drug to lower serum glucose level through an increase in insulin sensitivity. It is known to improve pathological symptoms in animals and humans with NAFLD. However, the underlying molecular mechanism of the protective effects of lobeglitazone against NAFLD has not been elucidated. Here, we show that under the physiological condition of acute lipogenesis, lobeglitazone inhibits hepatic lipid synthesis, the subsequent ER stress, and ω-oxidation of fatty acids by inhibiting the mTORC1 pathway. As a result, lobeglitazone protected mice from lipogenesis-induced oxidative liver injury. Taken together, lobeglitazone might be a suitable drug for the treatment of patients with diabetes and NAFLD.
非酒精性脂肪性肝病（NAFLD）是一种与2型糖尿病（T2D）密切相关的代谢紊乱疾病。NAFLD的进展与通过雷帕霉素复合物1（mTORC1）通路的过度激活诱导脂肪生成有关。脂肪生成增加会在内质网（ER）应激，并在NAFLD的发病机制中加速肝脏氧化损伤。罗格列酮是噻唑烷二酮类（TZDs）药物之一，作为一种抗糖尿病药物，通过提高胰岛素敏感性来降低血糖水平。已知它能改善患有NAFLD的动物和人类的病理症状。然而，罗格列酮对NAFLD保护作用的潜在分子机制尚未阐明。在此，我们表明，在急性脂肪生成的生理条件下，罗格列酮通过抑制mTORC1通路来抑制肝脏脂质合成、随后的ER应激以及脂肪酸的ω-氧化。结果，罗格列酮保护小鼠免受脂肪生成诱导的肝脏氧化损伤。综上所述，罗格列酮可能是治疗糖尿病和NAFLD患者的合适药物。
