Jung Tae Woo, Hwang Hwan-Jin, Hong Ho Cheol, Choi Hae Yoon, Yoo Hye Jin, Baik Sei Hyun, Choi Kyung Mook
The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
Mol Cell Endocrinol. 2014 Jun 25;391(1-2):30-40. doi: 10.1016/j.mce.2014.04.012. Epub 2014 Apr 28.
Research has indicated that stress on the endoplasmic reticulum (ER) of a cell affects the pathogenesis of metabolic disorders such as obesity, type 2 diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD). Resolvins, a novel family derived from ω-3 polyunsaturated fatty acids, have anti-inflammatory and insulin sensitizing properties, and it has been suggested that they play a role in the amelioration of obesity-related metabolic dysfunctions. This study showed that pretreatment with resolvin D1 (RvD1) attenuated ER stress-induced apoptosis and also decreased caspase 3 activity in HepG2 cells. Furthermore, RvD1 significantly decreased tunicamycin-induced triglycerides accumulation as well as SREBP-1 expression. However, tunicamycin-induced ER stress markers were not significantly affected by RvD1 treatment. Moreover, RvD1 treatment did not affect the tunicamycin-induced expression of chaperones that assist protein folding in the ER. These results suggest that RvD1-conferred cellular protection may occur downstream of the ER stress. This was supported by the finding that RvD1 significantly inhibited tunicamycin-induced c-Jun N-terminal kinase (JNK) expression, although P38 and ERK1/2 phosphorylation were not affected. In addition, anisomycin, a JNK activator, increased caspase 3 activity and apoptosis as well as triglycerides accumulation and SREBP1 expression, and RvD1 treatment reversed these changes. In conclusion, RvD1 attenuated ER stress-induced hepatic steatosis and apoptosis via the JNK-mediated pathway. This study may provide insight into a novel underlying mechanism and a strategy for treating NAFLD.
研究表明，细胞内质网（ER）上的应激会影响肥胖、2型糖尿病和非酒精性脂肪性肝病（NAFLD）等代谢紊乱的发病机制。消退素是一种源自ω-3多不饱和脂肪酸的新型家族，具有抗炎和胰岛素增敏特性，有人认为它们在改善肥胖相关的代谢功能障碍中发挥作用。本研究表明，用消退素D1（RvD1）预处理可减轻内质网应激诱导的细胞凋亡，并降低HepG2细胞中半胱天冬酶3的活性。此外，RvD1显著降低了衣霉素诱导的甘油三酯积累以及固醇调节元件结合蛋白-1（SREBP-1）的表达。然而，衣霉素诱导的内质网应激标志物并未受到RvD1处理的显著影响。此外，RvD1处理并未影响衣霉素诱导的在内质网中协助蛋白质折叠的伴侣蛋白的表达。这些结果表明，RvD1赋予的细胞保护作用可能发生在内质网应激的下游。这一观点得到了以下发现的支持：RvD1显著抑制衣霉素诱导的c-Jun氨基末端激酶（JNK）表达，尽管P38和细胞外信号调节激酶1/2（ERK1/2）的磷酸化未受影响。此外，JNK激活剂茴香霉素增加了半胱天冬酶3的活性和细胞凋亡，以及甘油三酯积累和SREBP1表达，而RvD1处理逆转了这些变化。总之，RvD1通过JNK介导的途径减轻内质网应激诱导的肝脂肪变性和细胞凋亡。本研究可能为治疗NAFLD的新潜在机制和策略提供见解。
