Resolvin D1 reduces ER stress-induced apoptosis and triglyceride accumulation through JNK pathway in HepG2 cells

• Published in: Molecular and cellular endocrinology 2014-06, Vol.391 (1-2), p.30-40
• Main Authors: Jung, Tae Woo, Hwang, Hwan-Jin, Hong, Ho Cheol, Choi, Hae Yoon, Yoo, Hye Jin, Baik, Sei Hyun, Choi, Kyung Mook
• Format: Article
• Language: English
• Subjects: Anisomycin - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Attenuation; c-Jun N-terminal kinase; Caspase 3 - genetics; Caspase 3 - metabolism; Cellular; Docosahexaenoic Acids - pharmacology; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum Stress - drug effects; ER stress; Gene Expression Regulation; Hep G2 Cells; Humans; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Non-alcoholic fatty liver; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Pathways; Phosphorylation; Proliferator-activated receptor-γ; Resolvin D1; Signal Transduction; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Stresses; Triglycerides; Triglycerides - antagonists & inhibitors; Triglycerides - biosynthesis; Tunicamycin - pharmacology
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2014.04.012

•Resolvin D1 suppresses palmitate-mediated ER stress-induced cellular dysfunction.•Resolvin D1 selctively reduced JNK phosphorylation through PPAR-g in hepatocytes.•Resolvin D1 does not affect expression change of ER stress markers and chaperones.•ALX/FPR2 and GPR32 are not involved in the effects of Resolvin D1. 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.