Decreased Hepatic Polyunsaturated Fatty Acids and Inflammatory Response in a Rat Model of Endoplasmic Reticulum Stress

In this study, we sought to evaluate the effect of endoplasmic reticulum (ER) stress on hepatic polyunsaturated fatty acids (PUFAs) and inflammatory response through cyclooxygenase (COX)-mediated pathway. Male Wistar rats which were allowed free access to standard rat chow were randomly divided into control, tunicamycin (TM) treated and TM + tauroursodeoxycholic acid (TUDCA) treated groups. Hepatic ER stress was induced by intraperitoneal injection of tunicamycin and the ER stress inhibitor TUDCA was injected 30 minutes before hepatic induction of ER stress. The presence of ER stress was confirmed by increased intracellular levels of C/EBP-homologous protein (CHOP) and 78-kDa glucose-regulated protein (GRP78). Necroinflammation was evaluated in liver sections stained with hematoxylin-eosin using the Ishak-modified hepatic activity index. Levels of arachidonic acid (AA, C20:4n-6), dihomo-gamma-linolenic acid (DGLA, C20:3n-6), eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) in liver tissue were determined by an optimized multiple reaction monitoring method using ultra fast-liquid chromatography coupled with tandem mass spectrometry. Phospholipase A2 (PLA2), COX and prostaglandin E2 (PGE2) were measured in tissue samples to evaluate changes in the inflammatory pathways. Tunicamycin treatment significantly decreased all measured PUFAs and increased AA/EPA ratio in liver tissue compared to controls. Tissue activity of PLA2, COX and PGE2 levels were significantly increased in liver tissue of TM treated rats compared to controls. Tauroursodeoxycholic acid lead to a partial restoration of liver PUFA levels and significantly decreased PLA2, COX and PGE2 levels compared to TM treated rats. The results of this study reveal the presence of a proinflammatory state in hepatic ER stress as shown by significantly increased AA/EPA ratio. To our best knowledge, this is the first study reporting altered PUFA levels in ER stress and supports the use of omega-3 fatty acids as adjuvant treatment in liver diseases demonstrating ER stress. Acknowledgement This study was supported by a grant from TUBITAK; # 214S223.