18beta‐glycyrrhetinic acid prevents free fatty acid‐induced lipotoxicity by inhibiting ER stress and oxidative stress

Abstract

The endoplasmic reticulum (ER) stress signal pathway has been linked to free fatty acid (FFA)‐induced inflammatory response and disease progression of nonalcoholic fatty liver disease in clinic. We have previously shown that 18?β‐glycyrrhetinic acid (GA) prevents FFA‐induced hepatic lipotoxicity by inhibiting cathepsin B expression and activity. But the underlying cellular mechanism remains unclear. This study determined if GA prevents FFA‐induced lipotoxicity by regulating ER stress signaling pathways.MethodsMouse macrophages, primary rat hepatocytes and Kupffer cells were used in this study. Cells were treated with palmitic acid (PA) and oleic acid (OA) in the presence or absence of GA. Activation of the UPR was determined by real time RT‐PCR and Western Blot analysis. The apoptosis was detected by fluorescence microscopy using Annexin V‐FITC/propidium iodide. Reactive oxygen species (ROS) was measured using dichlorofluorescein diacetate (DCFH‐DA).ResultsPA dose‐dependently induced UPR activation, ROS formation, and apoptosis both in macrophages and hepatocytes, while OA had no effect. GA not only inhibited PA‐induced UPR activation, but also inhibited PA‐induced ROS formation. PA‐induced ROS formation and cathepsin B expression were inhibited in CHOP knockout macrophages and hepatocytes.ConclusionGA prevents FFA‐induced lipotoxicity by inhibiting ER stress and oxidative stress.