Title: PTUPB ameliorates high-fat diet-induced non-alcoholic fatty liver disease via inhibiting NLRP3 inflammasome activation in mice.
Authors: Sun, Chen-Chen; Zhang, Chen-Yu; Duan, Jia-Xi; Guan, Xin-Xin; Yang, Hui-Hui; Jiang, Hui-Ling; Hammock, Bruce D; Hwang, Sung Hee; Zhou, Yong; Guan, Cha-Xiang; Liu, Shao-Kun; Zhang, Jun
Published In Biochem Biophys Res Commun, (2020 03 19)
Abstract: Non-alcoholic fatty liver disease (NAFLD) affects 25% of the global adult population, and no effective pharmacological treatment has been found. Products of arachidonic acid metabolism have been developed into a novel therapy for metabolic syndrome and diabetes. It has been demonstrated that protective actions of a novel dual cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) inhibitor, PTUPB, on the metabolic abnormalities. Here, we investigated the effects of PTUPB on hepatic steatosis in high-fat diet (HFD)-induced obese mice, as well as in hepatocytes in vitro. We found that PTUPB treatment reduced body weight, liver weight, liver triglyceride and cholesterol content, and the expression of lipolytic/lipogenic and lipid uptake related genes (Acc, Cd36, and Cidec) in HFD mice. In addition, PTUPB treatment arrested fibrotic progression with a decrease of collagen deposition and expression of Col1a1, Col1a3, and α-SMA. In vitro, PTUPB decreased palmitic acid-induced lipid deposition and downregulation of lipolytic/lipogenic genes (Acc and Cd36) in hepatocytes. Additionally, we found that PTUPB reduced the production of pro-inflammatory cytokines and suppressed the NLRP3 inflammasome activation in HFD mice and hepatocytes. In conclusion, dual inhibition of COX-2/sEH attenuates hepatic steatosis by inhibiting the NLRP3 inflammasome activation. PTUPB might be a promising potential therapy for liver steatosis associated with obesity.
PubMed ID: 31973813
MeSH Terms: Animals; Cell Line; Cyclooxygenase 2/metabolism; Diet, High-Fat/adverse effects*; Epoxide Hydrolases/metabolism; Inflammasomes/metabolism*; Inflammation/pathology; Liver Cirrhosis/enzymology; Liver Cirrhosis/pathology; Liver/enzymology; Liver/pathology; Male; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism*; Non-alcoholic Fatty Liver Disease/drug therapy*; Non-alcoholic Fatty Liver Disease/enzymology; Non-alcoholic Fatty Liver Disease/metabolism*; Non-alcoholic Fatty Liver Disease/pathology