PTUPB ameliorates high-fat diet-induced non-alcoholic fatty liver disease via inhibiting NLRP3 inflammasome activation in mice.

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.

• Authors: Chen-Chen Sun, Chen-Yu Zhang, Jia-Xi Duan, Xin-Xin Guan, Hui-Hui Yang, Hui-Ling Jiang, Bruce D Hammock, Sung Hee Hwang, Yong Zhou, Cha-Xiang Guan, Shao-Kun Liu, Jun Zhang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 523 Issue 4 Pg. 1020-1026 (03 19 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 31973813 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Cyclooxygenase 2
• Epoxide Hydrolases

Topics

• Animals
• Cell Line
• Cyclooxygenase 2 (metabolism)
• Diet, High-Fat (adverse effects)
• Epoxide Hydrolases (metabolism)
• Inflammasomes (metabolism)
• Inflammation (pathology)
• Liver (enzymology, pathology)
• Liver Cirrhosis (enzymology, pathology)
• Male
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Non-alcoholic Fatty Liver Disease (drug therapy, enzymology, metabolism, pathology)