Inhibition of mPGES-2 ameliorates NASH by activating NR1D1 via heme.

Abstract

BACKGROUND AND AIMS:

Nonalcoholic fatty liver disease (NAFLD), a complex metabolic syndrome, has limited therapeutic options. Microsomal prostaglandin E synthase-2 (mPGES-2) was originally discovered as a prostaglandin E 2 (PGE 2 ) synthase; however, it does not produce PGE 2 in the liver. Moreover, the role of mPGES-2 in NAFLD remains undefined. Herein, we aimed to determine the function and mechanism of mPGES-2 in liver steatosis and steatohepatitis.

APPROACH AND RESULTS:

To evaluate the role of mPGES-2 in NAFLD, whole-body or hepatocyte-specific mPGES-2-deficient mice fed a high-fat or methionine-choline-deficient diet were used. Compared with control mice, mPGES-2-deficient mice showed reduced hepatic lipid accumulation, along with ameliorated liver injury, inflammation, and fibrosis. Furthermore, the protective effect of mPGES-2 deficiency against NAFLD was dependent on decreased cytochrome P450 4A14 and increased acyl-CoA thioesterase 4 levels regulated by the heme receptor nuclear receptor subfamily 1 group D member 1 (NR1D1), but not PGE 2 . Heme regulated the increased NR1D1 activity mediated by mPGES-2 deficiency. Further, we confirmed the protective role of the mPGES-2 inhibitor SZ0232 in NAFLD therapy.

CONCLUSION:

Our study indicates the pathogenic role of mPGES-2 and outlines the mechanism in mediating NAFLD, thereby highlighting the therapeutic potential of mPGES-2 inhibition in liver steatosis and steatohepatitis.

• Authors: Dandan Zhong, Jie Cai, Cheng Hu, Jingshuo Chen, Rumeng Zhang, Chenyu Fan, Shanshan Li, Hongxing Zhang, Zhou Xu, Zhanjun Jia, Dong Guo, Ying Sun
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 78 Issue 2 Pg. 547-561 (08 01 2023) ISSN: 1527-3350 [Electronic] United States
• PMID: 35839302 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 American Association for the Study of Liver Diseases.

Chemical References

• Prostaglandin-E Synthases
• Heme

Topics

• Mice
• Animals
• Non-alcoholic Fatty Liver Disease (pathology)
• Prostaglandin-E Synthases (metabolism)
• Heme
• Disease Models, Animal
• Liver (pathology)
• Mice, Inbred C57BL