15-Hydroxyprostaglandin dehydrogenase inhibitor SW033291 ameliorates hepatic abnormal lipid metabolism, ER stress, and inflammation through PGE2/EP4 in T2DM mice

Abstract

Type 2 diabetes mellitus (T2DM) is a rapidly growing epidemic that results in increased morbidity, mortality, and soaring medical costs. Prostaglandin E2 (PGE2), a vital lipid mediator, has been reported to protect against hepatic steatosis, inflammation, endoplasmic reticulum (ER) stress, and insulin resistance, indicating its potential therapeutic role in T2DM. PGE2 can be degraded by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). SW033291, an inhibitor of 15-PGDH, has been reported to increase PGE2 levels, however, the effect of SW033291 in T2DM remains to be explored. This study aims to evaluate whether SW033291 protects against T2DM and explore its potential mechanisms. A T2DM mouse model was established through high-fat diet/streptozotocin injection, while palmitic acid-treated mouse primary hepatocytes were used as insulin-resistant cell models. SW033291 treatment reduced body weight, fat weight, fasting blood glucose, and improved impaired glucose tolerance and insulin resistance in T2DM mice. More importantly, SW033291 alleviated steatosis, inflammation, and ER stress in the liver of T2DM mice. Mechanistically, SW033291 decreased the expressions of SREBP-1c and ACC1, and increased the expression of PPARα in T2DM mice. Additionally, SW033291 inhibited NF-κB and eIF2α/CHOP signaling in T2DM mice. Further, we showed that the protective effects of SW033291 on the above-mentioned pathophysiological processes could be hindered by inhibition of the PGE2 receptor EP4. Overall, our study reveals a novel role of SW033291 in alleviating T2DM and suggests its potential as a new therapeutic strategy for T2DM.