Xiangya School of Public Health, Central South University, Changsha, 410013, China.
Children's Medical Center, People's Hospital, Hunan Province, Changsha, 410005, China.
Mol Nutr Food Res. 2024 Jun;68(12):e2300912. doi: 10.1002/mnfr.202300912. Epub 2024 Jun 7.
Diabetic liver injury (DLI) is one of the complications of diabetes mellitus, which seriously jeopardizes human health. Punicalagin (PU), a polyphenolic compound mainly found in pomegranate peel, has been shown to ameliorate metabolic diseases such as DLI, and the mechanism needs to be further explored. In this study, a HFD/STZ-induced diabetic mouse model is established to investigate the effect and mechanism of PU on DLI. The results show that PU intervention significantly improves liver histology and serum biochemical abnormalities in diabetic mice, significantly inhibits the expression of pyroptosis-related proteins such as NLRP3, Caspase1, IL-1β, and GSDMD in the liver of diabetic mice, and up-regulated the expression of autophagy-related proteins. Meanwhile, PU treatment significantly increases FoxO1 protein expression and inhibits TXNIP protein expression in the liver of diabetic mice. The above results are further verified in the HepG2 cell injury model induced by high glucose. AS1842856 is a FoxO1 specific inhibitor. The intervention of AS1842856 combined with PU reverses the regulatory effects of PU on pyroptosis and autophagy in HepG2 cells. In conclusion, this study demonstrates that PU may inhibit pyroptosis and upregulate autophagy by regulating FoxO1/TXNIP signaling, thereby alleviating DLI.
糖尿病肝损伤（DLI）是糖尿病的并发症之一，严重危害人类健康。鞣花酸（PU）是一种主要存在于石榴皮中的多酚化合物，已被证明可改善 DLI 等代谢疾病，其机制仍需进一步探讨。本研究建立了 HFD/STZ 诱导的糖尿病小鼠模型，以研究 PU 对 DLI 的作用及其机制。结果表明，PU 干预可显著改善糖尿病小鼠的肝组织学和血清生化异常，显著抑制糖尿病小鼠肝组织中 Nlrp3、Caspase1、IL-1β和 Gsdmd 等焦亡相关蛋白的表达，并上调自噬相关蛋白的表达。同时，PU 处理可显著增加糖尿病小鼠肝组织中 FoxO1 蛋白的表达，抑制 TXNIP 蛋白的表达。上述结果在高糖诱导的 HepG2 细胞损伤模型中得到进一步验证。AS1842856 是 FoxO1 的特异性抑制剂。AS1842856 联合 PU 的干预逆转了 PU 对 HepG2 细胞焦亡和自噬的调节作用。综上所述，本研究表明，PU 可能通过调节 FoxO1/TXNIP 信号通路抑制焦亡和上调自噬，从而减轻 DLI。
