Human PCSK9D374Y exacerbates methionine choline deficiency diet-induced nonalcoholic steatohepatitis in mice
10.16352/j.issn.1001-6325.2025.05.0637
- VernacularTitle:人源PCSK9D374Y加重蛋氨酸胆碱缺乏饮食诱导的小鼠非酒精性脂肪性肝炎
- Author:
ABIDAN·ABUDURUSULI
1
;
Xiaocui CHEN
;
Yuanfeng CUI
;
TUOLUONAYI·MIJITI
;
Lihui DENG
;
Bangdang CHEN
Author Information
1. 新疆医科大学基础医学院 新疆乌鲁木齐 830000
- Publication Type:Journal Article
- Keywords:
non-alcoholic steatohepatitis;
proprotein convertase subtilisin/kexin type 9(PCSK9);
methionine choline deficiency di-et;
inflammatory factor
- From:
Basic & Clinical Medicine
2025;45(5):637-643
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the effect of mutation human proprotein convertase subtilism/kexin type 9(hPCSK9D374Y)in PCSK9 gene on methionine choline deficiency diet(MCD)-induced nonalcoholic steato-hepatitis(NASH)in mice.Methods Sixteen C57BL/6J wild-type mice were selected and randomly divided into the hPCSK9D374Y group and the control GFP group.MCD was fed for 6 weeks,and then the serum level of hepatic triglyceride,alanine aminotransferase(ALT)and aspartate aminotransferase(AST)was examined.Oil Red O and Sirius Red staining microscopy were used to identify hepatic lipid infiltration and fibrosis severity.F4/80-positive cell infiltration was analyzed using immunohistochemistry.Lipid synthesis and inflammatory response-related proteins were detected by Western blot and related mRNA expression was analyzed by RT-qPCR.Results Hepatic hPCSK9 protein and mRNA were significantly up-regulated,LDLR protein expression was down-regulated,and ser-um level of ALT and AST was significantly elevated in the hPCSK9D374Y group of mice(P＜0.05).The degree of he-patic steatosis and fibrosis increased and F4/80-positive cells were significantly increased(P＜0.01).FASN and SCD1 proteins were significantly up-regulated and PPARα was down-regulated in the hPCSK9D374Y group;The ex-pression of TLR4 and p-P65 was elevated,whereas the expression of Iκ Bα was decreased(P＜0.001).RT-qPCR re-sults showed a significant increase of mRNA coding inflammatory factors TNF-α,IL-1β,IL-6,and MCP-1,and a significant up-regulation of fibrosis-associated mRNAs(collagen Ⅰα and collagen Ⅲα)was found(P＜0.001).Conclusions Functionally acquired mutation in the PCSK9 gene(hPCSK9D374Y)exacerbates MCD-induced hepatic steatosis,inflammatory response and fibrosis in mice.
