MFG-E8 Knockout Aggravated Nonalcoholic Steatohepatitis by Promoting the Activation of TLR4/NF-kappa B Signaling in Mice

作者全名："Hu, Jun; Du, Hui; Yuan, Yinglin; Guo, Peipei; Yang, Junxia; Yin, Xinru; Liu, Jin; Wu, Shengwang; Wan, Jingyuan; Gong, Xia"

作者地址："[Hu, Jun; Du, Hui; Yang, Junxia; Wan, Jingyuan] Chongqing Med Univ, Dept Pharmacol, Chongqing, Peoples R China; [Yuan, Yinglin] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Clin Immunol Translat Med Key Lab Sichuan Prov, Chengdu, Peoples R China; [Guo, Peipei] Army Med Univ, Xinqiao Hosp, Dept Clin Lab, Chongqing, Peoples R China; [Yin, Xinru] Army Med Univ, Daping Hosp, Inst Surg Res, Dept Gastroenterol, Chongqing, Peoples R China; [Liu, Jin] Chongqing Ninth Peoples Hosp, Dept Pharm, Chongqing, Peoples R China; [Wu, Shengwang; Gong, Xia] Chongqing Med Univ, Dept Anat, Chongqing, Peoples R China; [Wu, Shengwang] Army Med Univ, Xinqiao Hosp, Dept Hematol, Chongqing, Peoples R China"

通信作者："Wan, JY (通讯作者)，Chongqing Med Univ, Dept Pharmacol, Chongqing, Peoples R China.; Gong, X (通讯作者)，Chongqing Med Univ, Dept Anat, Chongqing, Peoples R China."

来源：MEDIATORS OF INFLAMMATION

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000820888600002

JCR分区：Q3

影响因子：4.6

年份：2022

卷号：2022

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Nonalcoholic steatohepatitis (NASH) is the common liver disease characterized by hepatic steatosis, inflammation, and fibrosis; there are no approved drugs to treat this disease because of incomplete understanding of pathophysiological mechanisms of NASH. Milk fat globule-epidermal growth factor-factor 8 (MFG-E8), a multifunctional glycoprotein, has shown anti-inflammation and antifibrosis. Here, MFG-E8 was shown to play a key role in NASH progression. Using methionine and choline deficient (MCD) diet-fed mice, we found MFG-E8 knockout exacerbated hepatic damage and steatosis as indicated by increased plasma transaminases activities and hepatic histopathologic change, higher hepatic triglycerides (TGs), and lipid accumulation. Moreover, liver fibrosis and inflammation elicited by MCD were aggravated in MFG-E8 knockout mice. Mechanistically, MFG-E8 knockout facilitated activation of hepatic toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-kappa B) signaling pathway in MCD-fed mice. In vitro experiment, the TLR4 specific antagonist TAK-242 rescued palmitic acid- (PA-) primed lipid formation and inflammation in MFG-E8 knockout primary murine hepatocytes. These findings indicated that MFG-E8 is involved in the progression of NASH and the possible mechanism by which MFG-E8 knockout exacerbated NASH in mice is associated with activation of the TLR4/NF-kappa B signaling pathway."

基金机构：National Natural Science Foundation of China [81600455]

基金资助正文："We thank Dr. Wei Huang, Tongji Medical College, Huazhong University of Science and Technology, for animal and experiment technical support. This work was supported by the grant from the National Natural Science Foundation of China (grant number 81600455)."