Protein Phosphatase 4 Promotes Hepatocyte Lipoapoptosis by Regulating RAC1/MLK3/JNK Pathway

被引：3

作者：

Huang, Xiuqing ^{[1
,2
]}

Yang, Guang ^{[1
,2
]}

Zhao, Li ^{[3
]}

Yuan, Huiping ^{[1
,2
]}

Chen, Hao ^{[1
,2
]}

Shen, Tao ^{[1
,2
]}

Tang, Weiqing ^{[1
,2
]}

Man, Yong ^{[1
,2
]}

Ma, Jiarui ^{[1
,2
]}

Ma, Yanyan ^{[4
]}

Dou, Lin ^{[1
,2
]}

Li, Jian ^{[1
,2
]}

机构：

[1] Chinese Acad Med Sci, Beijing Hosp, Natl Ctr Gerontol, Natl Hlth Commiss,Key Lab Geriatr,Beijing Inst Ge, Beijing 100730, Peoples R China

[2] Chinese Acad Med Sci, Inst Geriatr Med, Beijing 100730, Peoples R China

[3] Chinese Acad Med Sci, Beijing Hosp, Natl Ctr Gerontol, Inst Geriatr Med,Dept Gastroenterol, Beijing 100730, Peoples R China

[4] Qinghai Univ, Dept Sci Res, Affiliated Hosp, Xining 810001, Peoples R China

来源：

OXIDATIVE MEDICINE AND CELLULAR LONGEVITY | 2021年 / 2021卷

基金：

国家重点研发计划; 北京市自然科学基金; 中国国家自然科学基金;

关键词：

NONALCOHOLIC STEATOHEPATITIS; KINASE; ROLES; PHOSPHORYLATION; LIPOTOXICITY; MIGRATION; RAC1;

D O I：

10.1155/2021/5550498

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Lipotoxicity-induced apoptosis, also referred to as lipoapoptosis, is one of the important initial factors promoting the progression from hepatosteatosis to nonalcoholic steatohepatitis (NASH). Saturated free fatty acids (SFAs), which are increased significantly in NASH, are directly hepatotoxic which induce hepatocyte lipoapoptosis. Previously, we reported that protein phosphatase 4 (PP4) was a novel regulator of hepatic insulin resistance and lipid metabolism, but its role in hepatic lipoapoptosis remains unexplored. In this study, we found out that PP4 was upregulated in the livers of western diet-fed-induced NASH mice and SFA-treated murine primary hepatocytes and HepG2 cells. In addition, we found for the first time that suppression of PP4 decreased SFA-induced JNK activation and expression of key modulators of hepatocyte lipoapoptosis including p53-upregulated modulator of apoptosis (PUMA) and Bcl-2-interacting mediator (Bim) and reduced hepatocyte lipoapoptosis level as well both in vitro and in vivo. Further study revealed that PP4 induced JNK activation and lipoapoptosis-related protein expression by regulating the RAC1/MLK3 pathway instead of the PERK/CHOP pathway. The effects of palmitate-treated and PP4-induced lipoapoptosis pathway activation were largely abolished by RAC1 inhibition. Moreover, we identified that PP4 interacted with RAC1 and regulated GTPase activity of RAC1. In conclusion, these results demonstrated that PP4 was a novel regulator of hepatocyte lipoapoptosis and mediated hepatocyte lipoapoptosis by regulating the RAC1/MLK3/JNK signaling pathway. Our finding provided new insights into the mechanisms of this process.

引用

页数：16