<i>N</i>-glycosylation of SCAP exacerbates hepatocellular inflammation and lipid accumulation via ACSS2-mediated histone H3K27 acetylation

作者全名：Li, Xuemei; Tang, Xiaoqin; Xiang, Yue; Zhao, Zhibo; Li, Yanping; Ding, Qiuying; Zhang, Linkun; Xu, Jingyuan; Zhao, Lei; Chen, Yao

作者地址：[Li, Xuemei; Tang, Xiaoqin; Xiang, Yue; Zhao, Zhibo; Li, Yanping; Ding, Qiuying; Zhang, Linkun; Xu, Jingyuan; Zhao, Lei] Chongqing Med Univ, Affiliated Hosp 2, Ctr Lipid Res, Chongqing, Peoples R China; [Li, Xuemei; Tang, Xiaoqin; Xiang, Yue; Zhao, Zhibo; Li, Yanping; Ding, Qiuying; Zhang, Linkun; Xu, Jingyuan; Zhao, Lei] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect,Minist Educ,Key Lab Mol Biol Infect Di, Chongqing, Peoples R China; [Chen, Yao] Chongqing Med Univ, Affiliated Hosp 2, Ctr Hlth Med, Chongqing, Peoples R China

通信作者：Zhao, L (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Ctr Lipid Res, Chongqing, Peoples R China.; Zhao, L (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect,Minist Educ,Key Lab Mol Biol Infect Di, Chongqing, Peoples R China.; Chen, Y (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Ctr Hlth Med, Chongqing, Peoples R China.

来源：AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001241757000006

JCR分区：Q1

影响因子：3.9

年份：2024

卷号：326

期号：6

开始页：G697

结束页：G711

文献类型：Article

关键词：acetyl-CoA synthetase 2; histone acetylation; NASH; N-glycosylation modification; SCAP

摘要：Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a widely expressed membrane glycoprotein that acts as an important modulator of lipid metabolism and inflammatory stress. N-glycosylation of SCAP has been suggested to modulate cancer development, but its role in nonalcoholic steatohepatitis (NASH) is poorly understood. In this study, the N-glycosylation of SCAP was analyzed by using sequential trypsin proteolysis and glycosidase treatment. The liver cell lines expressing wild-type and N-glycosylation sites mutated SCAP were constructed to investigate the N-glycosylation role of SCAP in regulating inflammation and lipid accumulation as well as the underlying mechanisms. The hepatic SCAP protein levels were significantly increased in C57BL/6J mice fed with Western diet and sugar water (WD + SW) and diabetic db/db mice, which exhibited typical liver steatosis and inflammation accompanied with hyperglycemia. In vitro, the enhanced N-glycosylation by high glucose increased the protein stability of SCAP and hence increased its total protein levels, whereas the ablation of N-glycosylation significantly decreased SCAP protein stability and alleviated lipid accumulation and inflammation in hepatic cell lines. Mechanistically, SCAP N-glycosylation increased not only the SREBP-1-mediated acetyl-CoA synthetase 2 (ACSS2) transcription but also the AMPK-mediated S659 phosphorylation of ACCS2 protein, causing the enhanced ACSS2 levels in nucleus and hence increasing the histone H3K27 acetylation (H3K27ac), which is a key epigenetic modification associated with NASH. Modulating ACSS2 expression or its location in the nuclear abolished the effects of SCAP N-glycosylation on H3K27ac and lipid accumulation and inflammation. In conclusion, SCAP N-glycosylation aggravates inflammation and lipid accumulation through enhancing ACSS2-mediated H3K27ac in hepatocytes.

基金机构：National Natural Science Foundation of China [82270608, 81970510, 82241040, 31971084]; Chongqing Natural Science Foundation [cstc2019jcyj-msxmX0336, cstc2021ycjh-bgzxm0146]

基金资助正文：This study was supported by grants from the National Natural Science Foundation of China (82270608, 81970510, 82241040, 31971084) and Chongqing Natural Science Foundation (cstc2019jcyj-msxmX0336, cstc2021ycjh-bgzxm0146).