Macrophage SCAP Contributes to Metaflammation and Lean NAFLD by Activating STING-NF-kappa B Signaling Pathway

作者全名："Huang, Xinyu; Yao, Yingcheng; Hou, Xiaoli; Wei, Li; Rao, Yuhan; Su, Yu; Zheng, Guo; Ruan, Xiong Z.; Li, Danyang; Chen, Yaxi"

作者地址："[Huang, Xinyu; Yao, Yingcheng; Hou, Xiaoli; Wei, Li; Rao, Yuhan; Su, Yu; Zheng, Guo; Ruan, Xiong Z.; Li, Danyang; Chen, Yaxi] Chongqing Med Univ, Affiliated Hosp 2, Ctr Lipid Res, Chongqing 400016, Peoples R China; [Huang, Xinyu; Yao, Yingcheng; Hou, Xiaoli; Wei, Li; Rao, Yuhan; Su, Yu; Zheng, Guo; Ruan, Xiong Z.; Li, Danyang; Chen, Yaxi] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Minist Educ,Key Lab Mol Biol Infe, Chongqing 400016, Peoples R China; [Ruan, Xiong Z.] UCL, John Moorhead Res Lab, Ctr Nephrol, Med Sch, Royal Free Campus, London, England"

通信作者："Li, DY; Chen, YX (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Ctr Lipid Res, Chongqing 400016, Peoples R China.; Li, DY; Chen, YX (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Minist Educ,Key Lab Mol Biol Infe, Chongqing 400016, Peoples R China."

来源：CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000832817400001

JCR分区：Q1

影响因子：7.2

年份：2022

卷号：14

期号：1

开始页：1

结束页：26

文献类型：Article

关键词：Lean NAFLD; SCAP; Paigen Diet; Metaflammation; STING-NF-kappa B Pathway

摘要："BACKGROUND & AIMS: Sterol regulatory element binding protein cleavage-activating protein (SCAP) is a cholesterol sensor that confers a broad range of functional effects in metabolic diseases. Lean nonalcoholic fatty liver disease (NAFLD) is characterized by a decrease in subcutaneous fat and ectopic fat deposition in the liver. SCAP may mediate the development of lean NAFLD, but the mechanism of action remains unclear. METHODS: C57BL/6J wild-type and macrophage SCAP-specific knockout mice (SCAP(Delta M phi)) were subjected to Paigen diet (PD) feeding induced lean NAFLD. Inflammation and lipid metabolism of adipose and liver were evaluated. The STING-NF-kappa B signaling pathway was examined in vivo and in vitro to explore the underlying mechanism of macrophage SCAP on metaflammation. RESULTS: The data showed heterogeneity of lipid metabolic processes in liver and epididymal white adipose tissue due to inflammation mediated by macrophage infiltration. Meanwhile, we found that the macrophage SCAP was abnormally increased in the adipose and liver tissues of PD-fed mice. Intriguingly, the SCAP(Delta M phi) mice attenuated PD-induced metaflammation and ectopic lipid deposition by reducing hepatic stimulator of interferon gene (STING)-nuclear factor kappa B (NF-kappa B) pathway activation. In-depth molecular analysis revealed that SCAP specifically recruits the STING and tank-binding kinase 1 onto the Golgi to activate the NF-kappa B in macrophages, thereby promoting the release of inflammatory factors. This process ultimately led to an increased lipolysis in adipocytes and lipid uptake and synthesis in hepatocytes. CONCLUSIONS: Our findings suggest that SCAP acts as a novel regulator of the macrophage inflammatory response and the pathogenesis of lean NAFLD by activating the STING-NF-kappa B signaling pathway. Inhibition of macrophage SCAP may represent a new therapeutic strategy for the treatment of lean NAFLD."

基金机构："National Natural Science Foundation of China [82170586, 81900406]; Chongqing Research Program of Basic Research and Frontier Technology [cstc2020jcyj-zdxmX0007]; China Postdoctoral Science Foundation [2019M663448]; Natural Science Foundation of Chongqing Province [CSTC2019JCYJ-BSHX0094]; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University; 111 Project [D20028]"

基金资助正文："Supported by the National Natural Science Foundation of China (82170586, 81900406) ; the Chongqing Research Program of Basic Research and Frontier Technology (cstc2020jcyj-zdxmX0007) ; the China Postdoctoral Science Foundation (Grant No.2019M663448) ; the Natural Science Foundation of Chongqing Province (Grant No. CSTC2019JCYJ-BSHX0094) ; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University; and the 111 Project (No. D20028) ."