Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London, London, United Kingdom.
Cell Mol Gastroenterol Hepatol. 2022;14(1):1-26. doi: 10.1016/j.jcmgh.2022.03.006. Epub 2022 Mar 31.
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.
C57BL/6J wild-type and macrophage SCAP-specific knockout mice (SCAP) were subjected to Paigen diet (PD) feeding induced lean NAFLD. Inflammation and lipid metabolism of adipose and liver were evaluated. The STING-NF-κB signaling pathway was examined in vivo and in vitro to explore the underlying mechanism of macrophage SCAP on metaflammation.
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 mice attenuated PD-induced metaflammation and ectopic lipid deposition by reducing hepatic stimulator of interferon gene (STING)-nuclear factor kappa B (NF-κB) 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-κB 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.
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-κB signaling pathway. Inhibition of macrophage SCAP may represent a new therapeutic strategy for the treatment of lean NAFLD.
固醇调节元件结合蛋白裂解激活蛋白（SCAP）是一种胆固醇传感器，它在代谢性疾病中赋予广泛的功能效应。瘦型非酒精性脂肪性肝病（NAFLD）的特征是皮下脂肪减少和肝脏异位脂肪沉积。SCAP 可能介导瘦型 NAFLD 的发生，但作用机制尚不清楚。
C57BL/6J 野生型和巨噬细胞 SCAP 特异性敲除小鼠（SCAP）接受派根饮食（PD）喂养诱导瘦型 NAFLD。评估脂肪和肝脏的炎症和脂质代谢。在体内和体外研究 STING-NF-κB 信号通路，以探讨巨噬细胞 SCAP 对代谢炎症的潜在作用机制。
数据显示，由于巨噬细胞浸润介导的炎症，肝脏和附睾白色脂肪组织中的脂质代谢过程存在异质性。同时，我们发现 PD 喂养小鼠的脂肪和肝脏组织中巨噬细胞 SCAP 异常增加。有趣的是，SCAP 小鼠通过减少肝干扰素基因刺激物（STING）-核因子 kappa B（NF-κB）通路的激活，减轻 PD 诱导的代谢炎症和异位脂质沉积。深入的分子分析表明，SCAP 特异性地将 STING 和 tank-binding kinase 1 募集到高尔基体内以激活巨噬细胞中的 NF-κB，从而促进炎症因子的释放。这个过程最终导致脂肪细胞中的脂肪分解增加，以及肝细胞中的脂质摄取和合成增加。
我们的研究结果表明，SCAP 通过激活 STING-NF-κB 信号通路，作为巨噬细胞炎症反应和瘦型 NAFLD 发病机制的新型调节剂。抑制巨噬细胞 SCAP 可能代表治疗瘦型 NAFLD 的一种新的治疗策略。
