Department of Endocrinology, Diabetes and Nutrition, Hospital of Girona "Dr Josep Trueta", Departament de Ciències Mèdiques, University of Girona, Girona Biomedical Research Institute (IdibGi), Girona, Spain; CIBERobn Pathophysiology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain.
Department of Radiology, Diagnostic Imaging Institute (IDI), Dr Josep Trueta University Hospital, IDIBGI, Girona, Spain.
Clin Nutr. 2020 Nov;39(11):3408-3418. doi: 10.1016/j.clnu.2020.02.034. Epub 2020 Mar 8.
BACKGROUND & AIMS: Atherosclerosis is characterized by an inflammatory disease linked to excessive lipid accumulation in the artery wall. The Notch signalling pathway has been shown to play a key regulatory role in the regulation of inflammation. Recently, in vitro and pre-clinical studies have shown that apolipoprotein A-I binding protein (AIBP) regulates cholesterol metabolism (SREBP) and NOTCH signalling (haematopoiesis) and may be protective against atherosclerosis, but the evidence in humans is scarce.
We evaluated the APOA1bp-SREBF-NOTCH axis in association with atherosclerosis in two well-characterized cohorts of morbidly obese patients (n = 78) within the FLORINASH study, including liver transcriptomics, H NMR plasma metabolomics, high-resolution ultrasonography evaluating carotid intima-media thickness (cIMT), and haematological parameters.
The liver expression levels of APOA1bp were associated with lower cIMT and leukocyte counts, a better plasma lipid profile and higher circulating levels of metabolites associated with lower risk of atherosclerosis (glycine, histidine and asparagine). Conversely, liver SREBF and NOTCH mRNAs were positively associated with atherosclerosis, liver steatosis, an unfavourable lipid profile, higher leukocytes and increased levels of metabolites linked to inflammation and CVD such as branched-chain amino acids and glycoproteins. APOA1bp and NOTCH signalling also had a strong association, as revealed by the negative correlations among APOA1bp expression levels and those of all NOTCH receptors and jagged ligands.
We here provide the first evidence in human liver of the putative APOA1bp-SREBF-NOTCH axis signalling pathway and its association with atherosclerosis and inflammation.
动脉粥样硬化的特征是一种炎症性疾病，与动脉壁中脂质过度积累有关。 Notch 信号通路已被证明在调节炎症方面发挥着关键的调节作用。最近，体外和临床前研究表明载脂蛋白 A-I 结合蛋白（AIBP）调节胆固醇代谢（SREBP）和 Notch 信号（造血），并可能对动脉粥样硬化具有保护作用，但人类的证据很少。
我们在 FLORINASH 研究中对两个特征明确的病态肥胖患者队列（n=78）进行了 APOA1bp-SREBF-NOTCH 轴与动脉粥样硬化的相关性评估，包括肝转录组学、H NMR 血浆代谢组学、评估颈动脉内膜中层厚度（cIMT）的高分辨率超声以及血液学参数。
APOA1bp 的肝脏表达水平与较低的 cIMT 和白细胞计数、更好的血浆脂质谱和与较低动脉粥样硬化风险相关的循环代谢物水平（甘氨酸、组氨酸和天冬酰胺）相关。相反，肝 SREBF 和 NOTCH mRNAs 与动脉粥样硬化、肝脂肪变性、不利的脂质谱、较高的白细胞计数以及与炎症和 CVD 相关的代谢物水平升高（支链氨基酸和糖蛋白）呈正相关。APOA1bp 和 NOTCH 信号也有很强的相关性，这从 APOA1bp 表达水平与所有 NOTCH 受体和 jagged 配体的表达水平之间的负相关中可以看出。
我们首次在人类肝脏中提供了假定的 APOA1bp-SREBF-NOTCH 轴信号通路及其与动脉粥样硬化和炎症的关联的证据。
