Pagano Sabrina, Bakker Stephan J L, Juillard Catherine, Vossio Stefania, Moreau Dimitri, Brandt Karim J, Mach François, Dullaart Robin P F, Vuilleumier Nicolas
Division of Laboratory Medicine, Diagnostics Department, Geneva University Hospitals, Rue Michel Servet 1, 1211, Geneva, Switzerland.
Department of Medicine Specialties, Medical Faculty, Geneva University, Geneva, Switzerland.
J Transl Med. 2023 Oct 5;21(1):694. doi: 10.1186/s12967-023-04569-7.
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease increasing cardiovascular disease (CVD) morbidity and mortality. Autoantibodies against apolipoprotein A-1 (AAA-1) are a possible novel CVD risk factor promoting inflammation and disrupting cellular lipid homeostasis, two prominent pathogenic features of NAFLD. We explored the role of AAA-1 in NAFLD and their association with CVD risk.
HepaRG cells and liver sections from ApoE-/- mice exposed to AAA-1 were used for lipid quantification and conditional protein expression. Randomly selected sera from 312 subjects of the Prevention of Renal and Vascular End-stage Disease (PREVEND) general population cohort were used to measure AAA-1. A Fatty Liver Index (FLI) ≥ 60 and a 10-year Framingham Risk Score (FRS) ≥ 20% were used as proxy of NAFLD and high CVD risk, respectively.
In-vitro and mouse models showed that AAA-1 increased triglyceride synthesis leading to steatosis, and promoted inflammation and hepatocyte injury. In the 112 PREVEND participants with FLI ≥ 60, AAA-1 were associated with higher FRS, alkaline phosphatase levels, lower HDL cholesterol and tended to display higher FLI values. Univariate linear and logistic regression analyses (LRA) confirmed significant associations between AAA-1, FLI and FRS ≥ 20%, while in adjusted LRA, FLI was the sole independent predictor of FRS ≥ 20% (OR: 1.05, 95%CI 1.01-1.09, P = 0.003). AAA-1 was not an independent FLI predictor.
AAA-1 induce a NAFLD-compatible phenotype in vitro and in mice. Intricate associations exist between AAA-1, CVD risk and FLI in the general population. Further work is required to refine the role of AAA-1 in NAFLD and to determine if the AAA-1 association with CVD is affected by hepatic steatosis.
非酒精性脂肪性肝病（NAFLD）是一种常见的肝脏疾病，会增加心血管疾病（CVD）的发病率和死亡率。抗载脂蛋白A-1自身抗体（AAA-1）是一种可能的新型心血管疾病风险因素，可促进炎症并破坏细胞脂质稳态，这是NAFLD的两个突出致病特征。我们探讨了AAA-1在NAFLD中的作用及其与心血管疾病风险的关联。
使用暴露于AAA-1的HepaRG细胞和ApoE-/-小鼠的肝脏切片进行脂质定量和条件性蛋白表达分析。从预防终末期肾病和血管疾病（PREVEND）普通人群队列的312名受试者中随机选取血清来检测AAA-1。脂肪肝指数（FLI）≥60和10年弗明汉风险评分（FRS）≥20%分别用作NAFLD和高心血管疾病风险的替代指标。
体外和小鼠模型显示，AAA-1增加甘油三酯合成导致脂肪变性，并促进炎症和肝细胞损伤。在112名FLI≥60的PREVEND参与者中，AAA-1与更高的FRS、碱性磷酸酶水平、更低的高密度脂蛋白胆固醇相关，并且倾向于表现出更高的FLI值。单变量线性和逻辑回归分析（LRA）证实了AAA-1、FLI和FRS≥20%之间存在显著关联，而在调整后的LRA中，FLI是FRS≥20%的唯一独立预测因子（OR：1.05，95%CI 1.01-1.09，P = 0.003）。AAA-1不是FLI的独立预测因子。
AAA-1在体外和小鼠中诱导出与NAFLD相符的表型。在普通人群中，AAA-1、心血管疾病风险和FLI之间存在复杂的关联。需要进一步的研究来明确AAA-1在NAFLD中的作用，并确定AAA-1与心血管疾病的关联是否受肝脂肪变性影响。
