El-Sabawi Bassim, Tanriverdi Kahraman, Gajjar Priya, Nayor Matthew, Landman Joshua M, Below Jennifer E, Haff Madeleine, Long Michelle, Ezpeleta Mark, Freedman Jane E, Varady Krista, Shah Ravi, Perry Andrew S
Vanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University School of Medicine Nashville TN USA.
Sections of Cardiovascular Medicine and Preventive Medicine and Epidemiology, Department of Medicine Boston University School of Medicine Boston MA USA.
J Am Heart Assoc. 2025 May 20;14(10):e037100. doi: 10.1161/JAHA.124.037100. Epub 2025 May 15.
Weight reduction through lifestyle, activity, and dietary interventions are the mainstay of initial therapy for metabolic dysfunction associated steatotic liver disease. Data on the relative effectiveness and metabolic pathways linking weight loss and decreased hepatic steatosis are lacking. We sought to identify coordinated changes between the circulating proteome and hepatic steatosis within a randomized clinical trial of alternate day fasting and exercise and prioritize proteins relevant to hepatic steatosis within a broader context using a community cohort.
We quantified a broad cardiometabolic proteome (>300 proteins) in 67 individuals randomized in a 2×2 factorial design to alternate day fasting and exercise before and after the 3-month intervention to identify proteomic signatures of hepatic steatosis (measured by magnetic resonance imaging proton density fat fraction). Then, we analyzed the cross-sectional relationship of overlapping proteins (≈170) with hepatic attenuation (a computed tomographic technique linked to steatosis) in 707 participants from a community cohort. Principal component analysis demonstrated a proteomic signature associated with intrahepatic triglyceride content (Spearman rho=0.55, <0.001) and insulin resistance (homeostatic model assessment for insulin resistance, Spearman rho=0.39, =0.001). Changes in this proteomic signature were associated with changes in intrahepatic triglyceride content over the intervention period (beta=0.12, <0.001). Moreover, cross-sectional analysis of overlapping proteins with hepatic attenuation in the community cohort showed generally, directionally consistent associations with hepatic steatosis.
These findings highlight the potential for broad proteomic profiling in small nutritional interventional studies with serial phenotyping alongside confirmatory large cohort epidemiology to prioritize targets of hepatic steatosis and cardiometabolic risk for mechanistic study.
通过生活方式、运动和饮食干预减轻体重是代谢功能障碍相关脂肪性肝病初始治疗的主要方法。目前缺乏关于减肥与肝脂肪变性减轻之间相对有效性及代谢途径的数据。我们试图在隔日禁食和运动的随机临床试验中，确定循环蛋白质组与肝脂肪变性之间的协同变化，并在更广泛的背景下，利用社区队列确定与肝脂肪变性相关的蛋白质的优先级。
我们对67名个体进行了广泛的心脏代谢蛋白质组（>300种蛋白质）定量分析，这些个体按2×2析因设计随机分组，在3个月干预前后进行隔日禁食和运动，以确定肝脂肪变性的蛋白质组特征（通过磁共振成像质子密度脂肪分数测量）。然后，我们分析了来自社区队列的707名参与者中重叠蛋白质（约170种）与肝脏衰减（一种与脂肪变性相关的计算机断层扫描技术）的横断面关系。主成分分析显示了一种与肝内甘油三酯含量（斯皮尔曼相关系数ρ=0.55，P<0.001）和胰岛素抵抗（胰岛素抵抗稳态模型评估，斯皮尔曼相关系数ρ=0.39，P=0.001）相关的蛋白质组特征。在干预期间，这种蛋白质组特征的变化与肝内甘油三酯含量的变化相关（β=0.12，P<0.001）。此外，在社区队列中对重叠蛋白质与肝脏衰减的横断面分析显示，总体上与肝脂肪变性的关联在方向上是一致的。
这些发现突出了在小型营养干预研究中进行广泛蛋白质组分析的潜力，该研究采用系列表型分析，并结合大型队列流行病学验证，以确定肝脂肪变性的靶点和心脏代谢风险，用于机制研究。
