Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult (scRNA-Seq). Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult (scRNA-Seq)

Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is initially responding site, or if atherogenic-dyslipidemia affects other organs simultaneously, is unknown. Here we show that the liver responds to a dyslipidemic insult based on inducible models of familial hypercholesterolemia and APOB tracing. An acute transition to atherogenic APOB-lipoprotein levels resulted in uptake by Kupffer cells and rapid accumulation of triglycerides and cholesterol in the liver. Bulk and single-cell RNA-seq revealed an Kupffer cell-specific transcriptional program that was not activated by a high-fat diet alone, or detected in standard liver function or pathological assays, even in the presence of fulminant atherosclerosis. Depletion of Kupffer cells altered the dynamic of plasma and liver lipid concentrations, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins, whilst simultaneously secreting atherosclerosis-modulating factors into plasma. Our results place Kupffer cells as key sentinels in organizing systemic responses to lipoproteins at the initiation of atherosclerosis. Overall design: Liver sample from D374YmCherry-APOB mice. Mice were maintained on a chow diet for 10 days after tamoxifen.

载脂蛋白B（APOB）组装的脂蛋白可引发动脉粥样硬化。目前尚不明确血管系统是否为最初的响应位点，抑或是致动脉粥样硬化性血脂异常会同时影响其他器官。本研究依托家族性高胆固醇血症诱导型模型与APOB示踪技术，证实肝脏可响应血脂异常刺激。当血浆APOB脂蛋白水平急性升高至致动脉粥样硬化性水平时，库普弗细胞（Kupffer cells）会摄取此类脂蛋白，并快速引发肝脏内甘油三酯与胆固醇蓄积。批量与单细胞RNA测序结果显示，存在一套库普弗细胞特异性转录程序，该程序既无法被单纯高脂饮食激活，也无法在标准肝功能或病理检测中被检出，即便此时已出现暴发性动脉粥样硬化。库普弗细胞耗竭会改变血浆与肝脏脂质浓度的动态变化，表明这类肝脏巨噬细胞能够辅助抑制并缓冲致动脉粥样硬化性脂蛋白，同时还会向血浆中分泌调控动脉粥样硬化的相关因子。本研究结果将库普弗细胞确立为动脉粥样硬化起始阶段，响应脂蛋白并调控全身应答的关键哨兵。总体实验设计：采集自D374YmCherry-APOB小鼠的肝脏样本。小鼠在他莫昔芬处理后，于普通饲料中饲养10天。