Tim4在調(diào)節(jié)ABCA1+脂肪組織巨噬細(xì)胞和餐后膽固醇水平中的作用

中文摘要：

血脂異常是心血管疾病的主要驅(qū)動因素。巨噬細(xì)胞清除過量脂質(zhì)的能力使其在這一過程中的作用愈加重要，理解巨噬細(xì)胞脂質(zhì)代謝的機(jī)制是開發(fā)新治療方法的關(guān)鍵。在這項研究中，我們探討了脂肪組織巨噬細(xì)胞如何調(diào)節(jié)餐后膽固醇運(yùn)輸。單細(xì)胞RNA測序和保護(hù)性骨髓嵌合體展示了脂質(zhì)攝入導(dǎo)致一群表達(dá)Lyve1、Tim4和ABCA1的駐留巨噬細(xì)胞特異性轉(zhuǎn)錄激活。阻斷磷脂酰絲氨酸受體Tim4抑制了溶酶體激活以及高脂餐后高密度脂蛋白膽固醇的釋放。這兩種效應(yīng)均可通過氯喹重現(xiàn)，這是一種溶酶體功能抑制劑。此外，荷蘭氯膦酸鹽脂質(zhì)體介導(dǎo)的巨噬細(xì)胞耗竭提示Tim4駐留脂肪組織巨噬細(xì)胞在此過程中的作用。因此，這些數(shù)據(jù)顯示Tim4是餐后膽固醇運(yùn)輸和脂肪組織巨噬細(xì)胞功能的關(guān)鍵調(diào)節(jié)因子，并可能代表治療血脂異常的新途徑。

英文摘要：

Dyslipidemia is a main driver of cardiovascular diseases. The ability of macrophages to scavenge excess lipids implicate them as mediators in this process and understanding the mechanisms underlying macrophage lipid metabolism is key to the development of new treatments. Here, we investigated how adipose tissue macrophages regulate post-prandial cholesterol transport. Single-cell RNA sequencing and protected bone marrow chimeras demonstrated that ingestion of lipids led to specific transcriptional activation of a population of resident macrophages expressing Lyve1, Tim4, and ABCA1. Blocking the phosphatidylserine receptor Tim4 inhibited lysosomal activation and the release of post-prandial high density lipoprotein cholesterol following a high fat meal. Both effects were recapitulated by chloroquine, an inhibitor of lysosomal function. Moreover, clodronate-mediated cell-depletion implicated Tim4+ resident adipose tissue macrophages in this process. Thus, these data indicate that Tim4 is a key regulator of post-prandial cholesterol transport and adipose tissue macrophage function and may represent a novel pathway to treat dyslipidemia.

論文信息：

論文題目：Role of Tim4 in the regulation of ABCA1+ adipose tissue macrophages and post-prandial cholesterol levels

期刊名稱：Nature Communications

時間期卷：12, Article number: 4434 (2021)

在線時間：2021年7月21日

DOI：doi.org/10.1038/s41467-021-24684-7

產(chǎn)品信息：

貨號：C-010

規(guī)格：10ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes

辦事處：Target Technology(靶點科技)

Clodronate Liposomes氯膦酸鹽脂質(zhì)體清除肝臟和腹腔巨噬細(xì)胞，疾病模型為：高脂肪誘導(dǎo)的肥胖模型。脂肪組織（AT）的主要功能是儲存脂質(zhì)以建立能量儲備；脂肪細(xì)胞專業(yè)化于攝取膳食脂質(zhì)并將其儲存為甘油三酯（TGs）。在以低熱量食物為主的飲食背景下，一頓特別豐富的脂質(zhì)，因此成為脂肪細(xì)胞增加其TG儲存的生理機(jī)會。盡管對脂肪組織巨噬細(xì)胞（ATMs）在肥胖代謝適應(yīng)中的作用的理解日益加深，關(guān)于ATMs在脂質(zhì)富含的餐后脂質(zhì)代謝和脂肪儲存調(diào)節(jié)中的作用卻知之甚少。荷蘭Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes見刊于Nature Communications：Tim4在調(diào)節(jié)ABCA1⁺脂肪組織巨噬細(xì)胞和餐后膽固醇水平中的作用。

Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體的材料和方法：

Cell depletion

Mice were kept on control diet (11?kcal%Fat and corn starch, Research diet, D12328i). For overnight high fat feeding, mice were given HFD (58Kcal%Fat and sucrose, Research diet, D12331i) at 4 p.m. and were culled the next morning at 9 a.m. For Tim4 blocking, mice were i.p. injected, 72?h and on the day prior to the overnight HFD, with 100?μl of phosphate-buffered saline (PBS) containing either 200?μg of anti-Tim4 IgG2a (clone RMT4-53, Rat IgG2a, BE0171, BioXCell) or 200?μg of rat IgG2a control (BE0089, BioXCell). Mice were injected i.p. with 1?mg of chloroquine (Sigma) in 200?μl of PBS 72?h and on the day prior to the overnight HFD. Mice were injected with 200?μg clodronate liposomes (Liposoma, the Netherlands) in 200?μl PBS 48?h prior to overnight HFD.

材料和方法文獻(xiàn)截圖：