Fatty acid synthesis is indispensable for Kupffer cells to eliminate bacteria in ALD progression.

IF 8.3 2区材料科学 Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY ACS Applied Materials & Interfaces Pub Date : 2024-08-26 eCollection Date: 2024-09-01 DOI:10.1097/HC9.0000000000000522

Liuyu Xie, Beng Wu, Yuanyuan Fan, Ye Tao, Xiaoyong Jiang, Qing Li, Huaiping Zhu, Hua Wang, Chaojie Hu

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Abstract

Background: Dysregulated fatty acid metabolism is closely linked to the development of alcohol-associated liver disease (ALD). KCs, which are resident macrophages in the liver, play a critical role in ALD pathogenesis. However, the effect of alcohol on fatty acid metabolism in KCs remains poorly understood. The current study aims to investigate fatty acid metabolism in KCs and its potential effect on ALD development.

Methods: Wild-type C57BL/6 mice were fed a Lieber-DeCarli ethanol liquid diet for 3 days. Then, the liver injury and levels of intrahepatic bacteria were assessed. Next, we investigated the effects and underlying mechanisms of ethanol exposure on fatty acid metabolism and the phagocytosis of KCs, both in vivo and in vitro. Finally, we generated KCs-specific Fasn knockout and overexpression mice to evaluate the impact of FASN on the phagocytosis of KCs and ethanol-induced liver injury.

Results: Using Bodipy493/503 to stain intracellular neutral lipids, we found significantly reduced lipid levels in KCs from mice fed an alcohol-containing diet for 3 days and in RAW264.7 macrophages exposed to ethanol. Mechanistically, alcohol exposure suppressed sterol regulatory element-binding protein 1 transcriptional activity, thereby inhibiting fatty acid synthase (FASN)-mediated de novo lipogenesis in macrophages both in vitro and in vivo. We show that genetic ablation and pharmacologic inhibition of FASN significantly impaired KC's ability to take up and eliminate bacteria. Conversely, KCs-specific Fasn overexpression reverses the impairment of macrophage phagocytosis caused by alcohol exposure. We also revealed that KCs-specific Fasn knockout augmented KCs apoptosis and exacerbated liver injury in mice fed an alcohol-containing diet for 3 days.

Conclusions: Our findings indicate the crucial role of de novo lipogenesis in maintaining effective KCs phagocytosis and suggest a therapeutic target for ALD based on fatty acid synthesis in KCs.

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脂肪酸合成是 Kupffer 细胞在 ALD 进展过程中消灭细菌所不可或缺的。

背景：脂肪酸代谢失调与酒精相关性肝病（ALD）的发生密切相关。KCs是肝脏中的常驻巨噬细胞，在ALD发病机制中起着至关重要的作用。然而，人们对酒精对 KC 脂肪酸代谢的影响仍然知之甚少。本研究旨在调查 KCs 中的脂肪酸代谢及其对 ALD 发病的潜在影响：方法：给野生型 C57BL/6 小鼠喂食 Lieber-DeCarli 乙醇流质饮食 3 天。然后，评估肝损伤和肝内细菌水平。接着，我们在体内和体外研究了乙醇暴露对脂肪酸代谢和 KCs 吞噬的影响及其潜在机制。最后，我们产生了 KCs 特异性 Fasn 敲除和过表达小鼠，以评估 FASN 对 KCs 吞噬和乙醇诱导的肝损伤的影响：结果：利用Bodipy493/503对细胞内中性脂质进行染色，我们发现喂食含酒精食物3天的小鼠的KCs和暴露于乙醇的RAW264.7巨噬细胞中的脂质水平显著降低。从机理上讲，酒精暴露抑制了固醇调节元件结合蛋白 1 的转录活性，从而抑制了体外和体内巨噬细胞中脂肪酸合成酶（FASN）介导的新脂肪生成。我们的研究表明，对 FASN 的基因消减和药物抑制显著削弱了 KC 吸收和消灭细菌的能力。相反，KCs 特异性 Fasn 的过表达可逆转酒精暴露对巨噬细胞吞噬能力的损害。我们还发现，KCs特异性Fasn敲除会增加KCs的凋亡，并加剧小鼠在含酒精饮食中3天的肝损伤：我们的研究结果表明，新脂肪生成在维持有效的 KCs 吞噬功能中起着至关重要的作用，并提出了一种基于 KCs 中脂肪酸合成的 ALD 治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Applied Materials & Interfaces 工程技术-材料科学：综合

CiteScore

16.00

自引率

6.30%

发文量

4978

审稿时长

1.8 months

期刊介绍： ACS Applied Materials & Interfaces is a leading interdisciplinary journal that brings together chemists, engineers, physicists, and biologists to explore the development and utilization of newly-discovered materials and interfacial processes for specific applications. Our journal has experienced remarkable growth since its establishment in 2009, both in terms of the number of articles published and the impact of the research showcased. We are proud to foster a truly global community, with the majority of published articles originating from outside the United States, reflecting the rapid growth of applied research worldwide.