Department of Clinical Laboratory, Division of Life Science and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, PR China.
School of Pharmacy, Anhui Medical University, Hefei, China.
Hepatol Commun. 2024 Aug 26;8(9). doi: 10.1097/HC9.0000000000000522. eCollection 2024 Sep 1.
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.
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.
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.
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.
脂肪酸代谢失调与酒精相关性肝病（ALD）的发生发展密切相关。肝内驻留巨噬细胞库普弗细胞（KCs）在 ALD 的发病机制中起关键作用。然而，酒精对 KCs 中脂肪酸代谢的影响仍知之甚少。本研究旨在探讨 KCs 中的脂肪酸代谢及其对 ALD 发展的潜在影响。
采用野生型 C57BL/6 小鼠给予 Lieber-DeCarli 乙醇液体饮食 3 天，评估肝损伤和肝内细菌水平。然后，我们研究了乙醇暴露对 KCs 脂肪酸代谢和吞噬作用的影响及其潜在机制，包括体内和体外研究。最后，我们构建了 KCs 特异性 Fasn 敲除和过表达小鼠，以评估 FASN 对 KCs 吞噬作用和乙醇诱导的肝损伤的影响。
使用 Bodipy493/503 染色细胞内中性脂质，我们发现，给予含酒精饮食 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明显降低。在机制上，酒精暴露抑制固醇调节元件结合蛋白 1 的转录活性，从而抑制体外和体内巨噬细胞中脂肪酸合酶（FASN）介导的从头脂肪生成。我们表明，FASN 的遗传缺失和药理学抑制显著损害了 KCs 摄取和清除细菌的能力。相反，KCs 特异性 Fasn 过表达逆转了酒精暴露对巨噬细胞吞噬作用的损害。我们还揭示了 KCs 特异性 Fasn 敲除增强了 KCs 在给予含酒精饮食 3 天的小鼠中的细胞凋亡并加重了肝损伤。
我们的研究结果表明，从头脂肪生成在维持有效的 KCs 吞噬作用中起关键作用，并提示基于 KCs 中脂肪酸合成的 ALD 治疗靶点。
