Metabolic dysfunction–associated steatohepatitis (MASH) is regulated by complex interplay between the macrophages and surrounding cells in the liver. Here, we show that Atf3 regulates glucose-fatty acid cycle in macrophages attenuates hepatocyte steatosis, and fibrogenesis in hepatic stellate cells (HSCs). Overexpression of Atf3 in macrophages protects against the development of MASH in Western diet–fed mice, whereas Atf3 ablation has the opposite effect. Mechanistically, Atf3 improves the reduction of fatty acid oxidation induced by glucose via forkhead box O1 (FoxO1) and Cd36. Atf3 inhibits FoxO1 activity via blocking Hdac1-mediated FoxO1 deacetylation at K242, K245, and K262 and increases Zdhhc4/5-mediated CD36 palmitoylation at C3, C7, C464, and C466; furthermore, macrophage Atf3 decreases hepatocytes lipogenesis and HSCs activation via retinol binding protein 4 (Rbp4). Anti-Rbp4 can prevent MASH progression that is induced by Atf3 deficiency in macrophages. This study identifies Atf3 as a regulator of glucose-fatty acid cycle. Targeting macrophage Atf3 or Rbp4 may be a plausible therapeutic strategy for MASH.

中文翻译：

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Atf3介导的肝巨噬细胞代谢重编程协调代谢功能障碍相关的脂肪性肝炎


代谢功能障碍相关的脂肪性肝炎 (MASH) 受到肝脏中巨噬细胞和周围细胞之间复杂的相互作用的调节。在这里，我们发现 Atf3 调节巨噬细胞中的葡萄糖-脂肪酸循环，减轻肝细胞脂肪变性和肝星状细胞 (HSC) 中的纤维形成。 Atf3 在巨噬细胞中的过度表达可以防止西方饮食喂养的小鼠发生 MASH，而 Atf3 消除则具有相反的效果。从机制上讲，Atf3 通过叉头盒 O1 (FoxO1) 和 Cd36 改善葡萄糖诱导的脂肪酸氧化的减少。 Atf3 通过阻断 Hdac1 介导的 FoxO1 在 K242、K245 和 K262 处的脱乙酰化来抑制 FoxO1 活性，并增加 Zdhhc4/5 介导的 CD36 在 C3、C7、C464 和 C466 处的棕榈酰化；此外，巨噬细胞 Atf3 通过视黄醇结合蛋白 4 (Rbp4) 减少肝细胞脂肪生成和 HSC 活化。抗 Rbp4 可以阻止巨噬细胞中 Atf3 缺陷诱导的 MASH 进展。这项研究确定 Atf3 是葡萄糖-脂肪酸循环的调节剂。靶向巨噬细胞 Atf3 或 Rbp4 可能是 MASH 的一种可行的治疗策略。