Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, 44272, USA.
Department of Internal Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, 85004, USA.
Commun Biol. 2024 Oct 10;7(1):1300. doi: 10.1038/s42003-024-06915-x.
The crosstalk between adipose tissue and the liver is finely controlled to maintain metabolic health. Yet, how adipose tissue controls toxic free fatty acid overflow into the liver remains incompletely understood. Here, we show that adipocyte activating transcription factor 3 (ATF3) was induced in human or mouse obesity. Adipocyte Atf3 (Atf3) mice developed obesity, glucose intolerance, and metabolic dysfunction-associated steatohepatitis (MASH) in chow diet, high-fat diet, or Western diet-fed mice. Blocking fatty acid flux by inhibiting hepatocyte CD36, but not the restoration of hepatic AMPK signaling, prevented the aggravation of MASH in Atf3 mice. Further studies show that the loss of adipocyte ATF3 increased lipolysis via inducing adipose triglyceride lipase, which in turn induced lipogenesis and inflammation in hepatocytes. Moreover, Atf3 mice had reduced energy expenditure and increased adipose lipogenesis and inflammation. Our data demonstrate that adipocyte ATF3 is a gatekeeper in counteracting MASH development under physiological and pathological conditions.
脂肪组织和肝脏之间的串扰受到精细调控，以维持代谢健康。然而，脂肪组织如何控制有毒游离脂肪酸溢出到肝脏仍不完全清楚。在这里，我们表明脂肪细胞激活转录因子 3 (ATF3) 在人类或小鼠肥胖中被诱导。脂肪细胞 Atf3 (Atf3) 小鼠在 Chow 饮食、高脂肪饮食或西方饮食喂养的小鼠中发展为肥胖、葡萄糖不耐受和代谢功能障碍相关的脂肪性肝炎 (MASH)。通过抑制肝细胞 CD36 阻断脂肪酸通量，而不是恢复肝 AMPK 信号，可防止 Atf3 小鼠 MASH 的恶化。进一步的研究表明，脂肪细胞 ATF3 的缺失通过诱导脂肪甘油三酯脂肪酶增加脂肪分解，进而诱导肝细胞的脂肪生成和炎症。此外，Atf3 小鼠的能量消耗减少，脂肪组织的脂肪生成和炎症增加。我们的数据表明，脂肪细胞 ATF3 是在生理和病理条件下对抗 MASH 发展的守门员。
