The adverse metabolic impacts of branched-chain amino acids (BCAA) have been elucidated are mediated by isoleucine and valine. Dietary restriction of isoleucine promotes metabolic health and increases lifespan. However, a high protein diet enriched in BCAA is presently the most useful therapeutic strategy for nonalcoholic fatty liver disease (NAFLD), yet, its underlying mechanism remains largely unknown. Fatty liver hemorrhagic syndrome (FLHS), a specialized laying hen NAFLD model, can spontaneously develop fatty liver and hepatic steatosis under a high-energy and high-protein dietary background that the pathogenesis of FLHS is similar to human NAFLD. The mechanism underlying dietary BCAA control of NAFLD development in laying hens remains unclear. Herein, we demonstrate that dietary supplementation with 67 % High BCAA has unique mitigative impacts on NAFLD in laying hens. A High BCAA diet alleviates NAFLD, by inhibiting the tryptophan-ILA-AHR axis and MAPK9-mediated de novo lipogenesis (DNL), promoting ketogenesis and energy metabolism, and activating PPAR-RXR and pexophagy to promote fatty acid β-oxidation. Furthermore, we uncover that High BCAA strongly activates ubiquitin-proteasome autophagy via downregulating UFMylation to trigger MAPK9-mediated DNL, fatty acid elongation and lipid droplet formation-related proteins ubiquitination degradation, activating PPAR-RXR and pexophagy mediated fatty acid β-oxidation and lipolysis. Together, our data highlight moderating intake of high BCAA by inhibiting the AHR/MAPK9 are promising new strategies in NAFLD and FLHS treatment.

中文翻译：

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支链氨基酸通过抑制蛋鸡从头脂肪生成和激活脂肪酸β氧化来缓解 NAFLD


支链氨基酸 （BCAA） 的不良代谢影响是由异亮氨酸和缬氨酸介导的。异亮氨酸的饮食限制可促进代谢健康并延长寿命。然而，富含 BCAA 的高蛋白饮食是目前治疗非酒精性脂肪性肝病 （NAFLD） 最有用的治疗策略，但其潜在机制在很大程度上仍然未知。脂肪肝出血综合征 （FLHS） 是一种专门的蛋鸡 NAFLD 模型，在高能量、高蛋白饮食背景下可自发发生脂肪肝脂肪变性，FLHS 的发病机制与人 NAFLD 相似。日粮 BCAA 控制蛋鸡 NAFLD 发展的机制尚不清楚。在此，我们证明，添加 67% 高 BCAA 的膳食补充剂对蛋鸡的 NAFLD 具有独特的缓解作用。高 BCAA 饮食通过抑制色氨酸-ILA-AHR 轴和 MAPK9 介导的从头脂肪生成 （DNL） 来缓解 NAFLD，促进生酮和能量代谢，并激活 PPAR-RXR 和自噬以促进脂肪酸β氧化。此外，我们发现高 BCAA 通过下调 UFMylation 强烈激活泛素-蛋白酶体自噬，以触发 MAPK9 介导的 DNL、脂肪酸延伸和脂滴形成相关蛋白质泛素化降解，激活 PPAR-RXR 和自噬介导的脂肪酸β氧化和脂肪分解。总之，我们的数据强调了通过抑制 AHR/MAPK9 来调节高 BCAA 的摄入是 NAFLD 和 FLHS 治疗中很有前途的新策略。