Branched-chain amino acids alleviate NAFLD via inhibiting de novo lipogenesis and activating fatty acid β-oxidation in laying hens
Huafeng Jian,
Ru Li,
Xuan Huang,
Jiankui Li,
Yan Li,
Jiangang Ma,
Mingkun Zhu,
Xinyang Dong,
Hua Yang,
Xiaoting Zou
Affiliations
Huafeng Jian
Institute of Feed Science, College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou, 310058, China; Xianghu Laboratory, Hangzhou, 311231, China
Ru Li
Institute of Feed Science, College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou, 310058, China
Xuan Huang
Institute of Feed Science, College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou, 310058, China
Jiankui Li
Institute of Feed Science, College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou, 310058, China
Yan Li
Institute of Feed Science, College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou, 310058, China
Jiangang Ma
Xianghu Laboratory, Hangzhou, 311231, China
Mingkun Zhu
Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, 212100, China; Key Laboratory of Silkworm and Mulberry Genetic Improvement, Ministry of Agriculture and Rural Affairs, The Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, 212100, China
Xinyang Dong
Institute of Feed Science, College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou, 310058, China
Hua Yang
Institute of Agro‐product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China; Corresponding author.
Xiaoting Zou
Institute of Feed Science, College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou, 310058, China; Corresponding author.
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.
