Sun Ying, Cai Lingli, Yu Bowei, Zhang Haojie, Zhang Ziteng, Xu Xiaoqin, Yu Yuefeng, Li Jiang, Chen Chi, Xia Fangzhen, Lu Yingli, Zhang Kun, Wang Ningjian
Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China.
Department of Endocrinology and Metabolism and Department of Guideline and Rapid Recommendation, Cochrane China Centre, MAGIC China Centre, Chinese Evidence-Based Medicine Centre, West China Hospital, Sichuan University, Chengdu, China.
Mol Med. 2025 Jun 30;31(1):250. doi: 10.1186/s10020-025-01303-5.
L-Phenylalanine (L-Phe) levels are elevated in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, whether L-Phe induces liver steatosis and the underlying mechanism remain unknown. This study aimed to investigate the mechanism through which L-Phe promotes liver steatosis.
We utilized human data from the UK Biobank and SPECT-China studies. Plasma/serum samples were collected for metabolomic testing to measure L-Phe levels. A rat model with L-Phe in the drinking water was established to investigate changes in hepatic lipid metabolism. In addition, BNIP3 was overexpressed both in vitro and in vivo to validate the role of L-Phe in BNIP3-mediated mitophagy associated with liver steatosis.
In both populations, elevated L-Phe quartiles were associated with increased body mass index, triglyceride, and transaminase levels and increased odds of MASLD (all p < 0.05). Rats exposed to L-Phe had increased hepatic lipid deposition and decreased mitophagy in the liver. Differentially expressed proteins were enriched in the PPARα and fatty acid β-oxidation signalling pathways, with downregulation of the mitophagy marker BNIP3. Mitophagy was activated by rapamycin and then inhibited by L-Phe, indicating that elevated L-Phe promoted lipid accumulation by suppressing mitophagy. BNIP3 overexpression effectively mitigated L-Phe-induced hepatic steatosis by restoring mitophagy. Moreover, L-Phe regulates the BNIP3-mediated PPARα and AMPK/mTOR signalling pathways to promote hepatic steatosis.
Our study revealed the role of L-Phe in regulating lipid metabolism and promoting liver steatosis via BNIP3-mediated mitophagy. These findings provide novel insights into the link between L-Phe and liver steatosis, suggesting potential nutritional intervention strategies for preventing MASLD.
代谢功能障碍相关脂肪性肝病（MASLD）患者的L-苯丙氨酸（L-Phe）水平升高。然而，L-Phe是否诱导肝脏脂肪变性及其潜在机制尚不清楚。本研究旨在探讨L-Phe促进肝脏脂肪变性的机制。
我们利用了来自英国生物银行和SPECT-中国研究的人类数据。收集血浆/血清样本进行代谢组学检测以测量L-Phe水平。建立了饮用含L-Phe水的大鼠模型，以研究肝脏脂质代谢的变化。此外，在体外和体内均过表达BNIP3，以验证L-Phe在与肝脏脂肪变性相关的BNIP3介导的线粒体自噬中的作用。
在这两个人群中，L-Phe四分位数升高与体重指数、甘油三酯和转氨酶水平升高以及MASLD几率增加相关（所有p<0.05）。暴露于L-Phe的大鼠肝脏脂质沉积增加，肝脏线粒体自噬减少。差异表达的蛋白质在PPARα和脂肪酸β-氧化信号通路中富集，线粒体自噬标志物BNIP3下调。雷帕霉素激活线粒体自噬，然后被L-Phe抑制，表明L-Phe升高通过抑制线粒体自噬促进脂质积累。BNIP3过表达通过恢复线粒体自噬有效减轻L-Phe诱导的肝脏脂肪变性。此外，L-Phe调节BNIP3介导的PPARα和AMPK/mTOR信号通路以促进肝脏脂肪变性。
我们的研究揭示了L-Phe在通过BNIP3介导的线粒体自噬调节脂质代谢和促进肝脏脂肪变性中的作用。这些发现为L-Phe与肝脏脂肪变性之间的联系提供了新的见解，提示了预防MASLD的潜在营养干预策略。
