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L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagy
Sun, Ying Cai, Lingli Yu, Bowei Zhang, Haojie Zhang, Ziteng Xu, Xiaoqin Yu, Yuefeng Li, Jiang Chen, Chi Xia, Fangzhen
Sun, Ying
Cai, Lingli
Yu, Bowei
Zhang, Haojie
Zhang, Ziteng
Xu, Xiaoqin
Yu, Yuefeng
Li, Jiang
Chen, Chi
Xia, Fangzhen
Supervisor
Department
Machine Learning
Embargo End Date
Type
Journal article
Date
2025
License
Language
English
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Research Projects
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Journal Issue
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Citation
Y. Sun et al., “L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagy,” Molecular Medicine, vol. 31, no. 1, pp. 1–19, Dec. 2025, doi: 10.1186/S10020-025-01303-5/FIGURES/8
Source
Molecular Medicine
Conference
Keywords
Liver steatosis, L-Phenylalanine, Mitophagy, BNIP3
Subjects
Source
Publisher
Springer Nature