| Title: | L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagy |
| Journal: | Molecular Medicine |
| Published: | 30 Jun 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40588730/ |
| DOI: | https://doi.org/10.1186/s10020-025-01303-5 |
| URL: | https://molmed.biomedcentral.com/counter/pdf/10.1186/s10020-025-01303-5 |
Publication 16503
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
BackgroundL-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.MethodsWe 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.ResultsIn 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.ConclusionsOur 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.</p>
16 Keywords
- Animals
- Disease Models, Animal
- Fatty Liver
- Female
- Humans
- Lipid Metabolism
- Liver
- Male
- Membrane Proteins
- Middle Aged
- Mitochondrial Proteins
- Mitophagy
- Proto-Oncogene Proteins
- Rats
- Rats, Sprague-Dawley
- Signal Transduction
13 Authors
- Ying Sun
- Lingli Cai
- Bowei Yu
- Haojie Zhang
- Ziteng Zhang
- Xiaoqin Xu
- Yuefeng Yu
- Jiang Li
- Chi Chen
- Fangzhen Xia
- Yingli Lu
- Kun Zhang
- Ningjian Wang
Enabling scientific discoveries that improve human health