L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagy
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...
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BMC
2025-06-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-025-01303-5 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ying Sun |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e2eecac3a90d4c77baa60fce1a78b948 |
| institution | Kabale University |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj-art-e2eecac3a90d4c77baa60fce1a78b9482025-08-20T04:01:34ZengBMCMolecular Medicine1528-36582025-06-0131111910.1186/s10020-025-01303-5L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagyYing Sun0Lingli Cai1Bowei Yu2Haojie Zhang3Ziteng Zhang4Xiaoqin Xu5Yuefeng Yu6Jiang Li7Chi Chen8Fangzhen Xia9Yingli Lu10Kun Zhang11Ningjian Wang12Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of MedicineInstitute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of MedicineInstitute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of MedicineDepartment 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 UniversityInstitute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of MedicineInstitute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of MedicineInstitute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of MedicineInstitute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of MedicineDepartment of Endocrinology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineInstitute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of MedicineInstitute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of MedicineInstitute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of MedicineInstitute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of MedicineAbstract 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.https://doi.org/10.1186/s10020-025-01303-5Liver steatosisL-PhenylalanineMitophagyBNIP3 |
| spellingShingle | 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 L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagy Molecular Medicine Liver steatosis L-Phenylalanine Mitophagy BNIP3 |
| title | L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagy |
| title_full | L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagy |
| title_fullStr | L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagy |
| title_full_unstemmed | L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagy |
| title_short | L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagy |
| title_sort | l phenylalanine promotes liver steatosis by inhibiting bnip3 mediated mitophagy |
| topic | Liver steatosis L-Phenylalanine Mitophagy BNIP3 |
| url | https://doi.org/10.1186/s10020-025-01303-5 |
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