Leflunomide-Induced Weight Loss: Involvement of DAHPS Activity and Synthesis of Aromatic Amino Acids
<b>Background/Objectives:</b> Leflunomide, an isoxazole immunosuppressant, is widely used in the treatment of diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as lupus nephritis (LN). In recent years, clinical data have shown that some patients have obviou...
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2024-11-01
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| author | Xiaoyu Guo Kai Wang Hongli Chen Na Wang Dongmei Qiu Haiyun Huang Jiyu Luo Ao Xu Lingyun Xu Zejun Yu Yuanyuan Li Hongling Zhang |
| author_facet | Xiaoyu Guo Kai Wang Hongli Chen Na Wang Dongmei Qiu Haiyun Huang Jiyu Luo Ao Xu Lingyun Xu Zejun Yu Yuanyuan Li Hongling Zhang |
| author_sort | Xiaoyu Guo |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> Leflunomide, an isoxazole immunosuppressant, is widely used in the treatment of diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as lupus nephritis (LN). In recent years, clinical data have shown that some patients have obvious weight loss, liver injury, and other serious adverse reactions after taking leflunomide. However, the causes and mechanisms by which leflunomide reduces weight are unclear. <b>Methods:</b> Therefore, we used a mouse animal model to administer leflunomide, and we observed that the weight of mice in the leflunomide experimental group was significantly reduced (<i>p</i> < 0.01). In this animal experiment, a metabolomic method was used to analyze the livers of the mice in the experimental group and found that the main difference in terms of metabolic pathways was in the metabolism of aromatic amino acids, and it was confirmed that leflunomide can inhibit the limitations of phenylalanine, tyrosine, and tryptophan biosynthesis. <b>Results:</b> Our study revealed that leflunomide inhibited the activity of DAHPS in the gut microbiota, disrupting the metabolism of phenylalanine, tyrosine, and tryptophan, as well as the metabolism of carbohydrates and lipids. Leflunomide also increased endoplasmic reticulum stress by activating the PERK pathway, thereby promoting CHOP expression and increasing apoptosis-induced liver damage. <b>Conclusions:</b> These effects may be related to the observed weight loss induced by leflunomide. |
| format | Article |
| id | doaj-art-9a18284b3fd24fbca0b1df4320fa66f7 |
| institution | OA Journals |
| issn | 2218-1989 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj-art-9a18284b3fd24fbca0b1df4320fa66f72025-08-20T02:05:06ZengMDPI AGMetabolites2218-19892024-11-01141164510.3390/metabo14110645Leflunomide-Induced Weight Loss: Involvement of DAHPS Activity and Synthesis of Aromatic Amino AcidsXiaoyu Guo0Kai Wang1Hongli Chen2Na Wang3Dongmei Qiu4Haiyun Huang5Jiyu Luo6Ao Xu7Lingyun Xu8Zejun Yu9Yuanyuan Li10Hongling Zhang11School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, ChinaSchool of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, ChinaSchool of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, ChinaSchool of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, ChinaSchool of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, ChinaSchool of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, ChinaSchool of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, ChinaSchool of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, ChinaSchool of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, ChinaSchool of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, ChinaSchool of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaSchool of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, China<b>Background/Objectives:</b> Leflunomide, an isoxazole immunosuppressant, is widely used in the treatment of diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as lupus nephritis (LN). In recent years, clinical data have shown that some patients have obvious weight loss, liver injury, and other serious adverse reactions after taking leflunomide. However, the causes and mechanisms by which leflunomide reduces weight are unclear. <b>Methods:</b> Therefore, we used a mouse animal model to administer leflunomide, and we observed that the weight of mice in the leflunomide experimental group was significantly reduced (<i>p</i> < 0.01). In this animal experiment, a metabolomic method was used to analyze the livers of the mice in the experimental group and found that the main difference in terms of metabolic pathways was in the metabolism of aromatic amino acids, and it was confirmed that leflunomide can inhibit the limitations of phenylalanine, tyrosine, and tryptophan biosynthesis. <b>Results:</b> Our study revealed that leflunomide inhibited the activity of DAHPS in the gut microbiota, disrupting the metabolism of phenylalanine, tyrosine, and tryptophan, as well as the metabolism of carbohydrates and lipids. Leflunomide also increased endoplasmic reticulum stress by activating the PERK pathway, thereby promoting CHOP expression and increasing apoptosis-induced liver damage. <b>Conclusions:</b> These effects may be related to the observed weight loss induced by leflunomide.https://www.mdpi.com/2218-1989/14/11/645leflunomidekidney injuryaromatic amino acidsweight loss |
| spellingShingle | Xiaoyu Guo Kai Wang Hongli Chen Na Wang Dongmei Qiu Haiyun Huang Jiyu Luo Ao Xu Lingyun Xu Zejun Yu Yuanyuan Li Hongling Zhang Leflunomide-Induced Weight Loss: Involvement of DAHPS Activity and Synthesis of Aromatic Amino Acids Metabolites leflunomide kidney injury aromatic amino acids weight loss |
| title | Leflunomide-Induced Weight Loss: Involvement of DAHPS Activity and Synthesis of Aromatic Amino Acids |
| title_full | Leflunomide-Induced Weight Loss: Involvement of DAHPS Activity and Synthesis of Aromatic Amino Acids |
| title_fullStr | Leflunomide-Induced Weight Loss: Involvement of DAHPS Activity and Synthesis of Aromatic Amino Acids |
| title_full_unstemmed | Leflunomide-Induced Weight Loss: Involvement of DAHPS Activity and Synthesis of Aromatic Amino Acids |
| title_short | Leflunomide-Induced Weight Loss: Involvement of DAHPS Activity and Synthesis of Aromatic Amino Acids |
| title_sort | leflunomide induced weight loss involvement of dahps activity and synthesis of aromatic amino acids |
| topic | leflunomide kidney injury aromatic amino acids weight loss |
| url | https://www.mdpi.com/2218-1989/14/11/645 |
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