Role of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosis
Abstract Background The effectiveness of ketogenic diet (KD) in ameliorating fatty liver has been established, although its mechanism is under investigation. Fibroblast growth factor 21 (FGF21) positively regulates obesity-associated metabolic disorders and is elevated by KD. FGF21 conventionally in...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-04-01
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| Series: | Nutrition & Diabetes |
| Online Access: | https://doi.org/10.1038/s41387-024-00277-3 |
| _version_ | 1797208968541503488 |
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| author | Wanrong Guo Huanyi Cao Yunfeng Shen Wuguo Li Wei Wang Lidan Cheng Mengyin Cai Fen Xu |
| author_facet | Wanrong Guo Huanyi Cao Yunfeng Shen Wuguo Li Wei Wang Lidan Cheng Mengyin Cai Fen Xu |
| author_sort | Wanrong Guo |
| collection | DOAJ |
| description | Abstract Background The effectiveness of ketogenic diet (KD) in ameliorating fatty liver has been established, although its mechanism is under investigation. Fibroblast growth factor 21 (FGF21) positively regulates obesity-associated metabolic disorders and is elevated by KD. FGF21 conventionally initiates its intracellular signaling via receptor β-klotho (KLB). However, the mechanistic role of FGF21-KLB signaling for KD-ameliorated fatty liver remains unknown. This study aimed to delineate the critical role of FGF21 signaling in the ameliorative effects of KD on hepatic steatosis. Methods Eight-week-old C57BL/6 J mice were fed a chow diet (CD), a high-fat diet (HFD), or a KD for 16 weeks. Adeno-associated virus-mediated liver-specific KLB knockdown mice and control mice were fed a KD for 16 weeks. Phenotypic assessments were conducted during and after the intervention. We investigated the mechanism underlying KD-alleviated hepatic steatosis using multi-omics and validated the expression of key genes. Results KD improved hepatic steatosis by upregulating fatty acid oxidation and downregulating lipogenesis. Transcriptional analysis revealed that KD dramatically activated FGF21 pathway, including KLB and fibroblast growth factor receptor 1 (FGFR1). Impairing liver FGF21 signaling via KLB knockdown diminished the beneficial effects of KD on ameliorating fatty liver, insulin resistance, and regulating lipid metabolism. Conclusion KD demonstrates beneficial effects on diet-induced metabolic disorders, particularly on hepatic steatosis. Liver FGF21-KLB signaling plays a critical role in the KD-induced amelioration of hepatic steatosis. |
| first_indexed | 2024-04-24T09:47:14Z |
| format | Article |
| id | doaj.art-0228035661504c8fa0037f65197ae123 |
| institution | Directory Open Access Journal |
| issn | 2044-4052 |
| language | English |
| last_indexed | 2024-04-24T09:47:14Z |
| publishDate | 2024-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Nutrition & Diabetes |
| spelling | doaj.art-0228035661504c8fa0037f65197ae1232024-04-14T11:33:15ZengNature Publishing GroupNutrition & Diabetes2044-40522024-04-0114111010.1038/s41387-024-00277-3Role of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosisWanrong Guo0Huanyi Cao1Yunfeng Shen2Wuguo Li3Wei Wang4Lidan Cheng5Mengyin Cai6Fen Xu7Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of DiabetologyDepartment of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang UniversityAnimal Experiment Center, The First Affiliated Hospital of Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of DiabetologyGuangdong Provincial Key Laboratory of DiabetologyDepartment of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen UniversityDepartment of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen UniversityAbstract Background The effectiveness of ketogenic diet (KD) in ameliorating fatty liver has been established, although its mechanism is under investigation. Fibroblast growth factor 21 (FGF21) positively regulates obesity-associated metabolic disorders and is elevated by KD. FGF21 conventionally initiates its intracellular signaling via receptor β-klotho (KLB). However, the mechanistic role of FGF21-KLB signaling for KD-ameliorated fatty liver remains unknown. This study aimed to delineate the critical role of FGF21 signaling in the ameliorative effects of KD on hepatic steatosis. Methods Eight-week-old C57BL/6 J mice were fed a chow diet (CD), a high-fat diet (HFD), or a KD for 16 weeks. Adeno-associated virus-mediated liver-specific KLB knockdown mice and control mice were fed a KD for 16 weeks. Phenotypic assessments were conducted during and after the intervention. We investigated the mechanism underlying KD-alleviated hepatic steatosis using multi-omics and validated the expression of key genes. Results KD improved hepatic steatosis by upregulating fatty acid oxidation and downregulating lipogenesis. Transcriptional analysis revealed that KD dramatically activated FGF21 pathway, including KLB and fibroblast growth factor receptor 1 (FGFR1). Impairing liver FGF21 signaling via KLB knockdown diminished the beneficial effects of KD on ameliorating fatty liver, insulin resistance, and regulating lipid metabolism. Conclusion KD demonstrates beneficial effects on diet-induced metabolic disorders, particularly on hepatic steatosis. Liver FGF21-KLB signaling plays a critical role in the KD-induced amelioration of hepatic steatosis.https://doi.org/10.1038/s41387-024-00277-3 |
| spellingShingle | Wanrong Guo Huanyi Cao Yunfeng Shen Wuguo Li Wei Wang Lidan Cheng Mengyin Cai Fen Xu Role of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosis Nutrition & Diabetes |
| title | Role of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosis |
| title_full | Role of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosis |
| title_fullStr | Role of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosis |
| title_full_unstemmed | Role of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosis |
| title_short | Role of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosis |
| title_sort | role of liver fgf21 klb signaling in ketogenic diet induced amelioration of hepatic steatosis |
| url | https://doi.org/10.1038/s41387-024-00277-3 |
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