Dominant-negative HNF1α mutant promotes liver steatosis and inflammation by regulating hepatic complement factor D
Summary: Patients with HNF1A variants may develop liver steatosis, while the underlying mechanism is still unclear. Here, we established a mouse model carrying the dominant-negative HNF1α P291fsinsC mutation (hHNF1Amut/-) and found that the mutant mice developed liver steatosis spontaneously under t...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223020953 |
| _version_ | 1797647843785179136 |
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| author | Moke Liu Luna Liu Honglin Guo Xiude Fan Tianbao Liu Chao Xu Zhao He Yongfeng Song Ling Gao Shanshan Shao Jiajun Zhao Peng Lu |
| author_facet | Moke Liu Luna Liu Honglin Guo Xiude Fan Tianbao Liu Chao Xu Zhao He Yongfeng Song Ling Gao Shanshan Shao Jiajun Zhao Peng Lu |
| author_sort | Moke Liu |
| collection | DOAJ |
| description | Summary: Patients with HNF1A variants may develop liver steatosis, while the underlying mechanism is still unclear. Here, we established a mouse model carrying the dominant-negative HNF1α P291fsinsC mutation (hHNF1Amut/-) and found that the mutant mice developed liver steatosis spontaneously under the normal chow diet. Transcriptome analysis showed significant upregulation of Cfd and other genes related to innate immune response in the liver of hHNF1Amut/- mice. The changes in lipid metabolism and complement pathways were also confirmed by proteomics. We demonstrated that HNF1α inhibited CFD expression in hepatocytes, and the P291fsinsC mutant could reverse this inhibitory effect. Furthermore, the suppression of CFD with specific inhibitor or siRNAs reduced triglyceride levels in hepatocytes, suggesting that CFD regulated hepatocyte lipid deposition. Our results demonstrate that the HNF1α P291fsinsC mutant promotes hepatic steatosis and inflammation by upregulating CFD expression, and targeting CFD may delay the progression of nonalcoholic fatty liver disease. |
| first_indexed | 2024-03-11T15:22:21Z |
| format | Article |
| id | doaj.art-bbc44dfb0ae6452a8e9fdfdda28185d3 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-11T15:22:21Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-bbc44dfb0ae6452a8e9fdfdda28185d32023-10-28T05:09:19ZengElsevieriScience2589-00422023-10-012610108018Dominant-negative HNF1α mutant promotes liver steatosis and inflammation by regulating hepatic complement factor DMoke Liu0Luna Liu1Honglin Guo2Xiude Fan3Tianbao Liu4Chao Xu5Zhao He6Yongfeng Song7Ling Gao8Shanshan Shao9Jiajun Zhao10Peng Lu11Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan 250021, China; Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan 250021, ChinaKey Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan 250021, China; Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan 250021, ChinaKey Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, ChinaKey Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan 250021, China; Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan 250021, ChinaKey Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan 250021, China; Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan 250021, ChinaKey Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan 250021, China; Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan 250021, ChinaKey Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan 250021, China; Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan 250021, ChinaKey Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan 250021, China; Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan 250021, ChinaKey Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan 250021, China; Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan 250021, ChinaKey Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan 250021, China; Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan 250021, China; Corresponding authorKey Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan 250021, China; Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan 250021, China; Corresponding authorDepartment of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Corresponding authorSummary: Patients with HNF1A variants may develop liver steatosis, while the underlying mechanism is still unclear. Here, we established a mouse model carrying the dominant-negative HNF1α P291fsinsC mutation (hHNF1Amut/-) and found that the mutant mice developed liver steatosis spontaneously under the normal chow diet. Transcriptome analysis showed significant upregulation of Cfd and other genes related to innate immune response in the liver of hHNF1Amut/- mice. The changes in lipid metabolism and complement pathways were also confirmed by proteomics. We demonstrated that HNF1α inhibited CFD expression in hepatocytes, and the P291fsinsC mutant could reverse this inhibitory effect. Furthermore, the suppression of CFD with specific inhibitor or siRNAs reduced triglyceride levels in hepatocytes, suggesting that CFD regulated hepatocyte lipid deposition. Our results demonstrate that the HNF1α P291fsinsC mutant promotes hepatic steatosis and inflammation by upregulating CFD expression, and targeting CFD may delay the progression of nonalcoholic fatty liver disease.http://www.sciencedirect.com/science/article/pii/S2589004223020953Molecular physiologyMolecular biologyTranscriptomics |
| spellingShingle | Moke Liu Luna Liu Honglin Guo Xiude Fan Tianbao Liu Chao Xu Zhao He Yongfeng Song Ling Gao Shanshan Shao Jiajun Zhao Peng Lu Dominant-negative HNF1α mutant promotes liver steatosis and inflammation by regulating hepatic complement factor D iScience Molecular physiology Molecular biology Transcriptomics |
| title | Dominant-negative HNF1α mutant promotes liver steatosis and inflammation by regulating hepatic complement factor D |
| title_full | Dominant-negative HNF1α mutant promotes liver steatosis and inflammation by regulating hepatic complement factor D |
| title_fullStr | Dominant-negative HNF1α mutant promotes liver steatosis and inflammation by regulating hepatic complement factor D |
| title_full_unstemmed | Dominant-negative HNF1α mutant promotes liver steatosis and inflammation by regulating hepatic complement factor D |
| title_short | Dominant-negative HNF1α mutant promotes liver steatosis and inflammation by regulating hepatic complement factor D |
| title_sort | dominant negative hnf1α mutant promotes liver steatosis and inflammation by regulating hepatic complement factor d |
| topic | Molecular physiology Molecular biology Transcriptomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223020953 |
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