The role of KLF2 in regulating hepatic lipogenesis and blood cholesterol homeostasis via the SCAP/SREBP pathway
Liver steatosis is a common metabolic disorder resulting from imbalanced lipid metabolism, which involves various processes such as de novo lipogenesis, fatty acid uptake, fatty acid oxidation, and VLDL secretion. In this study, we discovered that KLF2, a transcription factor, plays a crucial role i...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227523001451 |
| _version_ | 1797347106749415424 |
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| author | Yuhong Huang Yi Fan Wang Xiong Zhong Ruan Chi Wai Lau Li Wang Yu Huang |
| author_facet | Yuhong Huang Yi Fan Wang Xiong Zhong Ruan Chi Wai Lau Li Wang Yu Huang |
| author_sort | Yuhong Huang |
| collection | DOAJ |
| description | Liver steatosis is a common metabolic disorder resulting from imbalanced lipid metabolism, which involves various processes such as de novo lipogenesis, fatty acid uptake, fatty acid oxidation, and VLDL secretion. In this study, we discovered that KLF2, a transcription factor, plays a crucial role in regulating lipid metabolism in the liver. Overexpression of KLF2 in the liver of db/db mice, C57BL/6J mice, and Cd36-/- mice fed on a normal diet resulted in increased lipid content in the liver. Additionally, transgenic mice (ALB-Klf2) that overexpressed Klf2 in the liver developed liver steatosis after being fed a normal diet. We found that KLF2 promotes lipogenesis by increasing the expression of SCAP, a chaperone that facilitates the activation of SREBP, the master transcription factor for lipogenic gene expression. Our mechanism studies revealed that KLF2 enhances lipogenesis in the liver by binding to the promoter of SCAP and increasing the expression of genes involved in fatty acid synthesis. Reduction of KLF2 expression led to a decrease in SCAP expression and a reduction in the expression of SREBP1 target genes involved in lipogenesis. Overexpression of KLF2 also increased the activation of SREBP2 and the mRNA levels of its downstream target SOAT1. In C57BL/6J mice fed a high-fat diet, overexpression of Klf2 increased blood VLDL secretion, while reducing its expression decreased blood cholesterol levels. Our study emphasizes the novelty that hepatic KLF2 plays a critical role in regulating lipid metabolism through the KLF2/SCAP/SREBPs pathway, which is essential for hepatic lipogenesis and maintaining blood cholesterol homeostasis. |
| first_indexed | 2024-03-08T11:42:35Z |
| format | Article |
| id | doaj.art-9066ce0e78ad41ee98a5c0b279fdb2c9 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-03-08T11:42:35Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-9066ce0e78ad41ee98a5c0b279fdb2c92024-01-25T05:22:31ZengElsevierJournal of Lipid Research0022-22752024-01-01651100472The role of KLF2 in regulating hepatic lipogenesis and blood cholesterol homeostasis via the SCAP/SREBP pathwayYuhong Huang0Yi Fan Wang1Xiong Zhong Ruan2Chi Wai Lau3Li Wang4Yu Huang5Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, PR China; Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shenzhen, ChinaSchool of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, PR ChinaCentre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, ChinaSchool of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, PR ChinaDepartment of Biomedical Sciences, City University of Hong Kong, Hong Kong, ChinaDepartment of Biomedical Sciences, City University of Hong Kong, Hong Kong, China; For correspondence: Yu HuangLiver steatosis is a common metabolic disorder resulting from imbalanced lipid metabolism, which involves various processes such as de novo lipogenesis, fatty acid uptake, fatty acid oxidation, and VLDL secretion. In this study, we discovered that KLF2, a transcription factor, plays a crucial role in regulating lipid metabolism in the liver. Overexpression of KLF2 in the liver of db/db mice, C57BL/6J mice, and Cd36-/- mice fed on a normal diet resulted in increased lipid content in the liver. Additionally, transgenic mice (ALB-Klf2) that overexpressed Klf2 in the liver developed liver steatosis after being fed a normal diet. We found that KLF2 promotes lipogenesis by increasing the expression of SCAP, a chaperone that facilitates the activation of SREBP, the master transcription factor for lipogenic gene expression. Our mechanism studies revealed that KLF2 enhances lipogenesis in the liver by binding to the promoter of SCAP and increasing the expression of genes involved in fatty acid synthesis. Reduction of KLF2 expression led to a decrease in SCAP expression and a reduction in the expression of SREBP1 target genes involved in lipogenesis. Overexpression of KLF2 also increased the activation of SREBP2 and the mRNA levels of its downstream target SOAT1. In C57BL/6J mice fed a high-fat diet, overexpression of Klf2 increased blood VLDL secretion, while reducing its expression decreased blood cholesterol levels. Our study emphasizes the novelty that hepatic KLF2 plays a critical role in regulating lipid metabolism through the KLF2/SCAP/SREBPs pathway, which is essential for hepatic lipogenesis and maintaining blood cholesterol homeostasis.http://www.sciencedirect.com/science/article/pii/S0022227523001451KLF2SCAPSREBPssteatosislipogenesisblood cholesterol |
| spellingShingle | Yuhong Huang Yi Fan Wang Xiong Zhong Ruan Chi Wai Lau Li Wang Yu Huang The role of KLF2 in regulating hepatic lipogenesis and blood cholesterol homeostasis via the SCAP/SREBP pathway Journal of Lipid Research KLF2 SCAP SREBPs steatosis lipogenesis blood cholesterol |
| title | The role of KLF2 in regulating hepatic lipogenesis and blood cholesterol homeostasis via the SCAP/SREBP pathway |
| title_full | The role of KLF2 in regulating hepatic lipogenesis and blood cholesterol homeostasis via the SCAP/SREBP pathway |
| title_fullStr | The role of KLF2 in regulating hepatic lipogenesis and blood cholesterol homeostasis via the SCAP/SREBP pathway |
| title_full_unstemmed | The role of KLF2 in regulating hepatic lipogenesis and blood cholesterol homeostasis via the SCAP/SREBP pathway |
| title_short | The role of KLF2 in regulating hepatic lipogenesis and blood cholesterol homeostasis via the SCAP/SREBP pathway |
| title_sort | role of klf2 in regulating hepatic lipogenesis and blood cholesterol homeostasis via the scap srebp pathway |
| topic | KLF2 SCAP SREBPs steatosis lipogenesis blood cholesterol |
| url | http://www.sciencedirect.com/science/article/pii/S0022227523001451 |
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