KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver Damage
Dysregulation of metabolic functions in the liver impacts the development of diabetes and metabolic disorders. Normal liver function can be compromised by increased inflammation via the activation of signaling such as nuclear factor (NF)-κB signaling. Notably, we have previously identified lysine de...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-09-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/10/1457 |
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| author | Matthew Martin Aishat Motolani Hyeong-Geug Kim Amy M. Collins Faranak Alipourgivi Jiamin Jin Han Wei Barry A. Wood Yao-Ying Ma X. Charlie Dong Raghavendra G. Mirmira Tao Lu |
| author_facet | Matthew Martin Aishat Motolani Hyeong-Geug Kim Amy M. Collins Faranak Alipourgivi Jiamin Jin Han Wei Barry A. Wood Yao-Ying Ma X. Charlie Dong Raghavendra G. Mirmira Tao Lu |
| author_sort | Matthew Martin |
| collection | DOAJ |
| description | Dysregulation of metabolic functions in the liver impacts the development of diabetes and metabolic disorders. Normal liver function can be compromised by increased inflammation via the activation of signaling such as nuclear factor (NF)-κB signaling. Notably, we have previously identified lysine demethylase 2A (KDM2A)—as a critical negative regulator of NF-κB. However, there are no studies demonstrating the effect of KDM2A on liver function. Here, we established a novel liver-specific <i>Kdm2a</i> knockout mouse model to evaluate KDM2A’s role in liver functions. An inducible hepatic deletion of <i>Kdm2a, Alb-Cre-Kdm2a<sup>fl/fl</sup></i> (<i>Kdm2a</i> KO), was generated by crossing the <i>Kdm2a</i> floxed mice (<i>Kdm2a<sup>fl/fl</sup></i>) we established with commercial albumin-Cre transgenic mice (B6.Cg-Tg(Alb-cre)21Mgn/J). We show that under a normal diet, <i>Kdm2a</i> KO mice exhibited increased serum alanine aminotransferase (ALT) activity, L-type triglycerides (TG) levels, and liver glycogen levels vs. WT (<i>Kdm2a<sup>fl/fl</sup></i>) animals. These changes were further enhanced in <i>Kdm2a</i> liver KO mice in high-fat diet (HFD) conditions. We also observed a significant increase in NF-κB target gene expression in <i>Kdm2a</i> liver KO mice under HFD conditions. Similarly, the KO mice exhibited increased immune cell infiltration. Collectively, these data suggest liver-specific KDM2A deficiency may enhance inflammation in the liver, potentially through NF-κB activation, and lead to liver dysfunction. Our study also suggests that the established <i>Kdm2a<sup>fl/fl</sup></i> mouse model may serve as a powerful tool for studying liver-related metabolic diseases. |
| first_indexed | 2024-03-10T21:25:04Z |
| format | Article |
| id | doaj.art-fe15b2cdd26a480d8b9e5d43cb4c7d13 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T21:25:04Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-fe15b2cdd26a480d8b9e5d43cb4c7d132023-11-19T15:49:29ZengMDPI AGBiomolecules2218-273X2023-09-011310145710.3390/biom13101457KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver DamageMatthew Martin0Aishat Motolani1Hyeong-Geug Kim2Amy M. Collins3Faranak Alipourgivi4Jiamin Jin5Han Wei6Barry A. Wood7Yao-Ying Ma8X. Charlie Dong9Raghavendra G. Mirmira10Tao Lu11Department of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USADepartment of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pathology and Laboratory Medicine, Indiana University Health, Indianapolis, IN 46202, USADepartment of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USADepartment of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USADepartment of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USADepartment of Pathology and Laboratory Medicine, Indiana University Health, Indianapolis, IN 46202, USADepartment of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USAUniversity of Chicago Medicine Kovler Diabetes Center, Chicago, IL 60637, USADepartment of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USADysregulation of metabolic functions in the liver impacts the development of diabetes and metabolic disorders. Normal liver function can be compromised by increased inflammation via the activation of signaling such as nuclear factor (NF)-κB signaling. Notably, we have previously identified lysine demethylase 2A (KDM2A)—as a critical negative regulator of NF-κB. However, there are no studies demonstrating the effect of KDM2A on liver function. Here, we established a novel liver-specific <i>Kdm2a</i> knockout mouse model to evaluate KDM2A’s role in liver functions. An inducible hepatic deletion of <i>Kdm2a, Alb-Cre-Kdm2a<sup>fl/fl</sup></i> (<i>Kdm2a</i> KO), was generated by crossing the <i>Kdm2a</i> floxed mice (<i>Kdm2a<sup>fl/fl</sup></i>) we established with commercial albumin-Cre transgenic mice (B6.Cg-Tg(Alb-cre)21Mgn/J). We show that under a normal diet, <i>Kdm2a</i> KO mice exhibited increased serum alanine aminotransferase (ALT) activity, L-type triglycerides (TG) levels, and liver glycogen levels vs. WT (<i>Kdm2a<sup>fl/fl</sup></i>) animals. These changes were further enhanced in <i>Kdm2a</i> liver KO mice in high-fat diet (HFD) conditions. We also observed a significant increase in NF-κB target gene expression in <i>Kdm2a</i> liver KO mice under HFD conditions. Similarly, the KO mice exhibited increased immune cell infiltration. Collectively, these data suggest liver-specific KDM2A deficiency may enhance inflammation in the liver, potentially through NF-κB activation, and lead to liver dysfunction. Our study also suggests that the established <i>Kdm2a<sup>fl/fl</sup></i> mouse model may serve as a powerful tool for studying liver-related metabolic diseases.https://www.mdpi.com/2218-273X/13/10/1457diabetesKDM2AlivermetabolismNF-κB |
| spellingShingle | Matthew Martin Aishat Motolani Hyeong-Geug Kim Amy M. Collins Faranak Alipourgivi Jiamin Jin Han Wei Barry A. Wood Yao-Ying Ma X. Charlie Dong Raghavendra G. Mirmira Tao Lu KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver Damage Biomolecules diabetes KDM2A liver metabolism NF-κB |
| title | KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver Damage |
| title_full | KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver Damage |
| title_fullStr | KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver Damage |
| title_full_unstemmed | KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver Damage |
| title_short | KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver Damage |
| title_sort | kdm2a deficiency in the liver promotes abnormal liver function and potential liver damage |
| topic | diabetes KDM2A liver metabolism NF-κB |
| url | https://www.mdpi.com/2218-273X/13/10/1457 |
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