Gamma-Aminobutyrate Transaminase Protects against Lipid Overload-Triggered Cardiac Injury in Mice
Lipid overload contributes to cardiac complications of diabetes and obesity. However, the underlying mechanisms remain obscure. This study investigates the role of gamma-aminobutyrate transaminase (ABAT), the key enzyme involved in the catabolism of γ-aminobutyric acid (GABA), in lipid overload-indu...
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MDPI AG
2022-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/4/2182 |
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| author | Mengxiao Zhang Huiting Zhong Ting Cao Yifan Huang Xiaoyun Ji Guo-Chang Fan Tianqing Peng |
| author_facet | Mengxiao Zhang Huiting Zhong Ting Cao Yifan Huang Xiaoyun Ji Guo-Chang Fan Tianqing Peng |
| author_sort | Mengxiao Zhang |
| collection | DOAJ |
| description | Lipid overload contributes to cardiac complications of diabetes and obesity. However, the underlying mechanisms remain obscure. This study investigates the role of gamma-aminobutyrate transaminase (ABAT), the key enzyme involved in the catabolism of γ-aminobutyric acid (GABA), in lipid overload-induced cardiac injury. Microarray revealed a down-regulation of ABAT mRNA expression in high fat diet (HFD)-fed mouse hearts, which correlated with a reduction in ABAT protein level and its GABA catabolic activity. Transgenic mice with cardiomyocyte-specific ABAT over-expression (Tg-ABAT/tTA) were generated to determine the role of ABAT in lipid overload-induced cardiac injury. Feeding with a HFD to control mice for 4 months reduced ATP production and the mitochondrial DNA copy number, and induced myocardial oxidative stress, hypertrophy, fibrosis and dysfunction. Such pathological effects of HFD were mitigated by ABAT over-expression in Tg-ABAT/tTA mice. In cultured cardiomyocytes, palmitate increased mitochondrial ROS production, depleted ATP production and promoted apoptosis, all of which were attenuated by ABAT over-expression. With the inhibition of ABAT’s GABA catabolic activity, the protective effects of ABAT remained unchanged in palmitate-induced cardiomyocytes. Thus, ABAT protects the mitochondrial function in defending the heart against lipid overload-induced injury through mechanisms independent of its GABA catabolic activity, and may represent a new therapeutic target for lipid overload-induced cardiac injury. |
| first_indexed | 2024-03-09T21:43:49Z |
| format | Article |
| id | doaj.art-2976215771bc4822aeaefdb8a0c967cb |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:43:49Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2976215771bc4822aeaefdb8a0c967cb2023-11-23T20:21:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-02-01234218210.3390/ijms23042182Gamma-Aminobutyrate Transaminase Protects against Lipid Overload-Triggered Cardiac Injury in MiceMengxiao Zhang0Huiting Zhong1Ting Cao2Yifan Huang3Xiaoyun Ji4Guo-Chang Fan5Tianqing Peng6Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, ChinaInstitutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, ChinaInstitutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, ChinaInstitutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, ChinaDepartment of Pathology and Laboratory Medicine, Western University, London, ON N6A 5C1, CanadaDepartment of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USADepartment of Pathology and Laboratory Medicine, Western University, London, ON N6A 5C1, CanadaLipid overload contributes to cardiac complications of diabetes and obesity. However, the underlying mechanisms remain obscure. This study investigates the role of gamma-aminobutyrate transaminase (ABAT), the key enzyme involved in the catabolism of γ-aminobutyric acid (GABA), in lipid overload-induced cardiac injury. Microarray revealed a down-regulation of ABAT mRNA expression in high fat diet (HFD)-fed mouse hearts, which correlated with a reduction in ABAT protein level and its GABA catabolic activity. Transgenic mice with cardiomyocyte-specific ABAT over-expression (Tg-ABAT/tTA) were generated to determine the role of ABAT in lipid overload-induced cardiac injury. Feeding with a HFD to control mice for 4 months reduced ATP production and the mitochondrial DNA copy number, and induced myocardial oxidative stress, hypertrophy, fibrosis and dysfunction. Such pathological effects of HFD were mitigated by ABAT over-expression in Tg-ABAT/tTA mice. In cultured cardiomyocytes, palmitate increased mitochondrial ROS production, depleted ATP production and promoted apoptosis, all of which were attenuated by ABAT over-expression. With the inhibition of ABAT’s GABA catabolic activity, the protective effects of ABAT remained unchanged in palmitate-induced cardiomyocytes. Thus, ABAT protects the mitochondrial function in defending the heart against lipid overload-induced injury through mechanisms independent of its GABA catabolic activity, and may represent a new therapeutic target for lipid overload-induced cardiac injury.https://www.mdpi.com/1422-0067/23/4/2182lipid overloadABATmitochondrial dysfunctionheart dysfunctionapoptosiscardiomyocytes |
| spellingShingle | Mengxiao Zhang Huiting Zhong Ting Cao Yifan Huang Xiaoyun Ji Guo-Chang Fan Tianqing Peng Gamma-Aminobutyrate Transaminase Protects against Lipid Overload-Triggered Cardiac Injury in Mice International Journal of Molecular Sciences lipid overload ABAT mitochondrial dysfunction heart dysfunction apoptosis cardiomyocytes |
| title | Gamma-Aminobutyrate Transaminase Protects against Lipid Overload-Triggered Cardiac Injury in Mice |
| title_full | Gamma-Aminobutyrate Transaminase Protects against Lipid Overload-Triggered Cardiac Injury in Mice |
| title_fullStr | Gamma-Aminobutyrate Transaminase Protects against Lipid Overload-Triggered Cardiac Injury in Mice |
| title_full_unstemmed | Gamma-Aminobutyrate Transaminase Protects against Lipid Overload-Triggered Cardiac Injury in Mice |
| title_short | Gamma-Aminobutyrate Transaminase Protects against Lipid Overload-Triggered Cardiac Injury in Mice |
| title_sort | gamma aminobutyrate transaminase protects against lipid overload triggered cardiac injury in mice |
| topic | lipid overload ABAT mitochondrial dysfunction heart dysfunction apoptosis cardiomyocytes |
| url | https://www.mdpi.com/1422-0067/23/4/2182 |
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