Gamma-Aminobutyrate Transaminase Protects against Lipid Overload-Triggered Cardiac Injury in Mice

• Published in: International journal of molecular sciences Vol. 23; no. 4; p. 2182
• Main Authors: Zhang, Mengxiao, Zhong, Huiting, Cao, Ting, Huang, Yifan, Ji, Xiaoyun, Fan, Guo-Chang, Peng, Tianqing
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16.02.2022; MDPI
• Subjects: 4-Aminobutyrate Transaminase - genetics; 4-Aminobutyrate Transaminase - metabolism; ABAT; Adenosine Triphosphate - metabolism; Animals; Apoptosis; Biosynthesis; Cardiomyocytes; Catabolism; Copy number; Diabetes; Diabetes mellitus; Diet; Diet, High-Fat - adverse effects; DNA microarrays; Fatty acids; Fibrosis; gamma-Aminobutyric Acid - metabolism; Gene expression; Glucose; Heart; heart dysfunction; Heart Injuries - etiology; High fat diet; Hypertrophy; Laboratory animals; lipid overload; Lipids; Mice; Mice, Inbred C57BL; Mitochondrial DNA; mitochondrial dysfunction; Myocytes, Cardiac - metabolism; Obesity; Overexpression; Overloading; Oxidation; Oxidative stress; Palmitates - metabolism; Palmitic acid; Pathological effects; Proteins; Therapeutic targets; Transaminase; Transaminases; Transgenic animals; Transgenic mice; γ-Aminobutyric acid; Canada; St Louis Missouri; Ann Arbor Michigan; United States > US; China; cardiomyocytes; ROS; apoptosis; ABAT; lipid overload; mitochondrial dysfunction; heart dysfunction
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23042182

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.