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

ABSTRACT: 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.

SUBMITTER: Zhang M 

PROVIDER: S-EPMC8874535 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature