GABA-T Inhibition and Its Effects on the Progression of Hepatocellular Carcinoma and Aging

Abstract

Outside of its role in the central nervous system as an inhibitory neurotransmitter, ɣ-aminobutyric-acid (GABA) acts as a hepatokine within the liver. NAFLD is associated with increased risk of developing HCC. We have previously demonstrated obesity increases production and excretion of hepatic GABA. Furthermore, GABA can drive the progression of HCC. In regards to aging, obesity shortens lifespan and healthspan, thus contributing to accelerated aging. We performed two studies assessing the effects of GABA-transaminase inhibition on NAFLD-associated HCC and age-associated metabolic and physical declines. To assess the role of GABA within NAFLD-associated HCC, we created an accelerated diet-sensitive mouse model and targeted hepatic GABA production using ethanolamine-O-sulfate (EOS), a GABA-transaminase inhibitor. We found HCC decreased mRNA expression of the GABA shunt enzymes (GABA-transaminase and succinate semialdehyde dehydrogenase), decreased mRNA expression of export-type GABA transporters (SLC6A12 and SCL6A13), and decreased mRNA expression of GABA A receptor subunits. Overall, GABA-transaminase inhibition using EOS had no effect on tumor burden after 16 weeks of exposure to cancer-causing stimuli. To assess the role of GABA in aging, we tested measures of metabolic and physical performance in 6 months-old-, 12 months-old-, and 18 months-old mice. After administering EOS for 4 weeks, we observed modest improvements to glucose clearance, basal insulin, and all-limb grip strength in aged mice. Additionally, GABA-transaminase inhibition caused weight loss and lowered serum triglycerides in both young and aged mice.