Betaine/γ-aminobutyric acid (GABA) transporter 1 (BGT-1 or Slc6a12) is a transporter for the neurotransmitter GABA and osmolyte betaine. To date, most studies on BGT-1 have focused on its functions in the nervous system and renal osmotic homeostasis. Despite its dominant distribution in the liver, the function of BGT-1 in hepatic physiology or disease remains unknown. Here, we report that BGT-1 was significantly downregulated in patients with liver failure as well as in mice with experimental acute liver failure (ALF). Furthermore, mice deficient in BGT-1 showed significant resistance to ALF compared with wild type (WT) mice, manifesting as improved survival rate, reduced alanine transaminase/aspartate aminotransferase levels, better histopathological symptoms and fewer apoptotic cells in the liver. Similarly, in primary hepatocytes, BGT-1 deficiency or treatment with a BGT-1 inhibitor, NNC 05-2090, attenuated TNF-α mediated apoptosis. In addition, BGT-1 deficiency or dosing with NNC 05-2090 stimulated the expression of the anti-apoptotic gene, c-Met in the liver, suggesting the involvement of c-Met in the function on hepatocytes of BGT-1 apoptosis. Our findings suggest BGT-1 is a promising candidate drug target to prevent and treat hepatocyte apoptosis related diseases, such as ALF.

中文翻译：

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小鼠中的甜菜碱/ GABA转运蛋白1（BGT-1）缺乏可防止体内急性肝衰竭和体外肝细胞凋亡。

甜菜碱/γ-氨基丁酸（GABA）转运蛋白1（BGT-1或Slc6a12）是神经递质GABA和渗透压甜菜碱的转运蛋白。迄今为止，关于BGT-1的大多数研究都集中在其在神经系统和肾渗透压稳态中的功能上。尽管其主要分布在肝脏中，但BGT-1在肝生理或疾病中的功能仍然未知。在这里，我们报道在肝衰竭患者以及实验性急性肝衰竭（ALF）小鼠中BGT-1明显下调。此外，与野生型（WT）小鼠相比，缺乏BGT-1的小鼠表现出对ALF的显着耐药性，表现为存活率提高，丙氨酸转氨酶/天冬氨酸转氨酶水平降低，组织病理学症状改善且肝脏中的凋亡细胞减少。同样，在原代肝细胞中 BGT-1缺乏或使用BGT-1抑制剂NNC 05-2090进行治疗可减弱TNF-α介导的细胞凋亡。此外，BGT-1缺乏或与NNC 05-2090一起给药可刺激肝脏抗凋亡基因c-Met的表达，表明c-Met参与了BGT-1凋亡对肝细胞的功能。我们的发现表明BGT-1是预防和治疗肝细胞凋亡相关疾病（例如ALF）的有希望的候选药物靶标。