Abstract：
Liver fibrosis is a determinant-stage process of many chronic liver diseases and affected over 7.9 billion populations worldwide with increasing demands of ideal therapeutic agents. Discovery of active molecules with anti-hepatic fibrosis efficacies presents the most attacking filed. Here, we revealed that hepatic L-aspartate levels were decreased in CCl4-induced fibrotic mice. Instead, supplementation of L-aspartate orally alleviated typical manifestations of liver injury and fibrosis. These therapeutic efficacies were alongside improvements of mitochondrial adaptive oxidation. Notably, treatment with L-aspartate rebalanced hepatic cholesterol-steroid metabolism and reduced the levels of liver-impairing metabolites, including corticosterone (CORT). Mechanistically, L-aspartate treatment efficiently reversed CORT-mediated glucocorticoid receptor β (GRβ) signaling activation and subsequent transcriptional suppression of the mitochondrial genome by directly binding to the mitochondrial genome. Knockout of GRβ ameliorated corticosterone-mediated mitochondrial dysfunction and hepatocyte damage which also weakened the improvements of L-aspartate in suppressing GRβ signaling. These data suggest that L-aspartate ameliorates hepatic fibrosis by suppressing GRβ signaling via rebalancing cholesterol-steroid metabolism, would be an ideal candidate for clinical liver fibrosis treatment.
摘要：
肝纤维化是许多慢性肝病的决定性阶段过程，并影响全球79亿人口，对理想治疗剂的需求不断增加。具有抗肝纤维化功效的活性分子的发现是最具攻击性的领域。这里,我们发现CCl4诱导的纤维化小鼠肝脏L-天冬氨酸水平降低。相反，补充L-天冬氨酸口服减轻肝损伤和纤维化的典型表现。这些治疗效果伴随着线粒体适应性氧化的改善。值得注意的是,治疗与L-天冬氨酸重新平衡肝胆固醇-类固醇代谢和降低肝损害代谢物的水平，包括皮质酮（CORT）。机械上,L-天冬氨酸治疗通过直接与线粒体基因组结合而有效地逆转了CORT介导的糖皮质激素受体β（GRβ）信号传导激活和随后的线粒体基因组转录抑制。基因敲除GRβ改善了皮质酮介导的线粒体功能障碍和肝细胞损伤，这也削弱了L-天冬氨酸抑制GRβ信号传导的改善。这些数据表明，L-天冬氨酸改善肝纤维化通过抑制GRβ信号通过再平衡胆固醇-类固醇代谢，将是临床肝纤维化治疗的理想候选者。
