Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
FASEB J. 2020 Oct;34(10):13239-13256. doi: 10.1096/fj.202000492R. Epub 2020 Aug 26.
Lactic acid (LA) is a byproduct of glycolysis resulting from intense exercise or a metabolic defect in aerobic processes. LA metabolism is essential to prevent lactic acidosis, but the mechanism through which LA regulates its own metabolism is largely unknown. Here, we identified a LA-responsive protein, named LRPGC1, which has a distinct role from PGC1α, a key metabolic regulator, and report that LRPGC1 particularly mediates LA response to activate liver LA metabolism. Following LA stimulation, LRPGC1, but not PGC1α, translocates from the cytoplasm to the nucleus through deactivation of nuclear export signals, interacts with the nuclear receptor ERRγ, and upregulates TFAM, which ensures mitochondrial biogenesis. Knockout of PGC1 gene in HepG2 hepatocarcinoma cells decreased the LA consumption and TFAM expression, which were rescued by LRPGC1 expression, but not by PGC1α. These LRPGC1-induced effects were mediated by ERRγ, concomitantly with mitochondrial activation. The response element for LRPGC1/ERRγ signaling pathway was identified in TFAM promoter. Notably, the survival rate of a mouse model of lactic acidosis was reduced by the liver-targeted silencing of Lrpgc1, while it was significantly ameliorated by the pharmacological activation of ERRγ. These findings demonstrate LA-responsive transactivation via LRPGC1 that highlight an intrinsic molecular mechanism for LA homeostasis.
乳酸（LA）是糖酵解的副产物，产生于剧烈运动或有氧过程中的代谢缺陷。LA 的代谢对于防止酸中毒至关重要，但 LA 调节自身代谢的机制在很大程度上尚不清楚。在这里，我们鉴定了一种 LA 反应蛋白，命名为 LRPGC1，它与 PGC1α（一种关键的代谢调节剂）具有不同的作用，并报告说 LRPGC1 特别介导 LA 反应以激活肝脏 LA 代谢。在 LA 刺激后，LRPGC1（而非 PGC1α）通过核输出信号的失活从细胞质易位到细胞核，与核受体 ERRγ 相互作用，并上调 TFAM，这确保了线粒体生物发生。在 HepG2 肝癌细胞中敲除 PGC1 基因会降低 LA 消耗和 TFAM 表达，而 LRPGC1 的表达可挽救这种降低，但 PGC1α 则不能。这些由 LRPGC1 诱导的作用是通过 ERRγ 介导的，同时伴随着线粒体的激活。在 TFAM 启动子中鉴定出 LRPGC1/ERRγ 信号通路的反应元件。值得注意的是，肝靶向沉默 Lrpgc1 会降低酸中毒小鼠模型的存活率，而通过药理学激活 ERRγ 则可显著改善这种情况。这些发现证明了通过 LRPGC1 的 LA 反应性反式激活，突出了 LA 动态平衡的内在分子机制。
