Novel metabolic system for lactic acid via LRPGC1/ERRγ signaling pathway.

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 PGC1 alpha, a key metabolic regulator, and report that LRPGC1 particularly mediates LA response to activate liver LA metabolism. Following LA stimulation, LRPGC1, but not PGC1 alpha, translocates from the cytoplasm to the nucleus through deactivation of nuclear export signals, interacts with the nuclear receptor ERR gamma, and upregulatesTFAM, which ensures mitochondrial biogenesis. Knockout of PGC1 gene in HepG2 hepatocarcinoma cells decreased the LA consumption andTFAMexpression, which were rescued by LRPGC1 expression, but not by PGC1 alpha. These LRPGC1-induced effects were mediated by ERR gamma, concomitantly with mitochondrial activation. The response element for LRPGC1/ERR gamma signaling pathway was identified inTFAMpromoter. Notably, the survival rate of a mouse model of lactic acidosis was reduced by the liver-targeted silencing ofLrpgc1, while it was significantly ameliorated by the pharmacological activation of ERR gamma. These findings demonstrate LA-responsive transactivation via LRPGC1 that highlight an intrinsic molecular mechanism for LA homeostasis.