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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\u2010responsive protein, named LRPGC1, which has a distinct role from PGC1\u03b1, a key metabolic regulator, and report that LRPGC1 particularly mediates LA response to activate liver LA metabolism. Following LA stimulation, LRPGC1, but not PGC1\u03b1, translocates from the cytoplasm to the nucleus through deactivation of nuclear export signals, interacts with the nuclear receptor ERR\u03b3, and upregulates\n                    <jats:italic>TFAM<\/jats:italic>\n                    , which ensures mitochondrial biogenesis. Knockout of PGC1 gene in HepG2 hepatocarcinoma cells decreased the LA consumption and\n                    <jats:italic>TFAM<\/jats:italic>\n                    expression, which were rescued by LRPGC1 expression, but not by PGC1\u03b1. These LRPGC1\u2010induced effects were mediated by ERR\u03b3, concomitantly with mitochondrial activation. The response element for LRPGC1\/ERR\u03b3 signaling pathway was identified in\n                    <jats:italic>TFAM<\/jats:italic>\n                    promoter. Notably, the survival rate of a mouse model of lactic acidosis was reduced by the liver\u2010targeted silencing of\n                    <jats:italic>Lrpgc1<\/jats:italic>\n                    , while it was significantly ameliorated by the pharmacological activation of ERR\u03b3. These findings demonstrate LA\u2010responsive transactivation via LRPGC1 that highlight an intrinsic molecular mechanism for LA homeostasis.\n                  <\/jats:p>","DOI":"10.1096\/fj.202000492r","type":"journal-article","created":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T03:10:11Z","timestamp":1598929811000},"page":"13239-13256","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Novel metabolic system for lactic acid via LRPGC1\/ERR\u03b3 signaling pathway"],"prefix":"10.1096","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0864-2433","authenticated-orcid":false,"given":"Takashi","family":"Tanida","sequence":"first","affiliation":[{"name":"Department of Anatomy and Neurobiology, Graduate School of Medical Science Kyoto Prefectural University of Medicine Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken 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