Novel metabolic system for lactic acid via LRPGC1/ERRγ signaling pathway
| Autor: | Takashi Tanida, Masaki Tanaka, Ken-ichi Matsuda |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Active Transport Cell Nucleus Response Elements Biochemistry 03 medical and health sciences Transactivation Mice 0302 clinical medicine Chlorocebus aethiops Genetics medicine Animals Humans Glycolysis Lactic Acid Rats Wistar Nuclear export signal Molecular Biology Cell Nucleus Mice Inbred ICR Chemistry Hep G2 Cells TFAM medicine.disease Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Cell biology Rats 030104 developmental biology Mitochondrial biogenesis Nuclear receptor Liver Receptors Estrogen Lactic acidosis COS Cells Acidosis Lactic Female Signal transduction 030217 neurology & neurosurgery Biotechnology Signal Transduction Transcription Factors |
| Zdroj: | FASEB journal : official publication of the Federation of American Societies for Experimental BiologyREFERENCES. 34(10) |
| ISSN: | 1530-6860 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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