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

Area of Science:

• Metabolic regulation
• Molecular biology
• Biochemistry

Background:

• Lactic acid (LA) is a byproduct of intense exercise and metabolic disorders, and its proper metabolism is crucial for preventing lactic acidosis.
• The precise mechanisms by which LA regulates its own metabolism are not fully understood.
• While PGC1α is a known metabolic regulator, the specific proteins involved in direct LA response remain largely unidentified.

Purpose of the Study:

• To identify and characterize a novel protein that responds to lactic acid and regulates its metabolism.
• To elucidate the molecular mechanism by which this protein activates liver lactic acid metabolism.
• To investigate the role of this protein in maintaining lactic acid homeostasis and its potential therapeutic implications.

Main Methods:

• Identification of a lactic acid-responsive protein (LRPGC1) distinct from PGC1α.
• Analysis of LRPGC1 subcellular localization upon LA stimulation.
• Investigation of LRPGC1 interaction with nuclear receptor ERRγ and its effect on TFAM expression.
• Functional studies using PGC1 gene knockout in HepG2 cells and rescue experiments.
• Assessment of LRPGC1 and ERRγ roles in a mouse model of lactic acidosis.

Main Results:

• LRPGC1, unlike PGC1α, translocates to the nucleus upon LA stimulation by deactivating nuclear export signals.
• LRPGC1 interacts with ERRγ to upregulate TFAM, promoting mitochondrial biogenesis and enhancing LA consumption.
• Knockout of PGC1 in HepG2 cells impaired LA consumption and TFAM expression, which were restored by LRPGC1 but not PGC1α.
• The LRPGC1/ERRγ pathway directly influences TFAM promoter activity.
• Liver-specific silencing of Lrpgc1 worsened lactic acidosis in mice, while ERRγ activation improved survival.

Conclusions:

• LRPGC1 is a key mediator of the liver's response to lactic acid, distinct from PGC1α.
• The LRPGC1/ERRγ signaling pathway represents a novel intrinsic mechanism for regulating lactic acid metabolism and maintaining homeostasis.
• Targeting the LRPGC1/ERRγ pathway offers a potential therapeutic strategy for managing lactic acidosis.