GPLD1

Glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) is an exercise-induced hepatokine that facilitates liver–brain crosstalk by cleaving GPI anchors to release membrane-bound proteins into the circulation, thereby transferring the systemic benefits of physical activity to the central nervous system PMID 40818821PMID 398182785; PMID 39456173. By upregulating brain-derived neurotrophic factor (BDNF) and suppressing the uPAR coagulation pathway, GPLD1 promotes hippocampal neurogenesis, offering therapeutic potential for mitigating age-related cognitive decline PMID 40818821PMID 39456173PMID 34782555.

• Enzymatic Cleavage: GPLD1 is a phospholipase that cleaves glycosylphosphatidylinositol (GPI) anchors. This cleavage releases membrane-bound GPI-anchored proteins from cells into the circulation, triggering downstream signaling cascades PMID 40818821, 2025; PMID 39456173PMID 34782555.
• Signaling Pathways:
• uPAR System: GPLD1 downregulates coagulation and complement components participant in the urokinase-type plasminogen activator receptor (uPAR) pathway. The suppression of this pathway is linked to the mitigation of age-associated cognitive decline PMID 40818821PMID 39456173.
• GAL3BP/APP Interaction: Overexpression of GPLD1 increases the secretion of galectin-3-binding protein (GAL3BP). GAL3BP interacts with the amyloid precursor protein (APP) to inhibit the production of amyloid-beta (Aβ), a hallmark of Alzheimer's disease PMID 40818821.
• Neurogenesis: GPLD1 upregulation leads to increased expression of Brain-Derived Neurotrophic Factor (BDNF) and promotes neurogenesis in the hippocampus PMID 39818278PMID 39456173.
• Blood-Brain Barrier (BBB) Impermeability: Crucially, GPLD1 does not cross the blood-brain barrier. Instead, it exerts its neuroprotective effects through peripheral mechanisms that subsequently influence the central nervous system via the liver–brain axis PMID 40818821PMID 35304603.

GPLD1 is classified as a hepatokine (liver-derived exerkine) because its circulating levels are modulated by physical activity and it mediates the systemic benefits of exercise on the brain though it is secreted by the liver.

• Exercise-Induced Secretion: Hepatic expression and plasma levels of GPLD1 are significantly upregulated following exercise, including resistance training and high-intensity interval training (HIIT) PMID 40818821PMID 39818278PMID 38917635.
• Transfer of Exercise Benefits: The "exerkine" status of GPLD1 was solidified by studies showing that transferring blood plasma from exercised aged mice to sedentary aged mice transferred the neurogenic and cognitive benefits of exercise. GPLD1 was identified as the critical blood factor responsible for this transfer PMID 39456173PMID 35304603.
• Correlation with Active Lifestyles: In humans, blood concentrations of GPLD1 are reported to be higher in active, healthy older adults compared to sedentary individuals PMID 39456173PMID 35304603.

• Cognitive Enhancement and Neurogenesis: Overexpression or administration of GPLD1 improves memory and cognitive function in aged mice. It promotes adult neurogenesis in the hippocampus and upregulates BDNF expression, effectively reversing age-related regenerative deficits PMID 39818278PMID 39456173PMID 35304603.
• Alzheimer’s Disease (AD): By promoting the secretion of GAL3BP, GPLD1 inhibits Aβ production, thereby ameliorating cognitive impairment associated with AD models PMID 40818821.
• Cerebrovascular Injury: GPLD1 may regulate platelet activity in stroke models, suggesting a role in modulating the liver-brain axis following cerebrovascular injury PMID 40818821.
• Clinical Limitations: While preclinical results are robust, the therapeutic potential in humans requires further validation. One cohort study noted a negative correlation between GPLD1 and processing speed in elderly individuals, contrasting with the positive findings in mice, which indicates a need for more clinical trials to clarify its role in human neurological disorders PMID 40818821.

1. Cardiovascular Protection

• Therapeutic Strategy: Increasing GPLD1 activity appears beneficial. Cardiac-specific overexpression of GPLD1 was found to ameliorate cardiac dysfunction and hypertrophy, whereas depletion exacerbated these conditions PMID 40631685.

2. Oncology and Drug Resistance

• Therapeutic Strategy: Targeting GPLD1 is proposed to overcome chemotherapy resistance. Ablating GPLD1-positive cells combined with 5-fluorouracil (5-FU) treatment significantly reduced tumor viability and regrowth in organoid models PMID 39743241.