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Lactate (Lct)

Lactate (Lct) and Disease: Metabolic Roles and Clinical Implications

Lactate (Lct), once viewed as a metabolic waste product, is now recognized as a critical energy substrate, signaling molecule, and biomarker in various diseases. Its dysregulation contributes to pathogenesis, prognosis, and therapeutic targets across multiple conditions.

Liver Diseases

1. Chronic Liver Disease (CLD) and Cirrhosis:
   • Elevated lactate (>2 mmol/L) correlates with organ failure and mortality in cirrhotic patients. Lactate clearance rates predict ICU survival, with survivors showing higher clearance (-9 to 50%) vs. non-survivors (-33 to 43%)1.
   • NAFLD/NASH: Lactate accumulation and impaired clearance exacerbate hepatic steatosis via LDHB acetylation (reducing lactate breakdown) and MCT1-mediated lipid uptake. Inhibiting PCAF (a regulatory enzyme) restores LDHB activity and alleviates steatosis1.
   • Acute Liver Failure (ALF): High lactate levels predict poor outcomes in acetaminophen-induced ALF and post-hepatectomy liver failure1.
2. Hepatocellular Carcinoma (HCC):
   • Lactate metabolism fuels tumor growth, while LDH isoforms and lactate-to-methionine ratio (LMR) serve as prognostic biomarkers1.

Neurodegenerative Diseases

1. Alzheimer’s Disease (AD):
   • Astrocyte-to-neuron lactate shuttling is disrupted, impairing neuronal energy metabolism and promoting degeneration26.
2. Parkinson’s Disease (PD):
   • Mitochondrial dysfunction in dopaminergic neurons alters lactate metabolism, contributing to oxidative stress and cell death6.
3. Multiple Sclerosis (MS) and Huntington’s Disease (HD):
   • Dysregulated lactate transport and metabolism exacerbate neuroinflammation and axonal damage5.

Mitochondrial Diseases

1. Mitochondrial Myopathy (MM):
   • Lactate becomes a vital fuel source in muscle tissue due to impaired glycolysis and mitochondrial dysfunction. Blocking lactate uptake worsens outcomes, highlighting its role in survival34.
   • Hif1alpha deficiency reduces glycolytic enzymes, shifting reliance to lactate metabolism3.

Cancer and Immune Evasion

1. Tumor Microenvironment (TME):
   • Lactate accumulation promotes m6A RNA modification in tumor-infiltrating myeloid cells (TIMs) via METTL3, enhancing immunosuppression and tumor immune escape2.
   • Lactylation of HMGB1 (via GPR81/MCTs) increases vascular permeability, contributing to sepsis-like endothelial dysfunction2.

Cardiovascular Disease

1. Lactylation:
   • Lactate-mediated protein modification (e.g., histones, enzymes) regulates vascular inflammation and atherosclerosis. Targeting lactylation pathways may offer therapeutic strategies8.

Clinical and Prognostic Utility

• Biomarker: Elevated lactate predicts mortality in cirrhosis, ALF, and sepsis12.
• Therapeutic Targets:
  • LDHB acetylation inhibitors (e.g., PCAF blockers) for NAFLD.
  • MCT1 suppression to reduce lactate-driven lipid uptake in liver disease.
  • Lactate supplementation in mitochondrial myopathy to sustain energy metabolism3.

Conclusion

Lactate’s role in disease is multifaceted, spanning energy metabolism, immune signaling, and biomarker utility. Dysregulation in lactate production, transport, or utilization underpins conditions from liver failure to neurodegeneration, offering novel therapeutic avenues.

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References

1. Role of Lactate in Liver Diseases
2. Lactate in Cancer and Sepsis
3. Lactate in Mitochondrial Myopathy
4. Mitochondrial Lactate Metabolism
5. Lactate in Neurodegenerative Diseases
6. Lactate in Alzheimer’s and Parkinson’s
7. Lactate Regulation in Disease
8. Lactylation in Cardiovascular Disease