To investigate the role of deoxyguanosine kinase (DGUOK) deficiency in purine metabolism, innate immune activation, and lipid accumulation in liver cells.
Approach:
Induction of DGUOK deficiency: Acute DGUOK deficiency was induced in HepG2 hepatocytes using siRNA-mediated knockdown.
Assessment methods: Mitochondrial integrity was evaluated through mtDNA quantification, mitochondrial morphology, and OXPHOS protein expression. Lipid accumulation was assessed using BODIPY staining, and transcriptomic changes were analyzed via bulk RNA sequencing.
Purine imbalance modeling: Wild-type cells were treated with 2′-deoxyadenosine to model purine imbalance, followed by assessments of DNA methylation, interferon signaling, and lipid accumulation.
Key Findings:
Acute DGUOK depletion resulted in a 2.9-fold increase in intracellular lipid droplet accumulation.
Activation of a type I interferon transcriptional program occurred despite preserved mtDNA content.
Bulk RNA sequencing revealed induction of human endogenous retroviruses (HERVs) and interferon-stimulated genes (ISGs), along with suppression of lipid metabolic pathways.
DGUOK-deficient cells showed approximately 40% reduction in global DNA methylation.
Interpretation:
Limitations:
The study primarily utilized HepG2 hepatocytes, which may not fully represent in vivo conditions and could affect the generalizability of the findings.
Further research is needed to explore the long-term effects of DGUOK deficiency on liver function and immune response.
Conclusion:
DGUOK deficiency links disrupted mitochondrial purine metabolism to immune and metabolic dysregulation in liver cells.
