Chunyan Hou | PubMed Health

PubMed2026

Genetically predicted lower FLT3L levels increase the risk of hypertrophic cardiomyopathy partly mediated by phosphate: Evidence from a 2-step Mendelian randomization analysis.

We performed a 2-step Mendelian randomization (MR) study to investigate the associations of Fms-related tyrosine kinase 3 ligand (FLT3L) and phosphate levels with the risk of hypertrophic cardiomyopathy (HCM). Genetic instruments for 75 circulating inflammatory factors were obtained from the NHGRI-EBI GWAS Catalog, while summary statistics for circulating phosphate and HCM were derived from the UK Biobank and FinnGen, respectively. Univariable MR analysis using the inverse-variance weighted method indicated that genetically predicted higher phosphate levels were associated with an increased risk of HCM (OR = 1.36, P = 4.82 × 10-2). Among the inflammatory markers, FLT3L emerged as a significant candidate and showed inverse associations with phosphate levels (β = -0.05, P = 1.70 × 10-9) and HCM (OR = 0.79, P = 4.10 × 10-2). Bidirectional MR analyses did not support a causal effect of phosphate on FLT3L. Mediation analysis suggested that phosphate levels accounted for an estimated 12.05% of the total effect of FLT3L on HCM. Genetic liability to lower FLT3L levels is associated with a higher risk of HCM, and this relationship may be partially mediated through circulating phosphate levels.

Humans↗

PubMed2025

O-GlcNAcylation of nuclear proteins in the mouse liver exhibit daily oscillations that are influenced by meal timing.

The liver circadian clock and hepatic transcriptome are highly responsive to metabolic signals generated from feeding-fasting rhythm. Previous studies have identified a number of nutrient-sensitive signaling pathways that could interpret metabolic input to regulate rhythmic hepatic biology. Here, we investigated the role of O-GlcNAcylation, a nutrient-sensitive post-translational modification (PTM) in mediating metabolic regulation of rhythmic biology in the liver. We observe daily oscillation of global nuclear protein O-GlcNAcylation in the liver of mice subjected to night-restricted feeding (NRF) using label-free global O-GlcNAc proteomics. Additional site-specific O-GlcNAc analysis by tandem mass tag mass spectrometry further supports temporal differences in O-GlcNAcylation by revealing day-night differences. Proteins involved in gene expression are enriched among rhythmically O-GlcNAcylated proteins, suggesting rhythmic O-GlcNAcylation may directly regulate the hepatic transcriptome. We show that rhythmic O-GlcNAcylation can also indirectly modulate nuclear proteins by interacting with phosphorylation. Several proteins harboring O-GlcNAcylation-phosphorylation interplay motif exhibit rhythmic O-GlcNAcylation and phosphorylation. Specifically, we show that O-GlcNAcylation occurs at a phospho-degron of a key circadian transcriptional activator, circadian locomotor output cycles kaput (CLOCK), thus regulating its stability and transcriptional output. Finally, we report that day-restricted feeding (DRF) in the nocturnal mouse significantly alters O-GlcNAcylation pattern. Whereas global O-GlcNAcylation analysis indicates dampening of global O-GlcNAcylation rhythm in mice fed under DRF, site-specific analysis reveals differential responses of O-GlcNAc sites when timing of food intake is altered. Notably, a substantial number of O-GlcNAcylation sites exhibit inverted day-night profiles when mice are subjected to DRF. This suggests the dysregulation of daily nuclear protein O-GlcNAcylation rhythm may contribute to the disruption in liver transcriptome previously observed in DRF condition. In summary, our results provide new mechanistic insights into metabolic regulation of hepatic transcriptional regulators via interplay between O-GlcNAcylation and phosphorylation and shed light on the deleterious effects of improper mealtimes.

Animals↗