Altered Hepatic Metabolism in Down Syndrome

Area of Science:

• Genetics and Genomics
• Metabolomics
• Human Health

Background:

• Down syndrome (DS), caused by Trisomy 21 (T21), is the most common chromosomal abnormality.
• Individuals with DS have increased risks for congenital heart defects, autoimmunity, and Alzheimer's disease.
• DS affects multiple organ systems, suggesting widespread physiological impacts.

Purpose of the Study:

• To investigate metabolic changes in individuals with Down syndrome using multi-omic analysis.
• To explore the impact of Trisomy 21 on bile acid metabolism and liver function.
• To examine the effects of dietary fat modulation on hepatic metabolism in a Down syndrome mouse model.

Main Methods:

• Multi-omic analysis of plasma from over 400 individuals with Down syndrome.
• Utilized a Down syndrome mouse model (Dp16) for mechanistic studies.
• Employed bulk RNA-sequencing and single-cell transcriptomics of liver tissue.
• Investigated the effects of dietary fat modulation on gene expression and metabolic profiles.

Main Results:

• Broad metabolic changes observed in the Down syndrome population, including elevated bile acid levels.
• Identified protein signatures indicative of liver dysfunction in individuals with DS.
• Confirmed conserved perturbations in bile acid metabolism and liver pathology in the DS mouse model.
• Revealed widespread impacts of Trisomy 21 on hepatic metabolism and inflammation, with specific cell types identified.

Conclusions:

• Down syndrome is associated with significantly altered hepatic metabolism, characterized by dysregulated bile acid pathways.
• Liver pathology and metabolic disturbances in Down syndrome are conserved in mouse models.
• Dietary fat intake can influence gene expression, bile acid profiles, and liver health in the context of Down syndrome.
• These findings suggest that diet represents a potential therapeutic avenue for managing metabolic complications in Down syndrome.