In a new study published in Cell Reports titled, “Altered hepatic metabolism in Down syndrome,” researchers at the University of Colorado Anschutz Linda Crnic Institute for Down Syndrome (Crnic Institute) have uncovered evidence that individuals with Down syndrome experience significant alterations in liver metabolism, including elevated levels of bile acids in the bloodstream and other biomarkers of liver dysfunction. Results suggest that these changes may be modifiable through diet, providing hope for improved health outcomes.
The liver removes toxins from blood, produces bile for fat digestion, metabolizes nutrients, and makes proteins for blood clotting, making it an essential organ for detoxification, metabolism and immunity. Using multi-omic analysis of plasma samples from more than 400 research participants in the Human Trisome Project, a large cohort study of the population with Down syndrome run by the Crnic Institute, the team identified consistent elevations in bile acids across the lifespan, independent of body mass index (BMI) or co-occurring conditions.
The study also demonstrated that hepatocytes, the most abundant cells in the liver, derived from induced pluripotent stem cells donated by individuals with Down syndrome exhibit intrinsic metabolic dysfunction, including altered bile acid production and abnormally high fat storage. These findings reinforce the observations in research participants and point to a genetic basis for liver abnormalities in Down syndrome.
To better understand the mechanisms underlying liver dysfunction in Down syndrome, Crnic Institute researchers turned to the Dp16 mouse model. These mice exhibited striking abnormalities in the liver, including inflammation, fibrosis, and a ductular reaction, a phenomenon involving bile duct proliferation and remodeling of blood vessels.
Metabolomic analysis revealed elevated bile acids like those observed in people with Down syndrome, and gene expression profiling uncovered widespread disruptions in metabolic and inflammatory signaling pathways. Notably, dietary fat intake profoundly influenced these outcomes: mice fed a high-fat diet developed steatosis, a form of liver disease, and exacerbated liver injury, while a low-fat diet mitigated these effects.
“Our data show that Down syndrome profoundly impacts hepatic metabolism,” says Kelly Sullivan, PhD, associate professor of pediatrics at the University of Colorado Anschutz and corresponding author of the study. “Importantly, we found that dietary fat intake can exacerbate or ameliorate these effects in the mouse models, suggesting that nutrition could play a key role in managing liver health in this population.”
Liver disease affects up to 100 million adults in the U.S., yet its prevalence in Down syndrome has been poorly understood. The study emphasizes the importance of early monitoring and dietary strategies to reduce risk.
“The liver is an incredibly important organ for many biological functions across the lifespan, even mild liver dysfunction can have broad impacts on human health,” said Joaquín Espinosa, PhD, executive director of the Crnic Institute and professor of pharmacology. “The fact that liver dysfunction had not been well documented in this population until now highlights the value of transformative research funding through the National Institutes of Health INCLUDE Project and the Global Down Syndrome Foundation.”
The research team plans to explore clinical interventions, including low-fat diets and lifestyle modifications, to determine their impact on liver health in individuals with Down syndrome.
