Altered hepatic metabolism in Down syndrome

Affiliations

¹ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO 80045, USA.
² Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO 80045, USA; Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
³ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO 80045, USA; Department of Pediatrics, Section of Developmental Pediatrics, University of Colorado Anschutz, Aurora, CO 80045, USA.
⁴ Department of Pathology, University of Colorado Anschutz, Aurora, CO 80045, USA.
⁵ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz, Aurora, CO 80045, USA; RNA Bioscience Initiative, University of Colorado Anschutz, Aurora, CO 80045, USA.
⁶ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz, Aurora, CO 80045, USA.
⁷ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO 80045, USA; RNA Bioscience Initiative, University of Colorado Anschutz, Aurora, CO 80045, USA; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz, Aurora, CO 80045, USA. Electronic address: kelly.d.sullivan@cuanschutz.edu.

PMID: 41538324
DOI: 10.1016/j.celrep.2025.116835

Free article

Altered hepatic metabolism in Down syndrome

Lauren N Dunn et al. Cell Rep. 2026.

Free article

. 2026 Jan 27;45(1):116835.

doi: 10.1016/j.celrep.2025.116835. Epub 2026 Jan 14.

Affiliations

¹ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO 80045, USA.
² Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO 80045, USA; Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
³ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO 80045, USA; Department of Pediatrics, Section of Developmental Pediatrics, University of Colorado Anschutz, Aurora, CO 80045, USA.
⁴ Department of Pathology, University of Colorado Anschutz, Aurora, CO 80045, USA.
⁵ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz, Aurora, CO 80045, USA; RNA Bioscience Initiative, University of Colorado Anschutz, Aurora, CO 80045, USA.
⁶ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz, Aurora, CO 80045, USA.
⁷ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz, Aurora, CO 80045, USA; RNA Bioscience Initiative, University of Colorado Anschutz, Aurora, CO 80045, USA; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz, Aurora, CO 80045, USA. Electronic address: kelly.d.sullivan@cuanschutz.edu.

PMID: 41538324
DOI: 10.1016/j.celrep.2025.116835

Abstract

Trisomy 21 (T21) gives rise to Down syndrome (DS), the most commonly occurring chromosomal abnormality in humans. T21 affects nearly every organ and tissue system in the body, predisposing individuals with DS to congenital heart defects, autoimmunity, and Alzheimer's disease, among other co-occurring conditions. Here, using multi-omic analysis of plasma from more than 400 people, we report broad metabolic changes in the population with DS typified by increased bile acid levels and protein signatures of liver dysfunction. In a mouse model of DS, we demonstrate conservation of perturbed bile acid metabolism accompanied by liver pathology. Bulk RNA sequencing revealed widespread impacts of the Dp16 model on hepatic metabolism and inflammation, while single-cell transcriptomics highlighted cell types associated with these observations. Modulation of dietary fat profoundly impacted gene expression, bile acids, and liver pathology. Overall, these data represent evidence for altered hepatic metabolism in DS that could be modulated by diet.

Keywords: CP: Metabolism; CP: Stem cell research; Down syndrome; bile acids; liver; metabolism.

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Conflict of interest statement

Declaration of interests J.M.E. has provided consulting services to Eli Lilly and Co., Gilead Sciences Inc., and Perha Pharmaceuticals.

Update of

Altered Hepatic Metabolism in Down Syndrome.
Dunn LN, Niemeyer BF, Eduthan NP, Schade KA, Waugh KA, Brown C, Rachubinski AL, Timkovich AE, Orlicky DJ, Galbraith MD, Espinosa JM, Sullivan KD. Dunn LN, et al. bioRxiv [Preprint]. 2025 May 31:2025.05.27.656393. doi: 10.1101/2025.05.27.656393. bioRxiv. 2025. Update in: Cell Rep. 2026 Jan 27;45(1):116835. doi: 10.1016/j.celrep.2025.116835. PMID: 40502193 Free PMC article. Updated. Preprint.

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Altered hepatic metabolism in Down syndrome

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Altered hepatic metabolism in Down syndrome

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