X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction

Peixiang Zhang, Joseph J. Munier, Carrie B. Wiese, Laurent Vergnes, Jenny C. Link, Fahim Abbasi, Emilio Ronquillo, Katherine Scheker, Antonio Muñoz, Yu-Lin Kuang, Elizabeth Theusch, Meng Lu, Gabriela Sanchez, Akinyemi Oni-Orisan, Carlos Iribarren, Michael J. McPhaul, Daniel K. Nomura, Joshua W. Knowles, Ronald M. Krauss, Marisa W. Medina and Karen Reue ()
Additional contact information
Peixiang Zhang: University of California
Joseph J. Munier: University of California
Carrie B. Wiese: University of California
Laurent Vergnes: University of California
Jenny C. Link: University of California
Fahim Abbasi: Stanford University School of Medicine
Emilio Ronquillo: University of California
Katherine Scheker: University of California
Antonio Muñoz: University of California, San Francisco
Yu-Lin Kuang: University of California, San Francisco
Elizabeth Theusch: University of California, San Francisco
Meng Lu: Kaiser Permanente
Gabriela Sanchez: Kaiser Permanente
Akinyemi Oni-Orisan: University of California
Carlos Iribarren: Kaiser Permanente
Michael J. McPhaul: Quest Diagnostics Nichols Institute
Daniel K. Nomura: University of California, Berkeley
Joshua W. Knowles: Stanford University School of Medicine
Ronald M. Krauss: University of California, San Francisco
Marisa W. Medina: University of California, San Francisco
Karen Reue: University of California

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.

Date: 2024
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DOI: 10.1038/s41467-024-49764-2

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