An evolutionary trade-off between host immunity and metabolism drives fatty liver in male mice.

Autor: Nikkanen J; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94143, USA.; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA., Leong YA; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA.; Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, 3800, Australia., Krause WC; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94143, USA., Dermadi D; Institute of Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.; Biomedical Informatics Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA., Maschek JA; Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA.; Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA., Van Ry T; Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA.; Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA., Cox JE; Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA.; Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA., Weiss EJ; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA., Gokcumen O; Department of Biological Sciences, University at Buffalo, Buffalo, NY 14260, USA., Chawla A; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA.; Departments of Physiology and Medicine, University of California San Francisco, San Francisco, CA 94143, USA., Ingraham HA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94143, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2022 Oct 21; Vol. 378 (6617), pp. 290-295. Date of Electronic Publication: 2022 Oct 20.
DOI: 10.1126/science.abn9886
Abstrakt: Adaptations to infectious and dietary pressures shape mammalian physiology and disease risk. How such adaptations affect sex-biased diseases remains insufficiently studied. In this study, we show that sex-dependent hepatic gene programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor B cell lymphoma 6 (BCL6), which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 protein comes at a cost during conditions of dietary excess, which result in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male survival during infection, thus establishing a sex-dependent trade-off between host defense and metabolic systems. Our findings offer strong evidence that some current sex-biased diseases are rooted in ancient evolutionary trade-offs between immunity and metabolism.
Databáze: MEDLINE
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