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

Open access
Nikkanen, Joni, Leong, Yew Ann, Krause, William C., Dermadi, Denis, Maschek, J. Alan, Van Ry, Tyler, Cox, James E., Weiss, Ethan J. +3 more·2022·Science
DOI 10.1126/science.abn9886PMC PMC9870047

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Abstract

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.

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  • Gender differences in the progression of NASH have also been observed in Bcl6 deficient mice.

    “Gender differences in the progression of NASH have also been observed in Bcl6 deficient mice40.”

    From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [40]

    The passage on hepatic Bcl6 deletion (section labeled Abstract; page unavailable) reports that deleting Bcl6 reduced fatty-liver features in male mice and reduced hepatic triglycerides more subtly in females. That supports a sex difference in fatty-liver outcomes, but the paper does not establish a sex difference in NASH progression in Bcl6-deficient mice. (LLM, conf=0.88)

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Research works printed but not linked: 27

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Authors
Nikkanen, J., Leong, Y. A., Krause, W. C., Dermadi, D., Maschek, J. A., Van Ry, T., Cox, J. E., Weiss, E. J., Gokcumen, O., Chawla, A., & Ingraham, H. A.
Affiliations
  • University of California, San Francisco (US)
  • Institute of Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • University of Utah (US)
  • Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA.
  • Department of Biological Sciences, University at Buffalo, Buffalo, NY 14260, USA.
Corresponding author
  • Chawla, Ajay
  • Ingraham, Holly A.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-10-21
Volume
378
Issue
6617
Pages
290-295
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.abn9886
PMC
PMC9870047
OpenAlex
W4306902090
Cited by
77
References
38
Citations by year
2026: 11 · 2025: 18 · 2024: 19 · 2023: 27 · 2022: 2
FWCI
12.97
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (1s10od016232-01, 1s10od021505-01, 1s10od018210-01a1)
  • University of California, San Francisco (P30DK026743, 7000/7002124)
  • National Health and Medical Research Council (1142229)
  • National Institute on Aging (R01AG062331)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK121657, R01DK101064, R00DK129763, K99DK129763, P30DK098722, P30DK026743, R01DK094641)
  • Liver Center, University of California, San Francisco (P30 DK026743, DK026743)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Keywords
BCL6, sex differences, hepatic steatosis, hepatic gene expression, bacterial infection, impaired glucose tolerance, puberty, evolutionary trade-offs, male survival
MeSH terms
Host Adaptation, Animals, Bacterial Infections, Biological Evolution, Fatty Liver, Female, Gene Expression Regulation, Liver, Male, Sex Factors, Gene Deletion, Mice, Proto-Oncogene Proteins c-bcl-6

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