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Cited by 67Circadian rhythm and melatoninLiver Disease Diagnosis and TreatmentDietary Effects on Health

XBP1 links the 12-hour clock to NAFLD and regulation of membrane fluidity and lipid homeostasis

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Meng, Huan, Gonzales, Naomi M., Lonard, David M., Putluri, Nagireddy, Zhu, Bokai, Dacso, Clifford C., York, Brian, O’Malley, Bert W.·2020·Nature Communications
DOI 10.1038/s41467-020-20028-zPMC PMC7718229
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Abstract

A distinct 12-hour clock exists in addition to the 24-hour circadian clock to coordinate metabolic and stress rhythms. Here, we show that liver-specific ablation of X-box binding protein 1 (XBP1) disrupts the hepatic 12-hour clock and promotes spontaneous non-alcoholic fatty liver disease (NAFLD). We show that hepatic XBP1 predominantly regulates the 12-hour rhythmicity of gene transcription in the mouse liver and demonstrate that perturbation of the 12-hour clock, but not the core circadian clock, is associated with the onset and progression of this NAFLD phenotype. Mechanistically, we provide evidence that the spliced form of XBP1 (XBP1s) binds to the hepatic 12-hour cistrome to directly regulate the 12-hour clock, with a periodicity paralleling the harmonic activation of the 12-hour oscillatory transcription of many rate-limiting metabolic genes known to have perturbations in human metabolic disease. Functionally, we show that Xbp1 ablation significantly reduces cellular membrane fluidity and impairs lipid homeostasis via rate-limiting metabolic processes in fatty acid monounsaturated and phospholipid remodeling pathways. These findings reveal that genetic disruption of the hepatic 12-hour clock links to the onset and progression of NAFLD development via transcriptional regulator XBP1, and demonstrate a role for XBP1 and the 12-hour clock in the modulation of phospholipid composition and the maintenance of lipid homeostasis.

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  • A majority of Hep-ID transcription factor genes (9 out of 13), including Mlxipl, were characterized by XBP-1-dependent ultradian expression patterns.

    “mining data from Meng et al (2020) revealed that a majority of Hep‐ID TF genes (9 out of 13), including for example Mlxipl, were characterized by XBP‐1‐dependent ultradian expression patterns (Fig 3C and D, and Table EV2).”

    From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Meng et al, 2020

    The Results sections on the hepatic 12-hour transcriptome and XBP1s cistrome report XBP1-dependent oscillating genes in mouse liver, supporting the general basis for the citing authors’ data-mining analysis. Our copy does not identify the Hep-ID transcription factor set, report that 9 of 13 have these patterns, or name Mlxipl as an example; those specifics cannot be checked against it. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Rhythmic and zonated hepatic gene expression are crucial to maintain appropriate liver metabolic and non-metabolic activities.

    “rhythmic and zonated hepatic gene expression are crucial to maintain appropriate liver metabolic and non‐metabolic activities (Mukherji et al, 2019; Meng et al, 2020; Pan et al, 2020; Paris & Henderson, 2022).”

    From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Meng et al, 2020

    The Introduction and Discussion (page not available in our copy) link rhythmic hepatic gene expression to metabolic homeostasis and describe coordination of metabolic and stress rhythms. The paper does not establish the claim about zonated gene expression or the maintenance of non-metabolic liver activities. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Several Hep-IDCONNECT transcription factors are central to establishment of rhythmic hepatocyte gene expression, including both circadian (BHLHE40, CLOCK, DBP, NFIL3, NR1D1/2) and ultradian (XBP1) rhythms.

    “Several Hep‐IDCONNECT TFs are central to establishment of rhythmic hepatocyte gene expression (Appendix Fig S11) including both circadian (BHLHE40, CLOCK, DBP, NFIL3, NR1D1/2; Mukherji et al, 2019) and ultradian (XBP1; Meng et al, 2020; Pan et al, 2020) rhythms.”

    From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Meng et al, 2020

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Cited by

Sorted by citations

Authors
Meng, H., Gonzales, N. M., Lonard, D. M., Putluri, N., Zhu, B., Dacso, C. C., York, B., & O’Malley, B. W.
Affiliations
  • Baylor College of Medicine (US)
  • University of Pittsburgh (US)
Corresponding author
  • York, Brian
  • O’Malley, Bert W.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-12-04
Volume
11
Issue
1
Pages
6215-6215
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-20028-z
PMC
PMC7718229
OpenAlex
W3107743857
Cited by
67
References
1
Citations by year
2026: 10 · 2025: 11 · 2024: 13 · 2023: 11 · 2022: 17 · 2021: 5
FWCI
4.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (1P01DK113954)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Physiology › Dietary Effects on Health
Keywords
XBP1, non-alcoholic fatty liver disease, circadian clock, hepatic gene transcription, membrane fluidity, lipid homeostasis, phospholipid remodeling, endoplasmic reticulum stress, liver-specific knockout
MeSH terms
X-Box Binding Protein 1, Animals, Fatty Acids, Gene Expression Regulation, Homeostasis, Humans, Liver, Male, Membrane Fluidity, Mice, Inbred C57BL, Mice, Transgenic, Phospholipids, Mice, Knockout, Circadian Clocks, Non-alcoholic Fatty Liver Disease

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