Feeding-induced resistance to acute lethal sepsis is dependent on hepatic BMAL1 and FXR signalling

Sarah S. Geiger (), Javier Traba, Nathan Richoz, Taylor K. Farley, Stephen R. Brooks, Franziska Petermann, Lingdi Wang, Frank J. Gonzalez, Michael N. Sack and Richard M. Siegel ()
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Sarah S. Geiger: National Institutes of Health
Javier Traba: National Institutes of Health
Nathan Richoz: National Institutes of Health
Taylor K. Farley: National Institutes of Health
Stephen R. Brooks: NIH
Franziska Petermann: National Institutes of Health
Lingdi Wang: National Institutes of Health
Frank J. Gonzalez: National Institutes of Health
Michael N. Sack: National Institutes of Health
Richard M. Siegel: National Institutes of Health

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract In mice, time of day strongly influences lethality in response to LPS, with survival greatest at the beginning compared to the end of the light cycle. Here we show that feeding, rather than light, controls time-of-day dependent LPS sensitivity. Mortality following LPS administration is independent of cytokine production and the clock regulator BMAL1 expressed in myeloid cells. In contrast, deletion of BMAL1 in hepatocytes globally disrupts the transcriptional response to the feeding cycle in the liver and results in constitutively high LPS sensitivity. Using RNAseq and functional validation studies we identify hepatic farnesoid X receptor (FXR) signalling as a BMAL1 and feeding-dependent regulator of LPS susceptibility. These results show that hepatocyte-intrinsic BMAL1 and FXR signalling integrate nutritional cues to regulate survival in response to innate immune stimuli. Understanding hepatic molecular programmes operational in response to these cues could identify novel pathways for targeting to enhance endotoxemia resistance.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22961-z

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DOI: 10.1038/s41467-021-22961-z

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