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

Nat Commun. 2021 May 12;12(1):2745. doi: 10.1038/s41467-021-22961-z.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism*
  • Animals
  • Circadian Rhythm / genetics
  • Disease Models, Animal
  • Disease Resistance
  • Feeding Behavior / physiology*
  • Hepatocytes / metabolism
  • Hypoglycemia / metabolism
  • Lipopolysaccharides / administration & dosage
  • Lipopolysaccharides / toxicity
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Sepsis / chemically induced
  • Sepsis / genetics
  • Sepsis / metabolism
  • Sepsis / mortality*
  • Signal Transduction

Substances

  • ARNTL Transcription Factors
  • Bmal1 protein, mouse
  • Lipopolysaccharides
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor