Parenteral nutrition results in peripheral ileal to hepatic circadian discordance in mice.

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  • Additional Information
    • Source:
      Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901227 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1547 (Electronic) Linking ISSN: 01931857 NLM ISO Abbreviation: Am J Physiol Gastrointest Liver Physiol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Bethesda, MD : American Physiological Society
    • Subject Terms:
      Ileum*/metabolism ; Parenteral Nutrition* ; Liver*/metabolism ; Circadian Rhythm* ; Bile Acids and Salts*/metabolism; Animals ; Mice ; Male ; Mice, Inbred C57BL ; Receptors, Cytoplasmic and Nuclear/metabolism ; Receptors, Cytoplasmic and Nuclear/genetics ; Signal Transduction ; Disease Models, Animal ; ARNTL Transcription Factors/genetics ; ARNTL Transcription Factors/metabolism ; Fibroblast Growth Factors/metabolism ; Fibroblast Growth Factors/genetics
    • Abstract:
      We have developed a mouse model of parenteral nutrition-associated liver disease (PNALD) in which parenteral nutrition (PN) infusion results in cholestatic liver injury. In the liver, the master circadian genes Arntl /Bmal drive rhythmic gene expression and regulate circadian expression of hepatic functions including bile acid synthesis. The aim of this study was to examine the effect of continuous PN on ileal and hepatic expression of circadian regulatory (CR) genes, farnesoid X receptor (FXR) signaling, and bile acid synthesis in mice. Wild-type mice were exposed to ad libitum Chow or continuous soy oil lipid emulsion-based PN infusion through a central venous catheter for 4 days (PN). Water was provided ad libitum, but no nutrients were provided enterally. On day 4 , separate groups of Chow and PN-fed mice were euthanized every 6 h (7 AM, 1 PM, 7 PM, and 1 AM), and ileal, hepatic tissue and serum harvested. From tissue samples, the relative expression of circadian transcription factors and FXR signaling was assessed. Administration of 4-day PN increased hepatic injury, inflammatory cytokine expression, and gut permeability. In the ileum, PN activated FXR and induced expression of Fgf15 and Nr0b2 . In the liver, expression of FXR-downstream targets was dysregulated. PN administrations impacted hepatic and ileal circadian transcription factor mRNA expression, which was discordant between the two organs. Dysregulation of circadian regulatory machinery is in part due to discordance of the gut-liver axis during PN. Pharmacological targeting of CR as a therapeutic strategy for PNALD thus deserves further investigation. NEW & NOTEWORTHY This study used a novel short-term model of parenteral nutrition (PN) that is translationally relevant. We find that short-term PN is sufficient to induce hepatic and ileal changes in circadian transcription factor expression and to prevent normal concordant coordination of circadian transcription factors between the ileum and liver. These data suggest that targeting circadian transcription may have some clinical benefit in patients receiving parenteral nutrition.
    • Grant Information:
      UL1TR002535 HHS | NIH | National Center for Advancing Translational Sciences (NCATS)
    • Contributed Indexing:
      Keywords: FXR; bile acids; cholestasis; circadian rhythm; parenteral nutrition-associated liver disease
    • Accession Number:
      0 (Bile Acids and Salts)
      0C5V0MRU6P (farnesoid X-activated receptor)
      0 (Receptors, Cytoplasmic and Nuclear)
      0 (ARNTL Transcription Factors)
      62031-54-3 (Fibroblast Growth Factors)
      0 (fibroblast growth factor 15, mouse)
    • Publication Date:
      Date Created: 20240920 Date Completed: 20241106 Latest Revision: 20241106
    • Publication Date:
      20241107
    • Accession Number:
      10.1152/ajpgi.00042.2024
    • Accession Number:
      39301965