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FGF1 orchestrates circadian hepatic triglyceride secretion.

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Circadian Fibroblast Growth Factor 1 (FGF1) regulates liver triglyceride secretion, impacting Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). This discovery highlights FGF1 as a key factor in liver lipid homeostasis.

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Area of Science:

  • Hepatology
  • Endocrinology
  • Molecular Biology

Background:

  • Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) involves disrupted liver triglyceride (TG) metabolism.
  • The interplay between circadian rhythms and hepatic lipid secretion is not fully understood.

Purpose of the Study:

  • To elucidate the mechanisms coordinating diurnal TG secretion with circadian timing.
  • To identify the role of Fibroblast Growth Factor 1 (FGF1) in hepatic lipid homeostasis.

Main Methods:

  • Investigated an autocrine regulatory pathway involving circadian hepatic FGF1 expression.
  • Utilized liver-specific FGF1 knockout mice and a Metabolic dysfunction-Associated Steatohepatitis (MASH) mouse model.
  • Analyzed the FGF1-FGFR4-mTORC1-IRE1-XBP1 signaling cascade.

Main Results:

  • Identified circadian hepatic FGF1 as a synchronizer of diurnal TG secretion.
  • Demonstrated that FGF1 activates FGFR4, initiating an mTORC1-IRE1-XBP1 cascade that enhances TG secretion.
  • Showed exacerbated MASLD in FGF1 knockout mice and halted MASH progression with exogenous FGF1.

Conclusions:

  • Established a causal link between FGF1 circadian rhythmicity and TG secretion.
  • Positioned FGF1 as a critical regulator of hepatic lipid homeostasis.
  • Suggests FGF1 as a potential therapeutic target for MASLD and MASH.