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<p>Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) represents a global health crisis associated with dysregulated hepatic triglyceride (TG) synthesis, oxidation and secretion. Despite progress in targeting hepatic lipid synthesis/oxidation for MASLD treatment and a well-documented relationship between circadian rhythms and lipid metabolism, the adaptive mechanisms coordinating TG secretion with circadian timing remain incompletely understood. Here we identify an autocrine regulatory pathway where circadian hepatic Fibroblast Growth Factor 1 (<i>Fgf1</i>) expression synchronizes diurnal TG secretion with the active phase. FGF1 activation of FGFR4 induces an mTORC1-IRE1-XBP1 signaling cascade involving atypical IRE1 activation that promotes TG secretion. Consistently, dietary-driven MASLD is exacerbated in liver-specific FGF1 knockout mice, while exogenous FGF1 halts disease progression in a Metabolic dysfunction-Associated Steatohepatitis (MASH) mouse model. This study causally associates FGF1 circadian rhythmicity with TG secretion to establish FGF1 as a crucial pacemaker in hepatic lipid homeostasis.</p>

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FGF1 orchestrates circadian hepatic triglyceride secretion

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月19日

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  • Benan Pelin Sermikli,
  • Sihao Liu,
  • Kyeongkyu Kim,
  • Linnea Hases,
  • Tim van Zutphen,
  • Ashley Untereiner,
  • Jocelyn Torres,
  • Mingxiao He,
  • Lillian Crossley,
  • Yang Dai,
  • Jonathan Zhu,
  • Chandra Lekha Koopari,
  • Weiwei Fan,
  • Morgan L. Truitt,
  • Johan W. Jonker,
  • Annette R. Atkins,
  • Michael Downes,
  • Ronald M. Evans

摘要

Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) represents a global health crisis associated with dysregulated hepatic triglyceride (TG) synthesis, oxidation and secretion. Despite progress in targeting hepatic lipid synthesis/oxidation for MASLD treatment and a well-documented relationship between circadian rhythms and lipid metabolism, the adaptive mechanisms coordinating TG secretion with circadian timing remain incompletely understood. Here we identify an autocrine regulatory pathway where circadian hepatic Fibroblast Growth Factor 1 (Fgf1) expression synchronizes diurnal TG secretion with the active phase. FGF1 activation of FGFR4 induces an mTORC1-IRE1-XBP1 signaling cascade involving atypical IRE1 activation that promotes TG secretion. Consistently, dietary-driven MASLD is exacerbated in liver-specific FGF1 knockout mice, while exogenous FGF1 halts disease progression in a Metabolic dysfunction-Associated Steatohepatitis (MASH) mouse model. This study causally associates FGF1 circadian rhythmicity with TG secretion to establish FGF1 as a crucial pacemaker in hepatic lipid homeostasis.