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Hepatocyte nuclear factor 1 in renal lipid metabolism: molecular mechanisms and therapeutic potentials

Wenhui Zhu1, Wenfan Wang1, Yayun Wang1

  • 1College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, No. 1035, BoShuo Street, Changchun, 130117, China.

Cell Biology and Toxicology
|November 25, 2025
PubMed

Insights

Hepatic nuclear factor-1 (HNF-1) family proteins are key regulators of kidney lipid metabolism. Dysregulation of HNF-1 is linked to kidney disease progression and lipotoxicity, suggesting HNF-1 as a therapeutic target.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Metabolic Disorders

Background:

  • Kidney disease is increasingly associated with disrupted lipid metabolism.
  • The molecular mechanisms underlying renal lipotoxicity are not fully understood.
  • Hepatic nuclear factor-1 (HNF-1) family proteins, specifically HNF-1α and HNF-1β, play a critical role in maintaining renal lipid homeostasis.

Purpose of the Study:

  • To review the pivotal role of HNF-1α and HNF-1β in renal lipid homeostasis.
  • To integrate clinical and experimental evidence on HNF-1's function in kidney metabolic disorders.
  • To highlight HNF-1 as a potential therapeutic target for precision nephrology.

Main Methods:

  • Literature review integrating clinical and experimental data.
  • Analysis of HNF-1 isoforms' transcriptional regulation of lipid synthesis, oxidation, and transport.
  • Examination of clinical associations between HNF-1 mutations and kidney disease progression.

Main Results:

  • HNF-1α regulates cholesterol efflux via ApoM and inhibits cholesterol uptake by modulating PCSK9 and LDLR.
  • HNF-1β promotes cholesterol synthesis (HMGCR/SREBF2), influences the PCSK9-LDLR axis, and coordinates triglyceride metabolism (FXR, PPARγ).
  • HNF-1β regulates mitochondrial fatty acid oxidation (FAO) via PPARGC1A; mutations in HNF-1α (MODY3) and HNF-1β (MODY5) are linked to dyslipidemia, proteinuria, and CKD.

Conclusions:

  • HNF-1 isoforms are crucial regulators of renal lipid metabolism and homeostasis.
  • Dysfunctional HNF-1 signaling contributes to renal lipotoxicity and CKD progression.
  • Targeting HNF-1 pathways with pharmacological or precision interventions offers promising therapeutic strategies for kidney metabolic disorders.
Keywords:
HNF-1Kidney diseaseLipotoxicityRenal lipid metabolismTargeted therapy

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