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

Abstract Kidney disease is increasingly linked to dysregulated lipid metabolism, yet the molecular mechanisms driving renal lipotoxicity remain poorly understood. This review elucidates the pivotal role of the hepatic nuclear factor-1 family (HNF-1α and HNF-1β) in renal lipid homeostasis, integrating clinical and experimental evidence. Functionally, HNF-1 isoforms regulate lipid synthesis, oxidation, and transport via conserved POU domains and transcriptional networks. HNF-1α enhances high-density lipoprotein (HDL)-mediated cholesterol efflux through ApoM, while concurrently regulating PCSK9 to promote LDL receptor (LDLR) endocytosis and degradation, thereby inhibiting cholesterol uptake; whereas, HNF-1β promotes cholesterol synthesis via activation of HMGCR/SREBF2 and modulates the PCSK9-LDLR axis. Additionally, HNF-1β coordinates triglyceride metabolism through farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways, and regulates mitochondrial fatty acid β-oxidation (FAO) via peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A). Clinically, HNF-1α (MODY3) and HNF-1β (MODY5) mutations are closely associated with dyslipidemia, proteinuria, and CKD progression, with lipotoxicity serving as a key pathogenic driver. Therapeutic strategies targeting HNF-1 include pharmacological agents (e.g., metformin, GLP-1 agonists) and natural compounds (berberine, resveratrol) that modulate its transcriptional activity, alongside CRISPR and miRNA-based precision interventions. This review summarizes the important and multifaceted role of HNF-1 in renal metabolic disorders, highlighting its potential as a therapeutic target and offering new strategies for precision nephrology. Graphical Abstract • The HNF-1 transcription factor regulates renal lipid metabolism by coordinating lipid synthesis, transport, and fatty acid oxidation. • The HNF-1α/β maintains renal cholesterol homeostasis by regulating the HMGCR, PCSK9-LDLR, and ApoM pathways. • HNF-1β deficiency impairs the PPARGC1A pathway, leading to dysfunction of fatty acid β-oxidation in the renal tubules. • Targeting HNF-1 offers a novel precision therapy strategy for diabetic nephropathy.