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Nitroxoline upregulates low-density lipoprotein receptors expression, enhances lipid metabolism, and reduces hepatic steatosis and atherosclerosis in Apoe-/- mice

  • 0Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei City 114202, Taiwan, ROC.
Biochimica Et Biophysica Acta. Molecular Basis of Disease +

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August 20, 2025

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August 20, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Nitroxoline boosts low-density lipoprotein receptor (LDLR) expression, improving cholesterol levels and reducing liver fat and atherosclerosis. This FDA-approved drug shows potential for treating metabolic disorders.

Area Of Science

  • Biochemistry
  • Pharmacology
  • Metabolic Disease Research

Background

  • Low-density lipoprotein receptors (LDLRs) are crucial for cholesterol homeostasis; their dysregulation links to atherosclerosis and steatohepatitis.
  • Identifying novel therapeutic strategies for lipid metabolism disorders is a significant unmet medical need.
  • Drug repurposing offers a faster route to clinical application for existing safe compounds.

Purpose Of The Study

  • To investigate the effects of nitroxoline on LDLR expression and its potential protective role in lipid dysregulation, hepatic steatosis, and atherosclerosis.
  • To elucidate the molecular mechanisms by which nitroxoline modulates LDLR and lipid metabolism.
  • To evaluate the therapeutic potential of nitroxoline in preclinical models of metabolic disease.

Main Methods

  • Screening of FDA-approved drugs to identify LDLR modulators.
  • In vitro studies using Huh7 cells (qPCR, Western blot, flow cytometry, RNA-seq) to assess LDLR expression and function.
  • In vivo studies in Apoe-/- mice to evaluate effects on serum lipids, liver histology, and atherosclerosis.
  • Mechanistic studies involving SREBF2, PPP2CA, AMPK, JNK, and RNA-binding proteins (HNRNPD).

Main Results

  • Nitroxoline significantly upregulated LDLR mRNA and protein, enhancing LDL uptake in vitro.
  • Nitroxoline promoted SREBF2 expression and stabilized LDLR mRNA via specific molecular pathways (AMPK, JNK, HNRNPD).
  • In vivo, nitroxoline reduced total cholesterol, triglycerides, and LDL-C, ameliorated hepatic steatosis and fibrosis, and attenuated atherosclerosis in Apoe-/- mice.

Conclusions

  • Nitroxoline effectively upregulates LDLR expression and improves hepatic lipid metabolism, demonstrating dual therapeutic actions.
  • Nitroxoline exhibits significant protective effects against diet-induced metabolic dysregulation and atherosclerosis in a preclinical model.
  • Nitroxoline's established safety profile and oral bioavailability suggest strong potential for repurposing in treating lipid disorders and cardiovascular disease.

Keywords:

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