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Nogo-B inhibition facilitates cholesterol metabolism to reduce hypercholesterolemia

Chao Xue1, Peng Zeng2, Ke Gong3

  • 1Department of Cardiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China; College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.

Cell Reports
|September 5, 2024
PubMed

Insights

Inhibiting Nogo-B promotes cholesterol excretion and uptake in the liver. This discovery offers a new strategy for lowering cholesterol levels by targeting Nogo-B expression.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Strategies for lowering cholesterol via enhanced excretion are limited.
  • Few molecular targets address multiple cholesterol metabolic pathways.

Purpose of the Study:

  • To investigate Nogo-B's role in cholesterol metabolism.
  • To identify Nogo-B as a potential therapeutic target for lowering cholesterol levels.

Main Methods:

  • Studied Nogo-B deficiency/inhibition in cellular and mouse models.
  • Analyzed the impact on hepatic cholesterol uptake and excretion pathways.
  • Investigated the interaction between Nogo-B and liver X receptor alpha (LXRα).

Main Results:

  • Nogo-B deficiency/inhibition simultaneously enhanced hepatic cholesterol uptake and excretion.
  • Nogo-B deficiency upregulated ATP-binding cassette transporters (ABCs), apolipoprotein E (ApoE), and low-density lipoprotein receptor (LDLR).
  • Nogo-B inhibition prevented LXRα ubiquitination degradation, boosting cholesterol excretion and promoting hepatic cholesterol uptake via SREBP2 and LDLR activation.

Conclusions:

  • Nogo-B deficiency/inhibition promotes both hepatic cholesterol uptake and excretion, offering a novel strategy to lower cholesterol.
  • Nogo-B inhibition reduced atherosclerotic plaques and cholesterol levels in mice.
  • Nogo-B levels correlate with plasma cholesterol in humans.
Keywords:
CP: MetabolismLXRαNogo-Batherosclerosischolesterol metabolismcoronary heart diseasehypercholesterolemia

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