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Hepatic proprotein convertases modulate HDL metabolism

Weijun Jin1, Xun Wang, John S Millar

  • 1Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. weijun@mail.med.upenn.edu

Cell Metabolism
|August 8, 2007
PubMed

Insights

Inhibiting liver proprotein convertases (PCs) lowers high-density lipoprotein cholesterol (HDL-C) by increasing endothelial lipase (EL) activity. This uncovers a new pathway controlling cholesterol homeostasis.

Area of Science:

  • Biochemistry
  • Cardiovascular Biology
  • Metabolic Research

Background:

  • Atherosclerosis risk correlates inversely with high-density lipoprotein cholesterol (HDL-C) levels.
  • HDL metabolism is not fully understood, with limited strategies to modify HDL-C.
  • Effective modulation of HDL-C remains a significant challenge in cardiovascular disease prevention.

Purpose of the Study:

  • To investigate the role of hepatic proprotein convertases (PCs) in regulating HDL metabolism.
  • To elucidate the mechanism by which hepatic PCs influence plasma HDL-C levels.
  • To identify novel therapeutic targets for modulating HDL-C and cholesterol homeostasis.

Main Methods:

  • Inhibition of classical proprotein convertases (PCs) in the liver.
  • Assessment of plasma HDL-C levels following PC inhibition.
  • Analysis of the expression and activity of endothelial lipase (EL) and angiopoietin-like protein 3 (ANGPTL3).

Main Results:

  • Inhibition of hepatic classical PCs, but not atypical PCs (S1P, PCSK9), decreased plasma HDL-C.
  • This effect was dependent on endothelial lipase (EL) expression.
  • Hepatic PCs regulate EL activity via direct cleavage of EL and activating cleavage of ANGPTL3, an EL inhibitor, leading to reduced HDL-C and impaired reverse cholesterol transport.

Conclusions:

  • The hepatic PC-ANGPTL3-EL-HDL pathway represents a novel mechanism controlling HDL metabolism.
  • Targeting hepatic PCs offers a potential strategy for modulating HDL-C levels.
  • Understanding this pathway is crucial for advancing cholesterol homeostasis research and cardiovascular disease treatment.

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