Hepatic proprotein convertases modulate HDL metabolism

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.