The pathophysiology of excess plasma-free cholesterol

Area of Science:

• Biochemistry
• Cardiovascular Science
• Metabolic Research

Background:

• Large studies indicate elevated all-cause and atherosclerotic cardiovascular disease mortality.
• Plasma HDL-cholesterol (HDL-C) is typically measured as a sum of free cholesterol (FC) and cholesteryl ester (CE).
• FC and CE have distinct metabolic pathways, suggesting differential roles in cardiovascular health.

Approach:

• Review of human studies and preclinical models (HDL-receptor deficient mice).
• Analysis of data associating high plasma HDL-C with increased mortality.
• Investigation into the specific contribution of HDL-FC to pathological effects.

Key Points:

• A subset of humans with high HDL-C exhibits increased mortality.
• Preclinical models (Scarb1-/- mice) with elevated HDL-C show similar mortality patterns.
• Evidence suggests that elevated HDL-FC, not total HDL-C, is the pathological component.

Conclusions:

• High plasma HDL-FC is associated with increased mortality.
• Clinical trials, particularly those involving high HDL-C levels, should differentiate between HDL-FC and HDL-CE.
• Measuring both free and esterified cholesterol provides a more accurate assessment of cardiovascular risk than total HDL-C alone.