HDL Is Not Dead Yet.

Area of Science:

• Cardiovascular Science
• Lipid Metabolism
• Biochemistry

Background:

• Epidemiological studies suggest an inverse correlation between high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD).
• The causal role of HDL-C in CHD protection remains uncertain, with conflicting results from drug trials and Mendelian randomization studies.
• Previous research has challenged the direct protective role of HDL-C against CHD.

Purpose of the Study:

• To investigate the relationship between HDL structure and function and CHD risk.
• To explore whether specific HDL functionalities, beyond HDL-C levels, are causally linked to reduced CHD.
• To evaluate novel in vitro assays for assessing HDL's protective activity in clinical settings.

Main Methods:

• Review of epidemiological studies, clinical trials, and Mendelian randomization studies.
• Analysis of cholesterol efflux capacity as a functional marker of HDL.
• Description of cell-based and cell-free in vitro assays for HDL structure and function.

Main Results:

• Some Mendelian randomization studies indicate that specific HDL characteristics, not just HDL-C levels, are causally related to decreased CHD.
• Cholesterol efflux capacity is associated with lower prevalent and incident CHD, independent of HDL-C and apolipoprotein A-1.
• Very high HDL-C levels, particularly with mutations affecting reverse cholesterol transport, may paradoxically increase CHD risk.

Conclusions:

• The 'HDL hypothesis' requires revision, shifting focus from HDL-C levels to HDL structure and function.
• Specific HDL functions, such as cholesterol efflux capacity, may be more accurate indicators of cardioprotection than HDL-C alone.
• Novel in vitro assays can help elucidate which HDL functions are most protective against CHD, suggesting the HDL hypothesis is not entirely disproven.