HDL and cholesterol: life after the divorce?

Area of Science:

• Cardiovascular Biology
• Lipid Metabolism
• Molecular Medicine

Background:

• High-density lipoprotein (HDL) and HDL-cholesterol (HDL-C) were historically considered interchangeable, with HDL-C levels a key therapeutic target for cardiovascular disease.
• Recent clinical trial failures demonstrated that raising HDL-C does not consistently reduce cardiovascular risk, necessitating a re-evaluation of HDL's role.
• Advances in understanding HDL's complex composition and biological functions have prompted a paradigm shift in its scientific definition.

Purpose of the Study:

• To redefine High-density lipoprotein (HDL) beyond its cholesterol-carrying capacity.
• To explore the functional significance of HDL's non-cholesterol cargo.
• To investigate HDL's role in endocrine-like systems through its transport of diverse molecules.

Main Methods:

• Review of current scientific literature on HDL composition and function.
• Analysis of recent findings regarding HDL's interactions with cellular and tissue systems.
• Characterization of HDL's non-cholesterol molecular cargo and their biological implications.

Main Results:

• HDL's functions are increasingly attributed to its diverse cargo, including proteins, small RNAs, hormones, and lipids, not solely cholesterol transport.
• HDL's ability to transport fat-soluble molecules impacts various endocrine-like systems.
• HDL interacts with nearly all cell types, delivering essential non-cholesterol components.

Conclusions:

• The scientific focus on HDL is moving from cholesterol-centric metrics to particle number, subclasses, and alternative measurements.
• HDL's non-cholesterol cargo plays a critical role in its biological functions and therapeutic potential.
• Understanding HDL's comprehensive cargo is essential for redefining its role in health and disease.