Deciphering structural aspects of reverse cholesterol transport: mapping the knowns and unknowns

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiovascular Research

Background:

• Atherosclerosis, a primary cause of cardiovascular disease (CVD), involves cholesterol accumulation in foam cells, forming atherosclerotic plaques.
• Cholesterol efflux from these cells via reverse cholesterol transport (RCT) is a potential therapeutic target for CVD.
• The RCT pathway involves a complex interplay of proteins including apolipoprotein A1 (ApoA1), lecithin cholesterol acyltransferase (LCAT), ATP binding cassette transporter A1 (ABCA1), and scavenger receptor-B1 (SR-B1).

Approach:

• This review extensively examines the structure-function relationships critical for the reverse cholesterol transport (RCT) pathway.
• It focuses on how genetic mutations affecting protein structural stability can impair RCT functionality.
• The review discusses the current limitations in understanding HDL function and RCT, hindering therapeutic development.

Key Points:

• The structural integrity of proteins involved in RCT directly influences their function and the efficiency of cholesterol removal.
• Genetic mutations disrupting protein structure can lead to non-functional or partially functional RCT pathways.
• A deeper understanding of the structural basis of RCT is essential for designing targeted therapies for atherosclerosis.

Conclusions:

• Current clinical trial failures in modulating RCT highlight a significant gap in understanding HDL function and RCT mechanisms.
• Further research into the structural aspects of RCT proteins and their interactions is necessary for successful therapeutic interventions.
• This review underscores the need for continued investigation into alternative theories and unresolved questions in RCT pathway research.