Genetics and regulation of HDL metabolism

Area of Science:

• Cardiovascular Disease Research
• Lipid Metabolism
• Genetics and Molecular Biology

Background:

• Inverse association between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease (CVD) risk is well-established.
• Pharmaceutical interventions targeting HDL-C to reduce CVD risk have been unsuccessful, challenging the 'HDL hypothesis'.
• HDL-C levels exhibit significant heterogeneity, influenced by genetic and environmental factors.

Purpose of the Study:

• To review recent advancements in understanding the genetic and regulatory mechanisms of HDL metabolism.
• To explore novel therapeutic opportunities for modulating HDL levels and potentially mitigating CVD risk.

Main Methods:

• Analysis of epidemiological studies demonstrating the link between HDL-C and CVD risk.
• Review of genetic studies, including genome-wide association and Mendelian randomization studies, identifying loci associated with HDL-C levels.
• Examination of transcriptional regulation by nuclear receptors (PPARs, LXRs, HNF-4) and transcription factors (FOXO, ATF) in the liver.
• Inclusion of recent findings on the role of non-coding RNAs in post-transcriptional regulation of HDL genes.

Main Results:

• Numerous genetic loci contribute to HDL-C heterogeneity.
• Key transcription factor families in the liver (nuclear receptors, FOXO, ATF) play crucial roles in HDL metabolism.
• Non-coding RNAs represent a significant layer of post-transcriptional regulation impacting HDL gene expression.

Conclusions:

• Understanding the complex genetics and regulatory pathways of HDL metabolism is critical.
• Recent insights into transcriptional and post-transcriptional regulation provide new avenues for therapeutic interventions targeting HDL.
• Further research is needed to translate these findings into effective strategies for CVD prevention.