Integrated omics approach for the identification of HDL structure-function relationships in PCSK9-related familial hypercholesterolemia.

Background: The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in dyslipidemia may go beyond its immediate effects on low-density lipoprotein receptor (LDL-R) activity.

Objective: This study aimed to assess PCSK9-derived alterations of high-density lipoprotein (HDL) physiology, which bear a potential to contribute to cardiovascular risk profile.

Methods: HDL was isolated from 33 patients with familial autosomal dominant hypercholesterolemia (FH), including those carrying PCSK9 gain-of-function (GOF) genetic variants (FH-PCSK9, n = 11), together with two groups of dyslipidemic patients employed as controls and carrying genetic variants in the LDL-R not treated (ntFH-LDLR, n = 11) and treated (tFH-LDLR, n = 11) with statins, and 11 normolipidemic controls.

High-density lipoproteins (HDL): Novel function and therapeutic applications.

The failure of high-density lipoprotein (HDL)-raising agents to reduce cardiovascular disease (CVD) together with recent findings of increased cardiovascular mortality in subjects with extremely high HDL-cholesterol levels provide new opportunities to revisit our view of HDL. The concept of HDL function developed to explain these contradictory findings has recently been expanded by a role played by HDL in the lipolysis of triglyceride-rich lipoproteins (TGRLs) by lipoprotein lipase. According to the reverse remnant-cholesterol transport (RRT) hypothesis, HDL critically contributes to TGRL lipolysis via acquirement of surface lipids, including free cholesterol, released from TGRL.

HDL and Reverse Remnant-Cholesterol Transport (RRT): Relevance to Cardiovascular Disease.

Cardiovascular diseases predominantly result from atherosclerosis, a natural biological phenomenon reflecting food intake and energy production in humans. Lipolysis of plasma triglyceride-rich lipoproteins (TGRLs) by lipoprotein lipase (LPL) is an essential element of energy production that delivers free fatty acids to peripheral cells. High-density lipoprotein (HDL) plays a key role in this process by acquiring surface lipids, including free cholesterol, that are released upon TGRL lipolysis.