Summary
Highlights
The intricate system of lipid transportation and utilization is crucial for cholesterol and triglyceride balance. Disruptions in this system lead to dyslipoproteinemias, characterized by abnormal plasma lipid levels and accumulation of cholesterol in arterial walls, increasing atherogenic risk.
Atheroprotective Apo A1 guided particles primarily carry HDL cholesterol, while atherogenic cholesterol resides in ApoB guided particles (non-HDL LDL, chylomicron remnants, VLDL, and IDL). Elevated triglycerides signal increased atherogenic non-HDL cholesterol, and an imbalance between ApoB and Apo A1 lipoproteins intensifies atherogenic burden. Pathological modification of apolipoproteins can also influence their atherogenicity.
Dyslipoproteinemias associated with premature cardiovascular disease originate from four main categories: elevated ApoB, formation of atherogenic remnants, decreased HDL, and metabolic syndrome. Reduced clearance or overproduction of ApoB particles, as seen in familial hypercholesterolemia or atherogenic dyslipidemia, leads to elevated ApoB.
Abdominal obesity causes the release of free fatty acids, leading to increased production of abnormally large, triglyceride-rich VLDL. These VLDL contain elevated Apo C3, which inhibits lipoprotein lipase, thus diminishing triglyceride hydrolysis and impairing VLDL catabolism. Prolonged circulation allows CETP to exchange cholesterol esters for triglycerides, enriching ApoB particles with cholesterol and forming atherogenic remnants.
Atherogenic remnants can lead to small dense LDL (sdLDL) when hepatic lipase hydrolyzes their triglyceride-enriched cores. SdLDL are easily oxidized and cleared by non-LDL receptor pathways, making them highly atherogenic. Decreased HDL often accompanies elevated triglyceride-rich ApoB particles. CETP-mediated exchange makes HDL susceptible to hepatic lipase, reducing its size and plasma concentration, thus diminishing reverse cholesterol transport.
Metabolic syndrome, an emerging epidemic, is driven by obesity, physical inactivity, and genetic factors. Insulin resistance is a key mechanistic link, disrupting glucose metabolism and promoting hyperinsulinemia and glucose intolerance. Abdominal obesity, particularly visceral fat, is central, as it releases excess free fatty acids that lead to large VLDL, non-HDL cholesterol accumulation, sdLDL formation, and reduced HDL. Adipose tissue also secretes PAI-1 and pro-inflammatory cytokines, contributing to a prothrombotic and pro-inflammatory state.