An increased flux of free fatty acids (FFA) from adipose tissue can result from insulin resistance or a defect in the acylation stimulatory protein (ASP) pathway. Enhanced hepatic uptake of FFA leads to increased triglyceride (TG), apolipoprotein (apo) B, and very-low-density lipoprotein (VLDL) production. The TG in VLDL is exchanged for cholesteryl esters (CE) from low-density lipoproteins (LDL) and high-density lipoproteins (HDL) by the cholesteryl ester transport protein (CETP), producing CE-depleted LDL and HDL. The TG in the core of LDL and HDL is then hydrolyzed by lipases, producing both small, dense LDL and HDL. Such HDL is more likely to be excreted by the kidney, resulting in low HDL-C levels. HL = hepatic lipase; IDL = intermediate-density lipoprotein; IR = insulin resistance; LCAT = lecithin-cholesterol acyltransferase; LPL = lipoprotein lipase.

Increased small dense low-density lipoprotein (LDL) production, combined with a lower affinity of small, dense LDL for the low-density lipoprotein receptor (LDL-R) and a longer residence time in plasma, leads to an increased number of small, dense LDL particles. The increased small, dense LDL cross the arterial wall more readily, bind more avidly to proteoglycans in the intimal matrix, and are more easily oxidized, characteristics all conducive to atherogenesis (16). Small, dense LDL promotes endothelial cell dysfunction, inducing greater production of plasminogen activator inhibitor (PAI)-I and thromboxane A₂ (TXA₂).