Pathogenesis of atherosclerosis: lipid metabolism

Abstract Lipids are carried in plasma as microparticles, lipoproteins, composed of a core of hydrophobic lipids and a surface of amphipathic lipids. In addition, the particles carry proteins (i.e. apolipoproteins). The proteins have key functions in the metabolism as receptor ligands, enzymes or activators. Lipoproteins are classified based on density into: chylomicrons, VLDL, IDL, LDL, and HDL. Retention of apoB-containing lipoproteins (LDL, IDL, and VLDL) in the arterial intima is the initiating event in the development of atherosclerosis. Retention is mediated by binding of apoB to structural proteoglycans in the intima. Increased plasma concentration of apoB-containing lipoproteins is the main risk factor for atherosclerotic cardiovascular disease (CVD) and the causative role of LDL has been demonstrated in several studies. Lp(a) is a subclass of LDL and elevated Lp(a) is an independent risk-factor, primarily genetically mediated. Genetic data support that high Lp(a) causes atherosclerosis. Elevated triglycerides in plasma are associated with increased risk for CVD. Whether triglycerides directly induce atherogenesis is still unclear, but current data strongly support that remnant particles from triglyceride-rich lipoproteins are causal. HDL are lipoproteins that have been considered to be important for reversed cholesterol transport. Low HDL is a strong risk-factor for CVD. However, the causative role of HDL is debated and intervention studies to raise HDL have not been successful. Reduction of LDL is the main target for prevention and treatment, using drugs that inhibit the enzyme HMG-CoA reductase, i.e. statins. Other drugs for LDL reduction and to modify other lipoproteins may further reduce risk, and new therapeutic targets are explored.