The Effects of Niacin on Lipoprotein Subclass Distribution

John M. Morgan, MD; Christina M. Carey, PA-C; Anne Lincoff, MD; David M. Capuzzi, MD, PhD

In This Article

Importance of Lipoprotein Subclasses

Lipoprotein subclasses containing apolipoprotein (apo) B, including VLDL, intermediate density lipoproptein (IDL), and LDL, promote atherosclerosis.[12] Particles of VLDL vary in size depending on their TG content. Increased serum TG levels promote the hepatic formation of large VLDL. Large VLDL formation is accelerated in patients with insulin resistance, such as occurs in obesity, metabolic syndrome, and type 2 diabetes. These particles have proatherogenic properties, particularly via the generation of other atherogenic lipoproteins such as IDL, a remnant lipoprotein and precursor of LDL.[5,12] When large VLDL concentrations are high, the action of cholesterol-ester transfer protein exchanges TG in the largest VLDL particles for cholesterol esters on large LDL. With large LDL partially depleted of cholesterol esters, hydrolysis of its acquired TG by hepatic lipase leads to the formation of small, dense LDL particles.[5]

Although small, dense LDL particles have reduced concentrations of free cholesterol, cholesterol ester, and phospholipids compared with larger, more buoyant LDL particles, they represent the most atherogenic LDL fraction.[13,14] The difference in composition appears to be associated with the increased susceptibility of small, dense LDL particles to lipid peroxidation, which promotes inflammation and foam cell formation.[15] Small, dense LDL particles have reduced affinity for hepatic LDL receptors, which prolong their presence in the circulation. Their small size may be responsible for the facility with which they cross the endothelium and penetrate the vascular wall.[12,16] Oxidized LDL also inhibits nitric oxide production and promotes thrombosis.[17] Persons with a predominance of small, dense particles are classified as having LDL phenotype pattern B, compared with pattern A characterized by large LDL particle predominance. Family studies suggest that pattern B is inherited as a dominant single-gene trait with a population frequency of 25%.[18] In addition, chylomicrons are another form of TG-rich lipoprotein that are formed in the intestine from dietary fat. Chylomicron remnants probably also have some atherogenic potential.[1]

HDL particles transport cholesterol from peripheral cells to the liver, but the different HDL subclasses have varying involvement in this process of reverse cholesterol transport and disparate effects on atherogenesis. Cholesterol-poor small HDL (HDL3) originates in the liver and intestines.[5,19] The HDL3 core expands with the accumulation and subsequent esterification of free cholesterol by lecithin-cholesterol acyltransferase. The result is a larger, more buoyant, mature HDL2 particle that transports esterified cholesterol to the liver. The HDL2 subfraction also has antioxidant properties, inhibits thrombotic factors, and is considered the more cardioprotective.[19,20]