The plasma lipoproteins (see Fig. 18.29) include chylomicrons, verylow-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). They function to keep lipids (primarily triacylglycerol [TAG] and cholesteryl esters) soluble as they transport them between tissues. Lipoproteins are composed of a neutral lipid (TAG, cholesteryl esters, or both) core surrounded by a shell of amphipathic apolipoproteins, phospholipid, and nonesterified cholesterol. Chylomicrons are assembled in intestinal mucosal cells from dietary lipids (primarily TAG). Each nascent chylomicron particle has one molecule of apolipoprotein (apo) B-48. They are released from the cells into the lymphatic system and travel to the blood, where they receive apo C-II and apo E from HDL. Apo C-II activates endothelial lipoprotein lipase (LPL), which degrades the TAG in chylomicrons to FA and glycerol. The FA that are released are stored (in adipose tissue) or used for energy (in muscle). The glycerol is metabolized by the liver. Patients with a deficiency of LPL or apo C-II show a dramatic accumulation of chylomicrons in the plasma (type I hyperlipoproteinemia or familial chylomicronemia) even if fasted. After most of the TAG is removed, apo C-II is returned to HDL, and the chylomicron remnant, carrying most of the dietary cholesterol, binds to a liver receptor that recognizes apo E. The particle is endocytosed, and its contents degraded by lysosomal enzymes. Defective uptake of these remnants (and IDL) causes type III hyperlipoproteinemia or dysbetalipoproteinemia. Nascent VLDL are produced in the liver and are composed predominantly of TAG. They contain a single molecule of apo B-100. Like chylomicrons, VLDL receive apo C-II and apo E from HDL in the plasma. VLDL carry hepatic TAG to the peripheral tissues where LPL degrades the lipid. Additionally, the VLDL particle receives cholesteryl esters from HDL in exchange for TAG. This process is accomplished by cholesteryl ester transfer protein (CETP). VLDL in the plasma is first converted to IDL and then to LDL, a much smaller, denser particle. Apo C-II and apo E are returned to HDL, but the LDL retains apo B-100, which is recognized by receptors on peripheral tissues and the liver. LDL undergo receptor-mediated endocytosis, and their contents are degraded in the lysosomes. The protease proprotein convertase subtilisin/kexin type 9 (PCSK9) prevents receptor recycling. Defects in the synthesis of functional LDL receptors causes type IIa hyperlipoproteinemia (familial hypercholesterolemia [FH]). The endocytosed cholesterol decreases expression of HMG CoA reductase (and LDL receptors) through prevention of SREBP-2 binding to the SRE. Some of it can be esterified by acyl CoA:cholesterol acyltransferase (ACAT) and stored. HDL are created by lipidation of apo A-1 synthesized in the liver and intestine. They have a number of functions, including 1) serving as a circulating reservoir of apo C-II and apo E for chylomicrons and VLDL; 2) removing cholesterol from peripheral tissues via ABCA1 and esterifying it using lecithin:cholesterol acyl transferase (LCAT), a liver-synthesized plasma enzyme that is activated by apo A-1; and 3) delivering these cholesteryl esters to the liver (reverse cholesterol transport) for uptake via scavenger receptor-B1 (SR-B1).