The transport of lipids between tissues is facilitated by various plasma lipoproteins, namely chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). These lipoproteins maintain the solubility of lipids such as triacylglycerol (TAG) and cholesteryl esters. Comprising a core of neutral lipids surrounded by amphipathic apolipoproteins, phospholipid, and nonesterified cholesterol, lipoproteins play a crucial role in this transport process. Chylomicrons, originating in the intestinal mucosal cells, are primarily assembled from dietary lipids (mainly TAG) and carry one molecule of apolipoprotein (apo) B-48. They are released into the lymphatic system and eventually reach the blood, where they acquire apo C-II and apo E from HDL. Apo C-II activates endothelial lipoprotein lipase (LPL), which breaks down the TAG in chylomicrons into free fatty acids (FA) and glycerol. The released FA are either stored in adipose tissue or utilized as an energy source in muscles. The liver metabolizes glycerol. In individuals with LPL or apo C-II deficiency, chylomicrons accumulate significantly in the plasma, resulting in type I hyperlipoproteinemia or familial chylomicronemia. Once most of the TAG is removed, apo C-II returns to HDL, while the chylomicron remnant, containing most of the dietary cholesterol, binds to a liver receptor that recognizes apo E. The particle is subsequently endocytosed, and its contents are degraded by lysosomal enzymes. Impaired uptake of these remnants (as well as IDL) leads to type III hyperlipoproteinemia or dysbetalipoproteinemia. The liver produces nascent VLDL, predominantly consisting of TAG, with a single molecule of apo B-100. Similar to chylomicrons, VLDL receives apo C-II and apo E from HDL in the plasma. VLDL carries hepatic TAG to peripheral tissues, where LPL degrades the lipid. Additionally, cholesteryl esters from HDL are exchanged for TAG within the VLDL particle, facilitated by cholesteryl ester transfer protein (CETP). Initially, VLDL is converted to IDL and then further transformed into LDL, a smaller and denser particle. While apo C-II and apo E return to HDL, LDL retains apo B-100, which is recognized by receptors in peripheral tissues and the liver. LDL undergoes receptor-mediated endocytosis, and its contents are degraded within lysosomes. The presence of the protease proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibits receptor recycling. Defects in the synthesis of functional LDL receptors cause type IIa hyperlipoproteinemia (familial hypercholesterolemia [FH]). The endocytosed cholesterol reduces the expression of HMG CoA reductase (and LDL receptors) by preventing SREBP-2 binding to the SRE. Some of the cholesterol can be esterified by acyl CoA:cholesterol acyltransferase (ACAT) and stored. HDL is generated through the lipidation of apo A-1 synthesized in the liver and intestine. HDL serves multiple functions, including acting as a circulating reservoir of apo C-II and apo E for chylomicrons and VLDL, removing cholesterol from peripheral tissues through ABCA1, and esterifying it using lecithin:cholesterol acyl transferase (LCAT), an enzyme synthesized in the liver that is activated by apo A-1. HDL also delivers these cholesteryl esters to the liver for uptake via scavenger receptor-B1 (SR-B1) in a process known as reverse cholesterol transport.
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).