| Apolipoprotein B is the nonexchangeable structural apolipoprotein of atherogenic lipoproteins and exists as two major isoforms, ApoB‑100 synthesized in hepatocytes and ApoB‑48 synthesized in enterocytes, both encoded by the APOB gene but generated by tissue‑specific mRNA editing, with ApoB‑100 supporting hepatic assembly of very low‑density lipoprotein (VLDL) and serving as the primary ligand for LDL receptor–mediated clearance of LDL, and ApoB‑48 supporting intestinal chylomicron formation and dietary fat absorption. ApoB‑100 is a very large, amphipathic protein whose primary structure includes long stretches of predicted α‑helical and β‑sheet domains that alternately bind the surface phospholipid monolayer and the neutral lipid core, and sequencing of its carboxyl‑terminal region has identified structural motifs implicated in receptor binding and lipid interaction; biophysical analyses show that ApoB is conformationally flexible yet anchored at triolein/water interfaces, forming a continuous belt around fat droplets that stabilizes nascent lipoprotein particles and remains bound throughout lipolysis, thereby preserving particle integrity from VLDL through intermediate‑density lipoprotein (IDL) to LDL. During lipoprotein assembly, ApoB‑100 interacts with microsomal triglyceride transfer protein (MTP) in the endoplasmic reticulum to acquire core triglycerides and cholesteryl esters, generating secretion‑competent VLDL that delivers triglycerides from liver to peripheral tissues; progressive hydrolysis of VLDL triglycerides by lipoprotein lipase produces IDL and then LDL, with ApoB‑100 remaining as the sole apolipoprotein on LDL, guiding its recognition by LDL receptors on hepatocytes and other cells and enabling receptor‑mediated endocytosis and intracellular cholesterol delivery. In the intestine, ApoB‑48 is produced by site‑specific C‑to‑U editing of APOB mRNA and is required for chylomicron assembly and secretion, mediating postprandial transport of dietary triglycerides and fat‑soluble vitamins to the circulation, with defective ApoB editing or secretion leading to fat malabsorption and hypocholesterolemia. ApoB‑containing lipoproteins are pivotal for lipid absorption and triglyceride homeostasis, but high plasma levels are causally linked to atherogenesis: review work emphasizes that ApoB defines the number of atherogenic particles (LDL, lipoprotein(a) and triglyceride‑rich remnants), that subendothelial retention of ApoB‑containing lipoproteins via specific proteoglycan‑binding sites on ApoB is a necessary initiating event for plaque formation, and that modified retained LDL releases bioactive lipids that trigger inflammatory and immune responses in the vessel wall. Rare APOB missense mutations that alter the LDL receptor–binding domain or lipid‑binding regions can cause familial hypercholesterolemia with severely elevated LDL and ischemic cardiovascular disease risk, whereas other variants reduce ApoB secretion and produce hypocholesterolemia with protection from atherosclerosis, illustrating how ApoB structural changes modulate both lipoprotein metabolism and disease susceptibility. At the immune interface, ApoB acts as an autoantigen in atherosclerosis: ApoB‑specific CD4+ T cells are detectable in most healthy individuals, and coronary artery disease and elevated cardiovascular risk profiles drive formation of ApoB‑specific central memory T cells that secrete both pro‑inflammatory IFN‑γ and anti‑inflammatory IL‑2 and IL‑10, suggesting that adaptive immune responses to ApoB‑containing LDL can modulate systemic inflammation in plaque development. |
