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The Cholesterol Hypothesis. Between the years 1955 and 1985, many epidemiologic studies showed a positive relation between cholesterol levels and atherosclerotic cardiovascular disease (ASCVD) events. Over the next 30 years, a host of randomized controlled clinical trials have demonstrated that lowering cholesterol levels will reduce the risk for ASCVD. This bidirectional relationship between cholesterol levels and ASCVD provides ample support for the cholesterol hypothesis.

Inhibition of Cholesterol Synthesis by Bempedoic Acid

Intestinal Triglyceride and Cholesterol Metabolism. In the intestinal lumen, dietary triglyceride (TG) and cholesterol are emulsified by bile salts which enhance their uptake. Lipases in the intestinal lumen digest triglycerides to free fatty acids (FFA) and monoacylglycerides (MAG). These are absorbed into the enterocyte where they are used in the synthesis of TG, phospholipid and cholesteryl ester (CE). Much of the synthesized TG in enterocytes is packaged, along with phospholipids, cholesterol and proteins into chylomicrons, which are secreted at the basolateral surface of the enterocyte and enter the lymphatic system. The assembly of chylomicrons begins in the endoplasmic reticulum. During the synthesis of apolipoprotein B48 (apoB48), the protein acquires phospholipid from the endoplasmic reticulum membrane and also cholesterol and TG to form a primordial chylomicron. Continued acquisition of TG and CE and smaller, exchangeable proteins (e.g. apolipoprotein A-IV and apolipoprotein C-III) in the endoplasmic reticulum enlarges the particle to form a prechylomicron. Prechylomcirons are transported to the Golgi apparatus in specialized COPII vesicles. In the Golgi apparatus, the prechylomicron matures into a chylomicron. The maturation process includes the glycosylation of apoB48, the acquisition of additional proteins (e.g. apolipoprotein A-I) and lipid. Secretory vesicles formed from the Golgi carry the mature chylomicrons to the basolateral surface of the enterocyte. Fusion of the secretory vesicle membrane with the plasma membrane releases the chylomicron into the extracellular space where it is taken up into lacteals near the enterocyte and, thus, enters the lymphatic circulation. Dietary cholesterol in the intestinal lumen is taken into the enterocyte by a process involving Niemann-Pick C1-like protein 1 (NPC1L1). Enterocyte cholesterol and CE can be incorporated into chylomicrons and secreted with TG. In addition, enterocyte cholesterol can be directly excreted into the intestinal lumen using the heterodimer ATP-binding cassette transporter G5 and G8 (ABCG5/G8). Enterocyte cholesterol can also be transported to and incorporated into the basolateral membrane for efflux into the circulation.

Macrophage Cholesterol Metabolism. Native LDL is recognized by the LDL receptor (LDLR). The LDL is endocytosed and trafficked to lysosomes, where the cholesteryl ester (CE) is hydrolyzed to free cholesterol (FC) by the acid lipase. The FC is transported to the endoplasmic reticulum (ER) to be esterified by acyl CoA:cholesterol acyltransferase (ACAT). Increased FC in an ER regulatory pool initiates a signaling cascade resulting in down-regulation of the LDL receptor. Cholesterol regulation of the LDLR prevents foam cell formation via this receptor in the setting of hypercholesterolemia. ApoB containing lipoproteins that also contain apoE (apoE remnants, VLDL) can cause cholesterol accumulation via interaction of apoE with apoE receptors including the LRP1 and the VLDL receptor, which are not regulated by cellular cholesterol. Uptake of native LDL by fluid phase pinocytosis may also contribute to foam cell formation. Modifications of apoB containing lipoproteins induce significant cholesterol accumulation via a number of mechanisms. Enzyme-mediated aggregation of apoB lipoproteins enhances uptake via phagocytosis. Oxidation and/or glycation enhances internalization via a number of receptors that are not regulated by cholesterol, including CD36, scavenger receptor A (SRA), lectin-like receptors (LOX), and toll-like receptors (TLR4). The CE generated by ACAT is stored in cytoplasmic lipid droplets, where there is a continual cycle of hydrolysis to FC by neutral cholesterol esterase and re-esterification by ACAT. Cytoplasmic CE is cleared by two main pathways. In one pathway, removal of FC from the plasma membrane stimulates transport of FC that has been generated by neutral cholesterol esterase away from ACAT to the plasma membrane. Alternatively, cytoplasmic CE is packaged into autophagosomes, which are transported to fuse with lysosomes, where the CE is hydrolyzed by acid lipase and the resulting FC is then transported to the plasma membrane. The efflux of FC to lipid-poor apolipoproteins or HDL occurs by a number of mechanisms to reduce foam cell formation. Exogenous lipid-free apoA-I or endogenous apoE that is produced by the macrophages interacts with ABCA1 to stimulate the efflux of phospholipid and FC to form nascent HDL particles (e.g. apoA-I or apoE containing phospholipid discs). ApoE produces the most buoyant, FC-enriched particles. ABCA1 plays a major role in the clearance of cytoplasmic CE via autophagy. The apoA-I/apoE discs as well as mature HDL containing apoA-I and/or ApoE stimulate FC efflux via three major mechanisms including ABCG1, SR-BI, and aqueous diffusion. ABCG1 may also play a role in the intracellular trafficking of cholesterol.