Atherosclerosis: Cholesterol Management

Abstract

Cardiovascular disease (CVD) in all its forms remains the single most common cause of death in the United States and the industrialized world [1, 2]. In the United States, CVD was responsible for over 840 000 deaths in 2016 and the associated direct and indirect costs to the US economy were estimated to be $351.1 billion in 2014–2015 [3]. The principal components of CVD included in these numbers are coronary heart disease (CHD), stroke, heart failure, and congenital heart disorders. Atherosclerosis, the chronic inflammatory arterial wall disease associated with the deposition of cholesterol into arterial plaques and hardening of the arteries, is a major contributor to CHD and is the principal cause of heart attacks and stroke. Although there are multiple risk factors for CHD including age, family history, obesity, sedentary lifestyle, smoking, diabetes, and high blood pressure, the risk factor most closely associated with a higher incidence of CHD is serum cholesterol levels. Cholesterol is carried in vivo in lipoprotein particles of varying density and with differing surface proteins. Low-density lipoproteins (LDLs) have been shown to cause atherosclerosis, and they have a cumulative effect [4]. High-density lipoproteins (HDLs) have also been hypothesized to be cardioprotective. This article focuses mainly on therapeutic agents that lower low-density lipoprotein cholesterol (LDL-C) levels as these agents have progressed to market for the treatment and/or prevention of atherosclerosis. Lipoproteins are lipid–protein complexes consisting of surface apoproteins, a phospholipid monolayer, and free cholesterol, with cores containing neutral lipids including triglycerides (TGs) and cholesteryl esters (CEs). As shown in Figure 1, LDL are derived from very-low-density lipoproteins (VLDLs) synthesized by the liver [5]. Hepatocytes package TGs and cholesterol along with apoprotein B (isoform B100) and phospholipids to form the TG-rich lipoprotein VLDL for secretion into plasma. VLDL TGs are hydrolyzed by lipoprotein lipase (LPL), releasing free fatty acids, which reduces the size of VLDL to intermediate-density lipoproteins (IDLs). IDL TGs are hydrolyzed by hepatic lipase, forming LDL that contains one molecule of apoB and primarily esterified cholesterol in its core. VLDL, IDL, and LDL obtain CEs through the exchange of TGs and CEs from HDLs by the activity of cholesteryl ester transfer protein (CETP). LDL transports cholesterol to peripheral tissues where it is taken up by the low-density lipoprotein receptor (LDL-R) [6]. LDL is cleared from the circulation primarily by hepatic LDL-Rs. LDL-Rs bind apoB and apoE enriched lipoproteins like LDL, internalize LDL through clathrin-coated pits, release the LDL into acidified endosomes, and the LDL-R recycles to the cell surface to bind additional LDL particles. Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) binds to the LDL-R and directs it to be degraded, interrupting the recycling LDL-R pathway (described in detail in Section 3.1 [7]). Since cholesterol is the principal component of the atherogenic lipoproteins, the two sources of this important biochemical merit mention. The majority of endogenous cholesterol comes from a complex biosynthetic pathway with over 25 dedicated synthetic steps beginning with acetate as depicted in Figure 2 [8]. The slowest or rate-determining step in this pathway is the synthesis of mevalonate via the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) 1