A century of cholesterol and coronaries: from plaques to genes to statins

Abstract

One-fourth of all deaths in industrialized countries result from coronary heart disease. A century of research has revealed the essential causative agent: cholesterol-carrying low-density lipoprotein (LDL). LDL is controlled by specific receptors (LDLRs) in liver that remove it from blood. Mutations that eliminate LDLRs raise LDL and cause heart attacks in childhood, whereas mutations that raise LDLRs reduce LDL and diminish heart attacks. If we are to eliminate coronary disease, lowering LDL should be the primary goal. Effective means to achieve this goal are currently available. The key questions are: who to treat, when to treat, and how long to treat.

Figure 1. LDL, A Cholesterol Carrier

LDL is a spherical particle with a diameter of 220 nm and a mass of ~3000 kDa. Each particle contains ~1500 molecules of cholesteryl ester in an oily core that is shielded from the aqueous plasma by a hydrophilic coat composed of ~800 molecules of phospholipid, ~500 molecules of unesterified cholesterol, and 1 molecule of a 500-kDa protein, apoB.

Figure 2. Feedback Regulation of Cholesterol Synthesis and LDL Receptors in Cultured Cells from Normal Subjects and Children with Homozygous FH

(A) Normal cells obtain cholesterol from two sources: 1) endogenous synthesis and 2) receptor-mediated uptake and lysosomal hydrolysis of LDL. (B) Lacking LDL receptors, FH cells maintain normal levels of cholesterol by increasing synthesis of cholesterol, leaving excess LDL in the culture medium.

Figure 3. The SREBP Pathway for Cholesterol Homeostasis in Animal Cells

(A) Cholesterol deficiency. When the cholesterol content of ER membranes falls below 5 mol% of its total lipids, Scap binds COPII proteins, which incorporate the Scap/SREBP complex into COPII-coated vesicles that move to the Golgi. In the Golgi, SREBPs are cleaved by two proteases, S1P and S2P, allowing the active portion to enter the nucleus where it activates genes that increase cholesterol synthesis and uptake. (B) Cholesterol excess. When ER cholesterol rises above 5 mol% of membrane lipids, cholesterol binds to Scap, thereby causing Scap to bind to Insig. This releases COPII proteins, abrogating transport to the Golgi. The fall in nuclear SREBP reduces transcription of genes for cholesterol synthesis and uptake.

Figure 4. Hepatic Response to Diet and Statins Mediated by the SREBP Pathway

(A) Low cholesterol diet. Proteolytic cleavage of SREBP is increased. The cleaved SREBP enters the nucleus to activate genes controlling cholesterol synthesis (including HMG CoA reductase) and uptake (LDL receptor). nSREBP, nuclear portion of cleaved SREBP. (B) High cholesterol diet. Proteolytic cleavage of SREBPs is decreased, resulting in decreased nuclear SREBP and decreased activation of target genes. The decrease in LDL receptors produces an increase in plasma LDL. (C) High cholesterol diet plus statin therapy. Statins inhibits HMG CoA reductase, causing a transient decrease in ER cholesterol. In response, SREBP cleavage is increased, and the resulting nuclear SREBP activates the genes for HMG CoA reductase and LDL receptor. The increased HMG CoA reductase is inhibited by the statin, and the increased LDL receptors lower plasma LDL.

Figure 5. Diagram Illustrating the Effects of Diet, Drugs, and Genes on Plasma LDL and Coronary Disease

(A) Diet. Idealized depiction of the frequency distribution of plasma cholesterol levels in the human species as extrapolated from surveys of middle-aged people in major populations of the world. The higher the cholesterol level, the higher the risk for coronary disease, as denoted by the graded red shading. (B) Drugs. Frequency of coronary events plotted against plasma level of LDL-cholesterol in four double-blind, placebo-controlled trials in which middle-aged people at risk for heart attacks were treated for five years with a statin or placebo. The number of subjects in each study were as follows: 4S Study, 4444; LIPID, 9014; CARE, 4159; and HPS, 20,536. (C) Genes. Difference in risk for coronary disease in middle-aged people depending on whether plasma LDL-cholesterol level is reduced over a lifetime (heterozygous loss-of-function of PCSK9) or for only five years (statin therapy).