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Hyperlipidemia and Atherosclerosis – 2005

Harvard-MIT Division of Health Sciences and Technology 
HST.151: Principles of Pharmocology 
Instructor: Dr. Robert Lees 
Hyperlipidemia and Atherosclerosis – 2005 
Robert S. Lees, M.D. 
BACKGROUND 
I. Atherosclerosis: A chronic inflammatory disease characterized by enzymatic 
destruction of the normal arterial skeleton (largely elastin, collagen and smooth muscle), 
and replacement by disorganized collagen and elastin, cholesterol, and foam cells. 
1. Afflicts all long-lived mammals. 
2. Major risk factors: 
• Longevity 
• Hypertension 
• Diabetes – glycosylation of plasma proteins and arterial wall proteins 
• Dyslipoproteinemia 
• Cigarette Smoking 
3. Homocysteinemia 
• Plasma homocysteine levels controlled by 3 genes related to 
methionine metabolism 
• High homocysteine is toxic to the endothelium and eventually 
atherogenic 
4. Lp(a) lipoprotein 
• Levels variable and genetically determined 
• Inhibits tissue plasminogen activator and allows thrombus formation, 
which may be atherogenic 
• Increases likelihood of thrombosis and clinical catastrophe when 
atherosclerosis is present 
5. Chronic bacterial infection 
II. Transmembrane Receptors on Mammalian Cells – Three Broad Classes 
1. Receptors mediating transmembrane signaling (e.g. β receptor) 
• Serve to amplify the effect of a tiny concentration of ligand 
2. Receptors regulating intracellular substrate concentration (e.g., LDL 
receptor) 
• Bind tiny fraction of substrate 
• Rapid cholesterol turnover involves translocation into the cell 
• Receptors supply cholesterol, when needed, to rapidly growing cells 
• Normally strongly down-regulated except in liver  2 
3. Scavenger receptors (e.g., asialoglycoprotein receptor) 
• Receptors of normal catabolism 
• Remove certain “worn out” proteins from the plasma or extracellular 
fluid. 
• Oldest of these, the asialoglycoprotein receptor, was described more 
than 30 years ago. Removes liver proteins which have become 
desialated over time from the plasma. 
• Recently, more scavenger receptors described which scavenge 
oxidized albumin, oxidized LDL, and many others 
• SR-B1 is the HDL scavenger receptor 
III. Apolipoproteins 
1. Proteins involved in the solubilization of fat for transport into and out of cells, 
from one place in the body to another. 
2. Many types, but most important are A1, B, and E 
• All three involved in cholesterol transport 
• A1 and B in triglyceride as well 
• ApoE has 3 common variants. Plays a critical role in cholesterol 
absorption, reverse cholesterol transport, and in inhibiting the 
accumulation in cells of certain hydrophobic proteins. 
III. Sterols 
1. Distinguishing feature between plants and animals is not the presence or absence 
of chlorophyll, but rather the sterols they synthesize. 
• Major plant sterol is sitosterol 
• Major animal sterol is cholesterol 
2. Animals differ widely in how they absorb and excrete sterols. 
3. Disease sitosterolemia highlights importance to human health of sterol absorption 
and excretion. 
4. Multiple sterol pumps regulate cellular and body sterol concentrations. These are 
energy-requiring ATP-dependent pumps. 
• ABC (ATP Binding Cassette) transporter family (recently discovered) 
• ABCA1 is a reverse cholesterol transporter in all cells. Defect causes 
Tangier disease (inherited HDL deficiency) 
• ABC5 and 8 are proteins which mediate sterol absorption by gut and 
sterol secretion by liver cells.  3 
IV. IMPORTANT LIPOPROTEIN CYCLES 
A. Exogenous Lipid Transport 
1. Cholesterol is variably absorbed in the small intestine and incorporated into 
chylomicrons by the gut mucosal cells. 
• Hydrophobic core = triglyceride (95%) + esterified cholesterol. 
• Amphipathic surface = Phospholipids, non-esterified cholesterol, and 
apolipoproteins (B48, C, E, A-I, A-II). 
2. Chylomicrons travel via the lacteals and the thoracic duct to the venous 
circulation. 
3. In muscle and adipose cells the triglyceride core is progressively hydrolyzed by 
hormone sensitive lipase (HSL) to form free fatty acids. This leaves a so-called 
VLDL
Capillary
ApoE,B-100
Apo AI,AII
Chylo. Remnants
ApoE,B-48
Dietary
Cholesterol
Remn-R
binds
ApoE LDL-R
binds ApoE,B
LDL-R
binds ApoB
Endogenous
Cholesterol
LIVER
ApoE,CII,B-48
Capillary
LP Lipase
ApoCII cofactor
FFA
Adipose Tissue
And Muscle
Chylomicrons
Dietary Fat
Bile Acids
+ Cholesterol
HDL
Plasma,LCAT
ApoB-100
LDL
LP Lipase
ApoCII cofactor
FFA
Adipose Tissue
And Muscle
EXOGENOUS PATHWAY
ENDOGENOUS PATHWAY
INTESTINE
EXTRAHEPATIC
TISSUES
IDL
Figure by MIT OCW. 4 
chylomicron remnant. (Apo C obtained from circulating HDL is required for 
this step.) 
4. Apo A and C are then removed and recycled to HDL, and the chylomicron 
remnants are taken up by hepatocytes. This process involves LDL receptormediated endocytosis and requires Apo E. 
5. The liver may now excrete the cholesterol into bile (either unchanged or as bile 
acids), incorporate it into membranes, or resecrete it into plasma as lipoprotein 
cholesterol. 
B. Endogenous Lipid Transport: The VLDL-LDL Cycle (Apo B100 System) 
1. This cycle allows the hepatocyte to export triglycerides and cholesterol to 
peripheral tissues as VLDL. VLDL synthesis requires microsomal triglyceride 
transfer protein (MTP). 
• Hydrophobic core = triglycerides (55-80%) + esterified cholesterol (5-
15%) 
• Surface = phospholipids (10-20%), Apo B100, C, E 
2. The triglycerides in hepatocytes come from two sources: 
• FFA synthesized de novo in liver 
• FFA and glycerol taken up from plasma and re-esterified. These are 
produced in adipose tissue and muscle by the action of HSL. HSL activity 
is regulated by adrenergic nerves and circulating catecholamines. 
3. The cholesterol in hepatocytes also comes from two sources 
• Uptake of chylomicron remnants 
• Synthesized de novo by HMG CoA-reductase 
4. Once the VLDL are circulating, the triglycerides may be hydrolyzed by HSL in 
plasma, and the fatty acids may be used to provide fuel for muscle cells, or reesterified and stored in adipocytes. When the VLDL particle has been depleted of 
triglycerides it becomes a smaller, denser particle called a VLDL remnant or 
IDL. 
5. Like chylomicron remnants, the triglyceride-poor VLDL remnants may reenter 
the liver. Unlike chylomicrons, the VLDL remnants may be further metabolized 
to become LDL. 
6. The major determinant of LDL concentration in plasma is the 
number/activity of LDL receptors. 
• Present on nearly all cells and account for 70-80% of LDL catabolism. 
• Most LDL taken up by liver and the rest by peripheral tissues, adrenals 
and gonads (the latter need cholesterol for steroid synthesis). 
• Apo E is critical ligand for binding of lipid particles to LDL receptor 
C. Endogenous Lipid Transport: The HDL Cycle (Apo A-I System) 
1. This “antiatherogenic” cycle allows cholesterol to be scavenged from
chylomicrons, VLDL and peripheral tissues by HDL particles.
• Core = triglycerides (5-10%) + esterified cholesterol (15-25%) 
• Surface = phospholipids, + Apo A-I, A-II, C, E  5 
2. Transport of cholesterol from tissue stores to HDL is mediated by ABCA1 
transporter. It is then esterified by lecithin-cholesterol acyltransferase (LCAT) 
to make bigger HDL particles. Esterified cholesterol is then disposed of by three 
primary mechanisms: 
• Transfer to VLDL, LDL, IDL, and chylomicron remnants by cholesteryl 
ester transfer protein (CETP) and subsequent endocytosis by 
hepatocytes. 
• Direct uptake in liver, adrenals, and gonads by the scavenger HDL 
receptor called SR-BI. 
• Hydrolysis by hepatic lipase 
V. Lipid Lowering Drugs 
1. HMG-CoA Reductase Inhibitors: Statins 
• Mechanism of Action: Structural analogs of 3-hydroxy-3-methylglutaric 
acid (HMG) that competitively inhibit HMG-CoA reductase, the rate-limiting 
step in cholesterol synthesis. 
• Endogenous Regulation: Hepatocytes maintain critical intracellular sterol 
pools. The genes for HMG-CoA reductase and the LDL receptor are under 
the transcriptional control of an SRE (sterol responsive element). When 
enough sterol is present in the cell, a repressor binds to the SRE inhibiting the 
transcription of enzyme and receptor and thus the production and recycling of 
more cholesterol. 
• Physiologic Response to HMG-CoA Reductase Inhibitors: By inhibiting 
cholesterol production, statins deplete sterol pools, “activating” the production 
of HMG-CoA reductase and the LDL receptor. The increase in LDL receptor 
levels results in the uptake of more IDL and LDL from the plasma. The net 
effect is that a new steady state is established with lower levels of plasma 
LDL. The most effective statins, such as atorvastatin and rosuvastatin can 
lower LDL by 60-70%. 
• It is thought that apoB-100 synthesis (requisite for VLDL) may also be 
inhibited resulting in decreased VLDL production. This may be one factor 
that explains the fall in triglycerides from 10% to 30%. 
• Usage: Statins are useful agents in all hyperlipidemias (except for 
homozygous LDL-R deficiency) 
• Adverse Effects: 
1. Co-administration with triazole antifungals, and certain other drugs 
can virtually arrest cholesterol synthesis, but produces severe toxicity. 
2. As a group, the statins are quite tolerable with rare serious adverse 
effects. Some of those effects can include rhabdomyolysis and liver 
abnormalities.  6 
2. Bile Acid Binding Resins: Cholestyramine, Colestipol, 
• Mechanism of Action: These are anion exchange resins that are not absorbed 
by the intestine. They exchange chloride anions for negatively charged bile 
acids. This results in increased excretion of bile acids. 
• Physiologic Response to Bile Acid Binding Resins: Since fewer bile acids 
are recycled, hepatocytes increase conversion of cholesterol to the production 
of bile acid. Again this depletes the intracellular sterol pool leading to 
upregulation of cholesterol synthesis enzymes and LDL receptor. Thus, 
hepatocyte pools are replenished as a result of increased production of 
cholesterol as well as enhanced uptake of LDL from plasma. A new steady 
state is reached with 10-25% less plasma LDL. 
• Usage: Resins are useful generally in hyperlipidemia (again except for 
homozygous LDL-R deficiency). 
• Adverse Effects: Since these agents are not absorbed, they are very safe. 
Gastrointestinal side effects include bloating, constipation, and abdominal 
discomfort. They also interfere with the absorption of many other drugs, 
although this problem can be minimized by appropriate timing of drug 
administration. 
3. Cholesterol absorption inhibitors: Sitostanol-ester margarine, Colesevelam, 
Ezetimibe 
• Mechanism of Action: Sitostanol-ester margarine is created by saturating the 
B-ring of sitosterol to produce sitostanol and then esterifying it. Colesevelam 
is a non-absorbed synthetic soluble fiber. These agents inhibit cholesterol 
absorption by unknown mechanisms. Ezetimibe is thought to inhibit ABC 
sterol pumps in gut and liver, reducing the absorption of cholesterol and 
increasing its secretion into bile. It is absorbed and glucuronidated and 
undergoes enterohepatic recirculation. 
• Physiologic response: All of these drugs lower LDL by 10-15%. None has 
much effect on HDL or triglycerides. 
• Usage: The margarine is available over the counter. The other drugs are 
prescribed most often as adjunctive therapy. Ezetimibe is marketed in a 
combination product with simvastatin. The combination has additive effects, 
so a large decrease in LDL occurs with a lower dose of statin. 
• Adverse effects: Almost none. 
4. Niacin (Nicotinic Acid, Vitamin B3) 
• Mechanism of Action and Physiologic Response: Niacin inhibits HSL in 
adipose tissue. This decreases the levels of free fatty acids in the plasma and 
the amount delivered to hepatocytes. As a result, less VLDL and triglycerides 
are synthesized. The reduction in plasma VLDL leads to a 10-15% decrease 
in LDL. Niacin also produces substantial increases in HDL, probably by 
decreasing the clearance of its major apolipoprotein, apoAI. Niacin is the 
only known lipid-lowering agent that has been reported to decrease Lp(a) 
levels.  7 
• Usage: This drug can produce a long-term improvement in both 
cardiovascular and total death rate. Niacin is very inexpensive and extremely 
useful for many patients. A multitude of annoying and occasionally 
dangerous side effects keep it from being a first-line agent for many. 
• Adverse Effects: Cutaneous flushing, headaches, pruritis, dermatitis. Some 
effects can be decreased by pretreatment with NSAIDs or use of sustainedrelease preparations. Niacin can cause hyperglycemia (and sometimes overt 
diabetes), hyperuricemia or gout, gastritis and GI bleeding. Serious liver 
abnormalities can occur when the drug is taken in large doses. 
5. Fibric Acid Derivatives: Gemfibrozil and fenofibrate 
• Mechanisms of Action and Physiologic Response: These agents stimulate 
the nuclear receptor peroxisome proliferator-activated receptor α, increasing 
the expression of many proteins involved in lipid metabolism. They stimulate 
HSL in muscle and thus, catabolism of triglyceride rich lipoproteins such as 
VLDL. This can lower the level of triglycerides in the plasma by as much as 
35%. Fibrates have also been reported to decrease production of VLDL in 
hepatocytes by inhibiting fatty acid synthesis. The decrease in VLDL usually 
leads to some decrease in LDL. 
• Fibrates can increase increase HDL levels by 15-25%. This is due to both an 
increase in HDL production and an increase in reverse cholesterol transport. 
• Usage: These drugs are used for hypertriglyceridemia, especially when HDL 
is low. They are also used in familial dysbetalipoproteinemia. 
• Adverse Effects: GI distress, cholelithiasis, myositis, and interaction with 
warfarin and other albumin bound drugs. 
VI. Non-drug Treatment: LDL apheresis 
• Two systems for selective removal of LDL from plasma by vein to vein 
apheresis in U.S. market 
• Highly effective in lowering LDL, even with homozygous LDL receptor 
deficiency. 
• Produces arrest and regression of both xanthomas and atherosclerosis 
• Limited by cost and inconvenience 
VII. Investigational Treatments 
1. ACAT (acyl cholesterol acyl transferase) inhibitors 
• Mechanism of Action: Inhibits the enzyme that esterifies cholesterol for 
storage in tissues and prevents cholesterol absorption and its storage in arterial 
foam cells. 
• Adverse effects: Unfortunately, it also prevents storage in the adrenals and 
gonads  8 
• Research to identify selective ACAT inhibitors – an arterial selective inhibitor 
may appear soon 
2. MTP (microsomal triglyceride transfer protein) inhibitors 
• Mechanism of Action: Inhibits VLDL production by the liver and lowers 
cholesterol by preventing its exit from the liver in VLDL and LDL. 
• Adverse Effects: Produces fatty liver and threat of cirrhosis. 
3. CETP (cholesterol ester transfer protein) inhibitors 
• Mechanism of Action: Decreases reverse cholesterol transport from HDL to 
VLDL or IDL, thereby increasing HDL while decreasing LDL production. 
4. Gene Therapy – still far off