8 Principles of Pharmacology - Hyperlipidermia and Artherosclerosis
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Course
Pharmacology
Institution
Pharmacology
The object of the course is to teach students an approach to the study of pharmacologic agents. It is not intended to be a review of the pharmacopoeia. The focus is on the basic principles of biophysics, biochemistry, and physiology as to the mechanisms of drug action, biodistribution and metabolis...
Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology
Instructor: Dr. Robert Lees
1
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.
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