Cholesterol

Presentation
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5997
C
27
H
46
0
The hydroxyl group makes the
hydrophilic head
The 4 hydrocarbon rings
means it is a sterol
The hydrocarbon tail is
nonpolar meaning it is
hydrophobic
These three sections of
cholesterol together make it
an amphipathic molecule
Background Information
Cholesterol is not water-soluble meaning it travels the bloodstream via
lipoproteins like Low Density Lipoprotein (LDL) and High Density Lipoprotein
(HDL)
Cholesterol is on the haploid human genome with a single LDL copy on
chromosome 19
LDL is about 45 kb with 18 exons and 17 introns
Cholesterol in plasma is present as either free cholesterol in the surface coat or
esterified cholesterol in the core
Cholesterol is used for cell membrane repair and growth
It is also a precursor for steroid hormone and Vitamin D synthesis in
specialized tissues like the adrenal gland, gonads, and skin
It modifies fluidity by maintaining barrier between inside and outside the cell
Only 25% of the cholesterol in the human body comes from diet while the
remaining 75% is synthesized by the body, mainly the liver
LDL Receptors
Receptor-Mediated Endocytosis
LDL receptors are synthesized in the ER then transported by vesicles to
the Golgi apparatus then finally combine with the cell surface creating a
clathrin protein coated pit
The LDL binds to the receptors and internalizes in an endosome
Through hydrolysis in the combination of the endosome and lysosome, the
LDL breaks down into amino acids and cholesterol
HMG CoA Reductase (a rate-determining enzyme of cholesterol
biosynthesis) decreases due to suppression of gene transcription
LDL receptor synthesis decreases due to the lower concentration of mRNA
cholesterol acyltransferase increases to store cholesterol droplets in the
cytoplasm
The LDL receptor vesicles recycle every 10 minutes
http://web.campbell.edu/faculty/nemecz/308_lect/lect4/lect4.html
Lipoprotein Cholesterol
HDL
High-Density Lipoprotein
Smaller in physical size (5-12 nm)
the surface membrane consists of
phospholipid, cholesterol, apolipoproteins
A and C
the core consists of mostly cholesteryl
ester and some triglycerides
LDL
Low-Density Lipoprotein
Larger in size than HDL (>75 nm)
the surface membrane consists of
phospholipid, cholesterol, and
apolipoprotein B-100
the core consists of mostly cholesteryl
ester
http://chemistry.ewu.edu/jcorkill/biochem/soap2000.html
Good vs. Bad Cholesterol
HDL
Good cholesterol
HDL removes cholesterol from
vascular system and deliver it to the
liver for disposal by reverse
cholesterol transport
Other benefits of HDL include:
anti-atherothrombotic
anti-inflammatory
immunomodulatory
antioxidant
antithrombotic
endothelial cell repair
LDL
Bad cholesterol
High LDL levels reduces the
bioavailability of nitric oxide
causing endothelial dysfunction
which is the preceding step to LDL
entry into the arterial intima (inner
layer of the arteries)
once built up, the plaque from the
LDL can block arteries causing
atherothrombosis which may lead to
myocardial infarctions
History of Cholesterol
1769: cholesterol first discovered in bile and gallstones by
Francois Poulletier de la Salle
unrealized
1815: rediscovered and named cholesterine
1833: first found in blood
1904: introduced term atherosclerosis
suggested it was responsible for almost all obstructive
processes in the arteries
1908: link between cholesterol-rich food and experimental
atherosclerosis
Atherosclerosis
Characterized by hardening of the arteries
Leading cause of cardiovascular disease and death
Macrophage malfunction
Long believed to be result of interaction between
uncontrolled cholesterol build-up and inflammation of the
heart and blood vessels
Immune system cells
ingest other cells or matter flagged as dangerous or
unfamiliar
Some fail to discard extra cholesterol, allowing it to collect
inside them as droplets of fat
Trigger certain genes to start inflammatory response
http://www.nhlbi.nih.gov/health/health-topics/topics/hbc/
http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=athero
http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=athero
http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=athero
History of Cholesterol, contd
1920: Adolf Windaus showed that lesions in arteries
contained more than 20x the amount of cholesterol in
healthy arterial wall
1928-1950: discoveries in molecular composition and
structure of cholesterol
1965: Robert Woodward managed to synthesize cholesterol
from simple compounds
Significant Discoveries
1973: Japanese scientists isolated a natural cholesterol-fighting
compound from a fungus, which blocks a key enzyme in
cholesterol synthesis
Led to cholesterol-lowering drugs (i.e. Lipitor)
1983: gene responsible for familial hypercholesterolemia
problem in cells, not in blood
deficiency of LDL receptors in liver
cholesterol removed from body by LDL receptors
lack of LDL receptors leads to build-up in arteries
Significant Research
Russian scientist Nikolai Anichkov performed an experiment where
he fed rabbits egg yolks with high amounts of cholesterol
rabbits developed atherosclerosis with the typical deposits on their
blood vessels
Helsinki study of genetic background of low HDL-cholesterol
studied Finnish individuals with either extremely high or extremely
low HDL-cholesterol
observed that many of the genes regulating inflammation and
immune response of the body were also associated with low HDL-
cholesterol levels in circulation
results tell us that some individuals are genetically more prone to
inflammation and the quality of the HDL particles may vary
References
Berman, Mones, Scott M. Grundy, and Barbara V. Howard, eds. Lipoprotein Kinetics and Modeling. New York:
Academic, 1982. Print.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Volume 1529, Issues 13, 15 December
2000, Pages 18
Brahmachari, Goutam, ed. Chemistry and Pharmacology of Naturally Occurring Bioactive Compounds. Boca Raton, FL:
CRC, 2013. Print.
Converse, Carolyn A., and E. Roy. Skinner, eds. Lipoprotein Analysis: A Practical Approach. Oxford: IRL, 1992. Print.
Fiket, Maja. "The Discovery of Cholesterol." LIVESTRONG.COM. N.p., 24 May 2010. Web. 22 Jan. 2014. http://www.
livestrong.com/article/130231-discovery-cholesterol/
Fitzgerald, Kelly. "New Discovery Leads Way For High Cholesterol Treatment." Medical News Today. MediLexicon
International, 1 Oct. 2012. Web. 22 Jan. 2014. http://www.medicalnewstoday.com/articles/250928.php
Gotto, Antonio M., and Henry J. Pownall. Manual of Lipid Disorders: Reducing the Risk for Coronary Heart Disease.
Third ed. Philadelphia: Lippincott Williams & Wilkins, 2003. Print
http://dx.doi.org.proxy1.cl.msu.edu/10.1016/S1388-1981(00)00133-5
http://onlinelibrary.wiley.com.proxy2.cl.msu.edu/doi/10.1111/j.1749-6632.2012.06480.x/full
References continued...
http://themedicalbiochemistrypage.org/cholesterol.php
http://www.heart.org/HEARTORG/Conditions/Cholesterol/AboutCholesterol/Hyperlipidemia_UCM_434965_Article.jsp
http://www.nobelprize.org/nobel_prizes/medicine/laureates/1985/brown-goldstein-lecture.pdf
http://www.nytimes.com/1985/10/15/us/2-americans-win-nobel-medicine-prize.html
http://www.sciencedaily.com/releases/2013/04/130430091629.htm
Konstantinov, Igor E. "Nikolai N. Anichkov and His Theory of Atherolsclerosis." Texas Heart Institute Journal. 33.4
(206): 417-423. Web. 22 Jan. 2014. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1764970/>.
Vance,Dennis E., Henk Van den Bosch Cholesterol in the year 2000.
"Research: Scientific Discoveries." UT Southwestern Medical Center. The University of Texas Southwestern Medical
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"What Is Cholesterol?" - NHLBI, NIH. U.S. Department of Health & Human Services, 19 Sept. 2012. Web. 20 Jan.
2014.http://www.nhlbi.nih.gov/health/health-topics/topics/hbc/