cholesterol synthesis and breakdown dr. carolyn k. suzuki 1
TRANSCRIPT
Cholesterol synthesis and breakdown
Dr. Carolyn K. Suzuki
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To compare and contrast the different mechanisms by which cholesterol biosynthesis are regulated.
To predict whether intracellular cholesterol synthesis will be up- or down-regulated in response to energy availability as influenced by diet, hormones and exercise.
To distinguish the different mechanisms by which plasma cholesterol levels are controlled by clinically adminstrered pharmacological agents.
OBJECTIVES
Cholesterol in cellular membranes
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hydrocarbon tail
steroid nucleusA
C D
B
cholesterolCholesterol•27 carbons all derived from acetate•C-3 hydroxyl group•C-17 side chain with 8 carbons
Sources in the body• synthesized primarily in liver and intestine• not required in diet• intestinal uptake from diet
Elimination• converted into bile acids and bile salts in liver• stored in gall bladder, secreted into intestine• small % excreted in feces
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3
cholesterol ester
fatty acid
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C D
B
Cholesterol esters• esterification at C-3 with fatty acid• primary form transported in plasma• packaged in lipoprotein particles
(e.g. LDL, HDL)
cytosolmitochondriaperoxisomes
A. Synthesis of HMG CoA
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2 acetyl CoA (2C)
2 acetoacetyl CoA (4C)
3-hydroxy-3-methylglutaryl CoA (6C)(HMG CoA)
thiolase
HMG CoA synthase
CoA
CoA
acetyl CoA
endoplasmicreticulum
B. Synthesis of mevalonic acid
HMG CoA (6C)
HMG CoA reductase2 NADPH
2 NADP+CoA
Mevalonic acid (6C)
RATE LIMITING STEP
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C. Cholesterol synthesis
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C. Cholesterol synthesis
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The transcription factor regulating cholesterol synthesis genes is SREBP- sterol responsive element binding protein
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SCAP- SREBP Cleavage Activating Protein a transmembrane protein has a sterol sensing domain binds to SREBP in the ER when ER sterols are low, SCAP-SREBP move to the GolgiProtease 1 and Protease 2- localized to the Golgi responsible for the two step cleavage of SREBP resulting in soluble, cytosolic SREBP
Mature, proteolytically-processed SREBP translocates from the Golgi to the nucleus activates the expression of cholesterol synthesis genes
SREBP- Sterol Regulatory Element Binding Protein a transmembrane protein has a DNA binding domain has a SCAP interacting domain
Sterol-dependent regulation of cholesterol synthesis genes
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nucleus
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SCAP and SREBPare transported to
the Golgi
when sterol levelsare low
step #1
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step #2
step #3
SREBP release
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SREBPtranslocatesto nucleus
step #4
transcriptional activation of sterol responsive element (SRE)
controlled genes
nucleus
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When intracellular cholesterol is low
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Cholesterol-dependent degradation of HMG CoA reductase
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(AMP kinase)
AMP kinase is different from cAMP-dependent kinase (PKA)
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Statins competitively inhibit HMGR-they mimic the transient intermediate mevadyl CoA
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Vytorin (ezetimibe + simvastatin)• ezetimibe administered in combination with a
simavastatin (i.e. a statin)• further reduces total cholesterol levels as compared
to statin alone• blocks cholesterol absorption in the intestine and
cholesterol synthesis in the liver• permits reduced doses of statins, which have
side effects
Zetia (ezetimibe)
Mechanism of action- • acts at small intestine brush border• does not enter the bloodstream, no side effects• inhibits absorption of cholesterol• does not block absorption of triglycerides or
fat-soluble vitamins
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Reduction of LDL-cholesterol across all tested statins
Mean %change in LDL-C
from baseline
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• cholesterol is the precursor of bile acids and bile salts• synthesized in the liver• stored in the gall bladder• secreted into intestine • aids digestion by emulsifying dietary lipids making them
accessible to pancreatic lipases• aids intestinal absorption of fat-soluble vitamins (A, D, E, K) • ~95% are reabsorbed in ileum and returned to liver• ~5% of bile salts are excreted in feces
Bile acids and bile salts
Excretion of bile salts is the principal mechanismfor eliminating cholesterol from the body
Enterohepatic circuit•synthesis in the liver•storage in the gall bladder•secretion into intestine•re-circulation to liver
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cholic acid-+ cholesterol
rate limiting step
Primary bile acidsare formed from
cholesterolcholesterol
cholic acid chenodeoxycholic acid
7--hydroxylase hydroxylation of C7addition of OH group
7--hydroxycholesterol
Primary bile acids
7--hydroxylase
cholic acid-
+ cholesterol
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• Hypercholesterolemia is often treated with “sequestrants” that bind bile acids in the intestine. These compounds:
prevent reabsorbtion of bile acidsincrease conversion of cholesterol to bile
acidsincrease bile salt elimination in feces
• Dietary fiber also sequesters bile acids
Secondary bile acids
Secondary bile acids
Primary bile acids
7--hydroxylase
cholic acid-+ cholesterol
30Increased elimination of cholesterol from the body
Secondary bile acids
Primary bile acids
Bile salts-glycine or taurine
conjugated tobile acids in liver5% lost in feces Recent R & D efforts focusing on bile acid receptors
as drug targets for treating liver disease, liver cancer, metabolic disease.
Review- you tell me !!!!
•How many carbons are there in cholesterol?
•Which carbons are the business ends of the cholesterol molecule?
•When cholesterol levels are high, HMG CoA reductase is regulated by which of the following mechanisms?
•When cholesterol levels are high, HMG CoA reductase is regulated by which of the following mechanisms?
•What organ STORES bile acids and bile salts?