Cholesterol and Atherosclerosis Flashcards
What is cardiovascular disease
Condition that affects the structure or function of the heart
Heart disease is the #1 killer in the USA
2nd leading cause of death in Canada
What is atherosclerosis? What are plaques? What is atherosclerosis caused by?
Occurs when your arteries become clogged with plaque, causing them to lose elasticity and become narrower
The hardening of the arteries
Plaques are hard deposits of cholesterol and macrophages
Caused by damage to the inner layers of the arteries (smoking, high blood pressure, high cholesterol)
INCREASED LDL = ATHEROSCLEROSIS
Plaque narrows the arteries and can rupture and block arteries
What is atherogenesis? What are the 5 steps?
Atherosclerotic plaque formation
- Damage to artery wall which causes accumulation of LDL
- Inflammatory response which attracts monocytes to damaged site
- Monocytes differentiate into macrophages which take up cholesterol
- Macrophages become lipid-rich foam cells
- Foam cells accumulate to form plaque
What is a macrophage foam cell
Cytoplasm filled with a large number of lipid droplets that contain cholesterol ester
roles of cholesterol
Bile acids
Steroid hormones
Membrane fluidity
cholesterol ester
Describe the synthesis of primary bile acids? What is the role of bile acids?
synthesis occurs in liver, the rate limiting step is when C7 of cholesterol is acted on by 7a-hydroxylase to become 7a hydroxycholesterol
Goes through a series of reactions to create primary bile acids
Bile acids are involved in dietary lipid digestion
acts as emulsifiers and help in cholesterol excretion
What is the rate-limiting step of bile acid synthesis
Rate-limiting step is cholesterol to 7a-hydroxycholesterol
Catalyzed by 7a-hydroxylase
Describe the synthesis of conjugate bile acids (bile salts)
Primary bile acids are converted to bile salts by the addition of glycine via an amide bond
Where are secondary bile acids produced
Produced in the small intestine by gut flora
What is the only significant way to eliminate cholesterol
Excretion of bile in feces
What percentage of bile acids are recycled
98%
Describe the enterohepatic circulation of bile acids
We also excrete 1g of cholesterol per day
Can pancreatic lipase degrade TG alone? What needs to happen to TG?
Pancreatic lipase cannot degrade TG efficiently so bile acids help this process
TG has to be emulsified into mixed micelles by bile acids so they can be acted upon by pancreatic lipase
Role of bile acids
Needed for intestinal breakdown of TG
Bile acids are detergents that solubilize dietary fats to facilitate their breakdown and absorption
Stored in gall bladder
Bile salt structure
Amphipathic
can interact with water and lipids
What do detergents do? example?
Bile salts are detergents
solubilize lipids by forming mixed micelles
What are gallstones? Cause? Treatment?
Solid particles that collect in gall bladder
formed from bile supersaturated with cholesterol
can block bile duct and lead to infection
Caused by high cholesterol and obesity
Drugs can dissolve gallstones
soundwave can break stones into smaller pieces to be passed
Gall bladder removal
three things
Importance of bile acids
Bile acid excretion in feces is the only significant way cholesterol can be eliminated
Can solubilize cholesterol preventing gallstone formation
Facilitate dietary fat absorption by acting as emulsifying agents
Sources of cholesterol
Diet and synthesized in body
majority synthesized in the body
How many stages is cholesterol synthesized in? Starting material?
4 stages
Starts with 3 acetyl CoA
Describe stage 1 of cholesterol synthesis
HMG CoA –> Mevalonate
Synthesized by HMG-CoA reductase
Rate limiting step of cholesterol biosynthesis
Stage 2 of cholesterol synthesis
Activated isoprene formation
Catalyzed by pyrophospho-mevalonate decarboxylase
Stage 3 of cholesterol synthesis
Condensation of 6 isoprene units to squalene
Takes 6 isoprene units to create squalene
catalyzed by squalene synthase
Stage 4 of cholesterol synthesis
Squalene undergoes cyclization to become lanosterol and then multiple steps to become cholesterol
Describe the esterification of cholesterol
cholesterol becomes cholesteryl ester
catalyzed by ACAT
What is cholesteryl ester
Storage form of cholesterol stored in lipid droplets
How is cholesterol balance maintained
cholesterol is synthesized in the liver and there is a balance between synthesis and dietary uptake
Diet leads to cholesterol
Cholesterol inhibits HMG CoA reductase which is the rate-limiting enzyme of cholesterol synthesis
What is the rate limiting enzyme of cholesterol biosynthesis
HMG-CoA reductase
Describe the Cholesterol and TG transport between tissues
Liver produces VLDL which goes to capillaries and interacts with LPL
Half of VLDL remnants are recycled by the liver
The other half is converted to LDL in circulation which can continue to the liver or be converted to HDL
So the liver indirectly creates LDL
Main job of LDL
Transport cholesterol to tissues
Describe the receptor mediated endocytosis of LDL
Highly specific process where molecules are absorbed into a cell through invagination of the plasma membrane
Apoprotein wraps around LDL which is recognized by LDL receptor which triggers receptor-mediated endocytosis
The receptor/ligand interaction gives specificity
What is the only protein on LDL
Apoprotein B-100
What is cholesterol synthesis regulated by?
Intracellular cholesterol levels
Effects of increased and decreased cholesterol levels
(HMG CoA reductase, LDL recptor, Synthesis and uptake, cholesterol ester)
How is HMG CoA reductase activity regulated
Regulation is layers
Phosphorylation/ dephosphorylation
Degradation
Transcription levels
How does a decrease in intracellular cholesterol lead to increased transcription of HMG CoA reductase
SREBP
Transcription factors that activates transcription of the gene for HMG-CoA reductase
Increases cholesterol synthesis and uptake
What are the integral membrane proteins in the ER
SREBP
Scap- SREBP Cleavage Activating Protein
Insig- Insulin Induced Gene
What are the 4 players of HMG-CoA reductase transcription? What are their roles
SREBP- regulates transcription of HMG-CoA reductase
Scap- Cholesterol sensor in ER, binds both SREBP and Insig
Insig- Scap binding protein in ER, Retains SREBP/Scap in ER
S1P and S2P- proteases in golgi, process SREBP to the active form in the golgi
Describe the transcription of HMG CoA reductase process
SREBP, Scap, and Insig are all bound together on the ER to start
When cholesterol is high, Scap tells insig to retain the other proteins in the ER
If cholesterol is low, Scap has a conformational change to unbind insig in the ER
Scap-SREBP get incorporated into a vesicle where it is transported to the golgi
S1P clips the the transmembrane proteins which releases Scap
S2P cleaves SREBP again which releases it from the golgi
SREBP is now mature and chaperon proteins bring it to the nucleus where it binds to the target gene to activate HMG CoA reductase transcription
What is hypercholesterolemia
high blood cholesterol which increases the risk for heart disease and stroke
Promotes atherosclerosis
Risk factors: Heredity, lack of exercise, overweight, high blood pressure, smoking
Diagnosis by blood test: High LDL cholesterol >200mg/dl)
describe familial hypercholesterolemia? (description, Mutation, effects)
Genetic disease caused by LDL receptor defects caused by genetic mutation
Many different mutations have been identified in the LDLR
LDL cannot be removed from the circulation resulting in high cholesterol in blood and can result in xanthomas and increased plaque formation
Heterozygous FH vs Homozygous FH
Heterozygous (relatively common)- 1/250, hypercholesterolemia and premature CV disease, LDL receptor is partially functional, will have high cholesterol, may have xanthomas or no symptoms
Homozygous- No functional LDL receptor, 1/1,000,000, Extremely high LDL-cholesterol, atherosclerosis and xanthomas, CV diseases in children, if untreated can be fatal by 30
How can heterozygous FH be treated
Exercise/weight loss
Dietary changes (reduce cholesterol)
Cholesterol lowering drugs (statins)
What are statins? What are their effects?
cholesterol lowering drug
HMG-CoA reductase inhibitor
Inhibit cholesterol synthesis and increase uptake
What are bile acid sequestrants (Resins)
Anion exchange resins prevent reabsorption of bile salts, effects additive when used with statins, may inhibit absorption of fat soluble vitamins
How do bile acid sequestrants affect bile acid recycling
increase cholesterol excretion as bile salts
How can homozygous FH be treated
LDL-apheresis which is the selective binding of apo B lipoproteins
Used every 2 weeks (2-4 hours) and it is $3000/treatment
What is PCSK9?
Protease produced by the liver which is secreted into the circulation
Protein that regulates plasma cholesterol
Directs the LDL receptor for degradation by the lysosome
How does PCSK9 function
Binds to LDL-R at the cell surface to promote LDLR degradation and prevents recycling
LDLR and PCSK9 complexes are internalized into the cell and undergoes lysosomal degradation
What do nonsense mutations in PCSK9 gene do? (inhibiting PCSK9)
hypocholesterolemia
Increased LDLR
LDLR recycling should be increased
Decrease blood cholesterol
What is a therapy using PCSK9 to reduce plasma cholesterol
PCSK9 antibody neutralizes PCSK9
resulted in increased LDLR and decreased plasma cholesterol
Describe PCSK9 inhibitors
They are antibodies
60% reduction in LDL
injection every 2-4 weeks
can cause mental confusion
15k/patient per year
Safe so far
What does lysosomal acid lipase (LAL) do
Hydrolyzes cholesterol ester to cholesterol
Moves from ER –> golgi –> lysosome via the mannose 6-phosphate pathway
What are NPC1/2
cholesterol transporters in the lysosome
What enzymes are used for cholesterol ester synthesis and hydrolysis
ACAT: Cholesterol–> cholesterol synthesis
LAL: reverse, hydrolysis
Describe intracellular cholesterol processing
LDL is internalized and brought to the lysosome and is converted to cholesterol ester
LAL makes it free cholesterol
NPC1/2 transport FC to the ER where it is sensed by SCAP and then converted to cholesterol ester and transported to lipid droplets
Effects of lysosomal acid lipase deficiency
No CE –> FC
Accumulation of cholesterol ester in lysosomes and decreased free cholesterol
SREBP is activated due to lack of FC
Stimulate cholesterol synthesis
Premature atherosclerosis
Two types of LAL deficiency
Complete absence –> Wolman disease
Residual activity (5-10%) –> CE storage disease
How can LAL deficiency be treated
Low fat diet
Statins
Liver transplant
Enzyme replacement therapy
What happened when skin cells from LAL patient was grown in medium from fibroblasts from a normal person
Decreased cholesterol ester in lysosomes
Cultured cells secrete and take up lysosomal hydrolases
Which cells can take up LAL
Cells that have mannose 6-phosphate receptor on cell surface
What is Sebalipase
recombinant LAL
infusion once a week
drug to fix LAL deficiency
improves liver function
What are the primary bile acids
Chenodeoxycholic acid and cholic acid
