Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

BMIS 435 > Cholesterol and Atherosclerosis > Flashcards

Cholesterol and Atherosclerosis Flashcards

1
Q

What is cardiovascular disease

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is atherosclerosis? What are plaques? What is atherosclerosis caused by?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is atherogenesis? What are the 5 steps?

A

Atherosclerotic plaque formation

  1. Damage to artery wall which causes accumulation of LDL
  2. Inflammatory response which attracts monocytes to damaged site
  3. Monocytes differentiate into macrophages which take up cholesterol
  4. Macrophages become lipid-rich foam cells
  5. Foam cells accumulate to form plaque
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is a macrophage foam cell

A

Cytoplasm filled with a large number of lipid droplets that contain cholesterol ester

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

roles of cholesterol

A

Bile acids
Steroid hormones
Membrane fluidity
cholesterol ester

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Describe the synthesis of primary bile acids? What is the role of bile acids?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is the rate-limiting step of bile acid synthesis

A

Rate-limiting step is cholesterol to 7a-hydroxycholesterol

Catalyzed by 7a-hydroxylase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Describe the synthesis of conjugate bile acids (bile salts)

A

Primary bile acids are converted to bile salts by the addition of glycine via an amide bond

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Where are secondary bile acids produced

A

Produced in the small intestine by gut flora

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is the only significant way to eliminate cholesterol

A

Excretion of bile in feces

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What percentage of bile acids are recycled

A

98%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Describe the enterohepatic circulation of bile acids

A

We also excrete 1g of cholesterol per day

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Can pancreatic lipase degrade TG alone? What needs to happen to TG?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Role of bile acids

A

Needed for intestinal breakdown of TG

Bile acids are detergents that solubilize dietary fats to facilitate their breakdown and absorption

Stored in gall bladder

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Bile salt structure

A

Amphipathic
can interact with water and lipids

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What do detergents do? example?

A

Bile salts are detergents

solubilize lipids by forming mixed micelles

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What are gallstones? Cause? Treatment?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

three things

Importance of bile acids

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Sources of cholesterol

A

Diet and synthesized in body

majority synthesized in the body

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

How many stages is cholesterol synthesized in? Starting material?

A

4 stages
Starts with 3 acetyl CoA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Describe stage 1 of cholesterol synthesis

A

HMG CoA –> Mevalonate

Synthesized by HMG-CoA reductase

Rate limiting step of cholesterol biosynthesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Stage 2 of cholesterol synthesis

A

Activated isoprene formation

Catalyzed by pyrophospho-mevalonate decarboxylase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Stage 3 of cholesterol synthesis

A

Condensation of 6 isoprene units to squalene
Takes 6 isoprene units to create squalene
catalyzed by squalene synthase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Stage 4 of cholesterol synthesis

A

Squalene undergoes cyclization to become lanosterol and then multiple steps to become cholesterol

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Describe the esterification of cholesterol

A

cholesterol becomes cholesteryl ester
catalyzed by ACAT

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What is cholesteryl ester

A

Storage form of cholesterol stored in lipid droplets

27
Q

How is cholesterol balance maintained

A

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

28
Q

What is the rate limiting enzyme of cholesterol biosynthesis

A

HMG-CoA reductase

29
Q

Describe the Cholesterol and TG transport between tissues

A

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

30
Q

Main job of LDL

A

Transport cholesterol to tissues

31
Q

Describe the receptor mediated endocytosis of LDL

A

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

32
Q

What is the only protein on LDL

A

Apoprotein B-100

33
Q

What is cholesterol synthesis regulated by?

A

Intracellular cholesterol levels

34
Q

Effects of increased and decreased cholesterol levels
(HMG CoA reductase, LDL recptor, Synthesis and uptake, cholesterol ester)

A
35
Q

How is HMG CoA reductase activity regulated

A

Regulation is layers
Phosphorylation/ dephosphorylation
Degradation
Transcription levels

36
Q

How does a decrease in intracellular cholesterol lead to increased transcription of HMG CoA reductase

A

SREBP
Transcription factors that activates transcription of the gene for HMG-CoA reductase

Increases cholesterol synthesis and uptake

37
Q

What are the integral membrane proteins in the ER

A

SREBP

Scap- SREBP Cleavage Activating Protein

Insig- Insulin Induced Gene

38
Q

What are the 4 players of HMG-CoA reductase transcription? What are their roles

A

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

39
Q

Describe the transcription of HMG CoA reductase process

A

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

40
Q

What is hypercholesterolemia

A

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)

41
Q

describe familial hypercholesterolemia? (description, Mutation, effects)

A

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

42
Q

Heterozygous FH vs Homozygous FH

A

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

43
Q

How can heterozygous FH be treated

A

Exercise/weight loss
Dietary changes (reduce cholesterol)
Cholesterol lowering drugs (statins)

44
Q

What are statins? What are their effects?

A

cholesterol lowering drug
HMG-CoA reductase inhibitor

Inhibit cholesterol synthesis and increase uptake

45
Q

What are bile acid sequestrants (Resins)

A

Anion exchange resins prevent reabsorption of bile salts, effects additive when used with statins, may inhibit absorption of fat soluble vitamins

46
Q

How do bile acid sequestrants affect bile acid recycling

A

increase cholesterol excretion as bile salts

47
Q

How can homozygous FH be treated

A

LDL-apheresis which is the selective binding of apo B lipoproteins

Used every 2 weeks (2-4 hours) and it is $3000/treatment

48
Q

What is PCSK9?

A

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

49
Q

How does PCSK9 function

A

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

50
Q

What do nonsense mutations in PCSK9 gene do? (inhibiting PCSK9)

A

hypocholesterolemia
Increased LDLR
LDLR recycling should be increased
Decrease blood cholesterol

51
Q

What is a therapy using PCSK9 to reduce plasma cholesterol

A

PCSK9 antibody neutralizes PCSK9

resulted in increased LDLR and decreased plasma cholesterol

52
Q

Describe PCSK9 inhibitors

A

They are antibodies
60% reduction in LDL
injection every 2-4 weeks
can cause mental confusion
15k/patient per year
Safe so far

53
Q

What does lysosomal acid lipase (LAL) do

A

Hydrolyzes cholesterol ester to cholesterol
Moves from ER –> golgi –> lysosome via the mannose 6-phosphate pathway

54
Q

What are NPC1/2

A

cholesterol transporters in the lysosome

55
Q

What enzymes are used for cholesterol ester synthesis and hydrolysis

A

ACAT: Cholesterol–> cholesterol synthesis
LAL: reverse, hydrolysis

56
Q

Describe intracellular cholesterol processing

A

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

57
Q

Effects of lysosomal acid lipase deficiency

A

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

58
Q

Two types of LAL deficiency

A

Complete absence –> Wolman disease
Residual activity (5-10%) –> CE storage disease

59
Q

How can LAL deficiency be treated

A

Low fat diet
Statins
Liver transplant
Enzyme replacement therapy

60
Q

What happened when skin cells from LAL patient was grown in medium from fibroblasts from a normal person

A

Decreased cholesterol ester in lysosomes
Cultured cells secrete and take up lysosomal hydrolases

61
Q

Which cells can take up LAL

A

Cells that have mannose 6-phosphate receptor on cell surface

62
Q

What is Sebalipase

A

recombinant LAL
infusion once a week
drug to fix LAL deficiency
improves liver function

63
Q

What are the primary bile acids

A

Chenodeoxycholic acid and cholic acid

BMIS 435 (17 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions