Cholesterol

Question 1

What is hypercholesterolemia?

Answer 1

high blood cholesterol; increases risk for heart disease and stroke; promotes plaque formation; blocks the flow of blood to the brain, heart other organs; plaques can break loose–causes heart attack or stroke

Question 2

what is SREBP?

Answer 2

Sterol Regulatory Element Binding Protien; Regulates cholesterol biosynth pathway– activates transcription of gene for HMG-CoA Reductase–>increases chol synth; regulates and increases the transcription of the LDL receptor–>brings more chol into cell

Question 3

what are all the plays involved in regulation of HMG-CoA Reductase

Answer 3

SREBP, Scap, Insig, S1P ad S2P

Question 4

what is the role of Scap?

Answer 4

SREBP Cleavage Activating Protein cholesterol sensor; found in ER; binds to both SREBP and Insig

Question 5

What is the role of insig?

Answer 5

Insulin Induced Gene; binds Scap in ER; retains SREBP/Scap in the ER when chol levels in the cell are sufficient

Question 6

what is the role of S1/2P

Answer 6

site 1/2 protease; found in golgi; processes SREBP–snips (release SREBP from golgi membrane)– S1P snips the loop bw transription factor and regulatory element; S2P snips the intermembrane domain to release it form the golgi

Question 7

Risk factors of hyperchol..emia

Answer 7

heredity–family history of heart disease; lack of exercise; diets high in sat fat; overweight/obese; high BP; smoking; diabetes

Question 8

what is familial hyperchol..emia due from?

Answer 8

LDL receptor deficiency/mutation–>unresponsive receptor on cell sruface/lack of LDL–>have high chol in blood

Question 9

symptoms of hyperchol..emia

Answer 9

none; xanthomas–> may only find out after recovering from heart attack in hospital

Question 10

treatment of hetero FH

Answer 10

reduce blood chol–>reduce risk of atherosclerosis; reduce sat fat intake (less red meat); low fat dairy, no egg yolks; weight loss/exercise; only moderately successful; mainly use chol-lowering drugs: statins (results in ~60% reduced LDL-Chols

Question 11

what are statins?

Answer 11

inhibit HMG-CoA reductase; thought to reduce chol synth which will decrease [chol]i; force more chol to be removed from the circulation; competitive inhibitor (bind to active site of enzyme)–taking advantage of partially working LDL receptor in hetero FH

Question 12

treatment for homo FH

Answer 12

liver transplant; exercise, monitoring diet–> no effect; ezetimibe

Question 13

what is the role of ezetimibe

Answer 13

binds to brush border of small int; inhibits absorption of chol; binds to receptor which brings chol–> reduces blood chol; commonly used with statin, additive effect on reducing blood chol

Question 14

ezetimibe controversy

Answer 14

reduces LDL without a doubt; does not seem to decrease the events of cardiovascular problems (heart attacks); arterial wall thickness stays the same– plaque still builds up

Question 15

what are bile acid sequestrants?

Answer 15

anion exchange resins; positively charged beads bind to negatively-charged BAs–> reduce absorptions of bile salts–>excreted; also inhibit absorption of fat sol vits (need a multi-vit supplement if taking)

Question 16

how do BA sequestrants work?

Answer 16

Bile acids, when bound to resins can’t be recycled– the 2% that was excreted normally is increased– not enough BAs coming back to liver–> liver needs to use up chol to make Bas; increase more LDL receptors on cell surface when it gets low in liver cells–> bring more in from blood–>lower blood chol

Question 17

what is LDL-apheresis?

Answer 17

Hooked up to IV –> blood is removed, ran through system of filters– >filters contain resins that have an affinity for apoB (LDL, VLDL, and chylomicrons contain them) –> contained –> blood is put back into you–> lower chol; very effective (80%); used every 2 weeks, and 3000$ per treatment

Question 18

what is PCSK-9?

Answer 18

serine protease; also cleaves itself; produced and secreted by and from liver at the ER–> released into circulation

Question 19

what do mutations in PCSK-9 cause?

Answer 19

low blood chol; increased LDL-receptors on cell surface–> increase chol uptake–> which will decrease plasma chol; mutations prevent the degradation of LDL-receptor

Question 20

what is PCSK-9’s role?

Answer 20

binds to LDL-receptor which promotes LDL receptor degradation/prevents recycling to cell surface

Question 21

can exploit the data collected on PCSK-9 mutations to understand how PCSK-9 plays into blood chol

Answer 21

can use Abs on nonmutated PCSK-9 to lower blood chol

Question 22

PCSK-9 inhibitors pros and cons

Answer 22

very effective at lowering chol (LDL)–> 60%; patients 50% less likely to have stroke; must be given injection every 2-4 weeks; possible cognitive issues; high cost– 15,000$ per year; long term safety unknown

Question 23

how are chylomicrons/ VLDLs produced?

Answer 23

particles of a TAG-rich core with a small content of cholesteryl esters, a surface monolayer of phospholipids and cholesterol and lipoproteins are produced in the intenstine/liver cells–> released into circulation

Question 24

how is LDL made?

Answer 24

produced in circulati0n from VLDL; cholesteryl ester-rich core

Question 25

mechanism of CM/VLDL assembly

Answer 25

microsomal triglyceride transfer protein (MTP)--> found in lumen of ER (inside of ER); function is dependent on binding to protein diphosphide isomerase (heterodimer)--> catalyzes transfer of TAG to CM/VLDL

Question 26

functions of MTP

Answer 26

generation of lumenal lipid droplets; translation/translocation of apoB into ER lumen; cotranslational addition of TG to apoB; post-translational addition of TAG to fully translocated apoB

Question 27

if not enough TAG is around, apoB degraded by the lysosome--always at the ready to form a lipoprotein; fasting--> not much TAG being consumed; apoB degraded

Answer 27

ya

Question 28

what is the disease of mutation in MTP, what happens

Answer 28

abetalipoproteinemia; rare; impaired dietary fat absorption; absence of plasma liporpteins (CM, VLDL, LDL); low conc of TAG and chol; symptoms: failure to grow in infancy; fatty, pale stools (steatorrhea); neuro degeneration (balance and coordination problems); loss of vision;

Question 29

what is NPC disease?

Answer 29

Niemann-Pick C Disease; fatal (no effective treatment), occurs 1/150 000; high incidence in Yarmouth Country, NS, involved neurodegeneration in children (like alzheimer's); enlargement of liver; premature death; no affective treatment

Question 30

cause of NPC disease

Answer 30

mutatins in the NPC1 (95%) and NPC2 genes (5%)

Question 31

why might NPC disease affect the brain?

Answer 31

1/5 of the brain is cholesterol; lots of it is associated with myelin, which coats nerve fibres and is integral for nerve transmssion, learning, and memory

Question 32

role of NPC1 or 2

Answer 32

proteins that bind chol present in lysosome; npc1 is in the plasma membrane and 2 is in the interior of the cell; npc2 graps chol, gives to npc1; npc1 flips it across the lysosomal membrane into the cytosol-->therefore either 1 or 2 can be defective and chol will accumulate in lysosome

Question 33

describe how receptor-mediated endocytosis plays a role in absorption of cholesterol

Answer 33

LDL receptor (from synth in the ER, modified in the golgi) goes to the membrane and combines with LDl (apoB 100); membrane invaginates around the receptor and LDL particle, creating the endosome--> pH drops to 5 which causes hte receptor to dissociate from the LDL particle; the lysosome fuses with the endosome and the cholesteryl ester droplets do things lol idk

Question 34

where are bile acids synthesized?

Answer 34

the liver

Question 35

bile acids act as emulsifiers and are needed for chol excretion

Answer 35

ya

Question 36

what is the RLS of bile acid synthesis catalyzed by?

Answer 36

7-alpha-hydroxylase

Question 37

what regulates 7-a-hydroxylase?

Answer 37

bile acids inhibit, chol induces

Question 38

what are the modified forms of bile acids?

Answer 38

primary bile acids +glycine/taurine

Question 39

98% of bile acids are reabsorbed via enterohepatic circulation; stored in the gall bladder (bilirubin) until needed; 2% is excreted in feces

Answer 39

ya

Question 40

why are bile acids necessary?

Answer 40

pancreatic lipase cannot degrade TAGs directly--need to be in special form; PL is sol. in water, while fats aren't-->need to solubilize them by using BAs as an emulsifier

Question 41

how do bile salts act as an emulsifier?

Answer 41

form micelles around the TAGs

Question 42

emulsification of bile salts causes dietary fat to form small globules which greatly increases SA-->makes TAGs accessible to pancreatic lipase and accelerate the activity of PL

Answer 42

ya

Question 43

what are gallstones?

Answer 43

solid particles that collect in gall bladder-->can range from the size of a salt grain to golf ball; normally, BSs keep chol solubilized but when there is to much chol and not enough BSs, chol ppts

Question 44

what are the causes of gall stones?

Answer 44

high chol; overweight/obesity; age; bile salt deficiency

Question 45

symptoms of gall stones?

Answer 45

abdominal pain after a fatty meal

Question 46

treatment of gall stones?

Answer 46

sound waves-->sonification; gall bladder removal

Question 47

what is the regulatory enzyme of chol synth?

Answer 47

HMG-CoA reductase; chol inhibits HMG-CoA R--CELLULAR chol levels (not blood levels) regulate chol synth

Question 48

how does chol regulate HMG-CoA R activity?

Answer 48

through reductase phos and dephos, transcription of reductase gene, translation of reductase to mRNA, and degradation of reductase

Question 49

what is SRE?

Answer 49

sterol regulatory/response element-->binds SREBP-->SREBP can then transcribe

Question 50

describe the induced transcription of HMG-CoA R

Answer 50

A conf change in Scap causes Insig to dissociate; Scap and SREBP bubble off the ER membrane and go to the golgi; there, s1P cleaves the transmembrane loop between the domains; s2P then cleaves s that SREBP can be freed from teh golgi so SREBP can enter the nucleus, bind to SRE, and then activate transcription

Question 51

hypercholesterolemia prevalence (hetero and homo)

Answer 51

1/500; homo 1/ 1 000 000

Question 52

symptoms of abetalipoproteinemia and how to manage tehm (treatment)

Answer 52

symptoms: failure to grow in infancy; fatty, pale stools (steatorrhea); neuro degeneration (balance and coordination problems); loss of vision; manage symptoms by restriction of dietary fat

Question 53

how can MTP be used to reduce high blood chol?

Answer 53

inhibit it

Question 54

what is ApoB ASO?

Answer 54

Antisense oligonucleotide therapy for ApoB; create ApoB mRNA and then antisense mRNA which is complementary; causes RnaseH to degrade-->no ApoB--> reduced VLDL and LDL levels

Question 55

what was the problem with ApoB ASO?

Answer 55

increased ALT and liver TG