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BIOC 435 > Cholesterol > Flashcards

Cholesterol Flashcards

1
Q

What is hypercholesterolemia?

A

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

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2
Q

what is SREBP?

A

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

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3
Q

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

A

SREBP, Scap, Insig, S1P ad S2P

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4
Q

what is the role of Scap?

A

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

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5
Q

What is the role of insig?

A

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

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6
Q

what is the role of S1/2P

A

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

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7
Q

Risk factors of hyperchol..emia

A

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

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8
Q

what is familial hyperchol..emia due from?

A

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

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9
Q

symptoms of hyperchol..emia

A

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

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10
Q

treatment of hetero FH

A

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

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11
Q

what are statins?

A

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

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12
Q

treatment for homo FH

A

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

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13
Q

what is the role of ezetimibe

A

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

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14
Q

ezetimibe controversy

A

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

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15
Q

what are bile acid sequestrants?

A

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)

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16
Q

how do BA sequestrants work?

A

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

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17
Q

what is LDL-apheresis?

A

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

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18
Q

what is PCSK-9?

A

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

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19
Q

what do mutations in PCSK-9 cause?

A

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

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20
Q

what is PCSK-9’s role?

A

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

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21
Q

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

A

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

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22
Q

PCSK-9 inhibitors pros and cons

A

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

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23
Q

how are chylomicrons/ VLDLs produced?

A

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

24
Q

how is LDL made?

A

produced in circulati0n from VLDL; cholesteryl ester-rich core

25
Q

mechanism of CM/VLDL assembly

A

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

26
Q

functions of MTP

A

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

27
Q

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

A

ya

28
Q

what is the disease of mutation in MTP, what happens

A

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;

29
Q

what is NPC disease?

A

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

30
Q

cause of NPC disease

A

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

31
Q

why might NPC disease affect the brain?

A

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

32
Q

role of NPC1 or 2

A

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

33
Q

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

A

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

34
Q

where are bile acids synthesized?

A

the liver

35
Q

bile acids act as emulsifiers and are needed for chol excretion

A

ya

36
Q

what is the RLS of bile acid synthesis catalyzed by?

A

7-alpha-hydroxylase

37
Q

what regulates 7-a-hydroxylase?

A

bile acids inhibit, chol induces

38
Q

what are the modified forms of bile acids?

A

primary bile acids +glycine/taurine

39
Q

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

A

ya

40
Q

why are bile acids necessary?

A

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

41
Q

how do bile salts act as an emulsifier?

A

form micelles around the TAGs

42
Q

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

A

ya

43
Q

what are gallstones?

A

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

44
Q

what are the causes of gall stones?

A

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

45
Q

symptoms of gall stones?

A

abdominal pain after a fatty meal

46
Q

treatment of gall stones?

A

sound waves–>sonification; gall bladder removal

47
Q

what is the regulatory enzyme of chol synth?

A

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

48
Q

how does chol regulate HMG-CoA R activity?

A

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

49
Q

what is SRE?

A

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

50
Q

describe the induced transcription of HMG-CoA R

A

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

51
Q

hypercholesterolemia prevalence (hetero and homo)

A

1/500; homo 1/ 1 000 000

52
Q

symptoms of abetalipoproteinemia and how to manage tehm (treatment)

A

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

53
Q

how can MTP be used to reduce high blood chol?

A

inhibit it

54
Q

what is ApoB ASO?

A

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

55
Q

what was the problem with ApoB ASO?

A

increased ALT and liver TG

BIOC 435 (18 decks)

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