SYLLABUS 10: Cholesterol Metabolism Flashcards Preview

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Flashcards in SYLLABUS 10: Cholesterol Metabolism Deck (27):
1

cholesterol fxn in membranes

provides order, rigidity

2

cholesterol fxn in liver

precursor of the bile salts which emulsify and digest fats

3

cholesterol fxn in endocrine tissues

precursor of steroid hormones, e.g. glucocorticoids, mineralocorticoids, sex hormones, vitamin D

4

what is cholesterol synthesized from?

acetyl CoA 

so all nutrients - glucose, fatty acids, amino acids, alc - provide C atoms for cholesterol biosynthesis

5

where is cholesterol synthesized

all tissues

but liver is most active organ 

6

what is the structure of cholesterol 

hydrophobic sterol ring structure

7

where in the cell does cholesterol synthesis occur

cytosol and endoplasmic reticulum 

 

8

how do statin drugs work?

they inhibit the rate-limiting enzyme of cholesterol biosynthesis, HMGCoA reductase 

these lower cholesterol levels 

9

describe biosynthesis of cholesterol

1. 2 acetyl CoA -> acetoaceyl CoA + Acetyl CoA via Thiolase

2. HMGCoA REDUCTASE reaction, rate limiting, makes this into HMGCoA 

uses 2 NADPHs 

3. Mevalonate is metabolized in 2 steps to isopentyl pyrophosphate 

4. Isopentyl pyrophosphate ultimately produces choelsterol 

 

10

what can isopentyl pyrophosphate produce

cholesterol 

ubiquinone (Q10) 

dolichol, which is in membraen glycolipids 

vitamins E and A 

11

what makes HMGCoA? 

1) made in liver mito from 3 acetyl CoA by a specific HMGCoA synthase for ketogenesis 

2) made in cytosol of most cells by another isoform for cholesterol and isoprene units

12

what activates HMGCoA reductases activity?

dephosphorylated state (-OH) = activated state 

transcriptionally activated by insulin activation, via increase in SREBP2 or protein-phosphatase 1, and thus dephosphorylation

also increased in low levels of cholesterol states

 

13

what deactivates HMGCoA reductase activity?

-OP (phosphorylated) is inactive form of enzyme

1. glucagon and epi, via phosphorylation 

2. AMP kinase

3. end product inhibition by cholesterol, which decreases processing of SREBP and increases ubiquitination of HMGCoA R and increases proteosomal degradation 

4. statins

14

how does high cholesterol impact HMGCoA Reductase activity

1) it inhibits transcription of the HMGCoA reductase gene by preventing the processing and nuclear translocation of the txn factor SREBP-1, which binds to the sterol regulatory element of the HMGCoA reductase gene & activates it when cholesterol and otehr sterols are low 

 

2) promotes degredation of HMGCoA reductase enznyme (decreases the half-life) 

15

how does low cholesterol impact HMGCoA reductase activity

1) when cholesterol is low, SREBP-1 is a txn factor that binds to sterol regulatory element of HMGCoA R gene, activates it. and SREBP-1 is activated by insulin. 

2) low cholesterol elevates synthesis of HMGCoAR by not downregulating HMGCoAR transcription or stability 

16

function of LDL

transports high amounts of cholesterol and cholesterol esters in the blood 

 

17

how does LDL receptor work

cholesterol binds to LDL receptors 

receptor-mediated endocytosis occurs 

lysosomal degredation of the choelsterol

18

what's the impact of high levels of intracellular cholesterol on LDL receptor?

downregulates LDL receptor synthesis 

this lowers the entry of LDLs / LDL-derived cholesterol into cells 

 

19

what do mutations in the LDL receptor cause

1) atherosclerosis, because circulating LDLs are not efficienctly removed from the blood 

so serum cholesterol levels are high

 

2) accumulated LDLs in blood are subjected to oxidation of their phospholipids by oxygen radicals, produce oxidized LDLs, which macrophages engulf, and results in formation of foam cells

20

what are foam cells? what do they cause?

macrophages that mistakenly engulf oxidized LDL receptors because they recognize them as oxygen radicals 

foam cells clog endothelial space of blood vessels, produce fatty streaks and atherosclerotic plaques

21

besides statins, what treatments can lower cholesterol?

1) statins inhibit HMGCoA R 

2) limitation of certain foods - liver, meats 

3) cholestyramine, a postively-charged bile salt binding resin, lowers the reabsorption of bile salts and pushes liver to synthesize more bile salts from cholesterol, thus lowering cholesterol levels

22

why is HDL / LDL "good" / "bad" cholesterol

physicians test HDL/LDL levels to estimate risk of atherosclerosis 

HDL transport cholesterol from blood to liver for metabolism 

LDL contain high amounts of cholesterol 

23

where are chylomicrons produced? 

what is their function? 

what do they contain?

produced in GI tract 

carry triglycerides to liver & adipose, NOT much cholesterol 

contain triglycerides/lipids

24

where is VLDL produced? 

what is its function? 

what does it contain?

produced in liver 

packages excess FA made in liver into triglycerides for delivery in blood, esp. to adipose to store 

contains mainly triglyceides, some cholesterol

25

where are intermediate density lipoproteins produced? what is their function? what do they contain?

produced in blood from VLDL 

function is endocytosed by liver or converted to LDL 

contain high cholesterol, intermediate triglycerides

26

where is HDL produced? function? contains?

produced in liver and intestine 

returns cholesterol from peripheral tissue to liver 

is raised by Vitamin B Niacin and moderate alcohol consumption 

consists of apolipoprotein A, C, E, high in protein, low in triglycerides / cholesterol

27

where is LDL produced? 

function? 

what does it contain?

produced in blood, as end product of VLDL metabolism 

functions: 

1) taken up into cell via LDL receptor mediated endocytosis, then lysosomal digestion, then cholesterol released 

2) high levels of intracellular cholesterol DOWNREGULATE LDL receptor synthesis 

3) many mutations of LDL receptor occur -> atherosclerosis 

4) LDL accumulated in blood can be targeted by oxygen radicals -> oxidized LDLs 

5) oxidized LDLs recognized by macrophages, when they accumulate, macrophages -> foam cells which clog endothelial space -> plaques 

 

contain: apolipoprotein B, high in cholesterol and their esters

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