SYLLABUS 10: Cholesterol Metabolism

Question 1

cholesterol fxn in membranes

Answer 1

provides order, rigidity

Question 2

cholesterol fxn in liver

Answer 2

precursor of the bile salts which emulsify and digest fats

Question 3

cholesterol fxn in endocrine tissues

Answer 3

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

Question 4

what is cholesterol synthesized from?

Answer 4

acetyl CoA

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

Question 5

where is cholesterol synthesized

Answer 5

all tissues

but liver is most active organ

Question 6

what is the structure of cholesterol

Answer 6

hydrophobic sterol ring structure

Question 7

where in the cell does cholesterol synthesis occur

Answer 7

cytosol and endoplasmic reticulum

Question 8

how do statin drugs work?

Answer 8

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

these lower cholesterol levels

Question 9

describe biosynthesis of cholesterol

Answer 9

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

Question 10

what can isopentyl pyrophosphate produce

Answer 10

cholesterol

ubiquinone (Q10)

dolichol, which is in membraen glycolipids

vitamins E and A

Question 11

what makes HMGCoA?

Answer 11

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

Question 12

what activates HMGCoA reductases activity?

Answer 12

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

Question 13

what deactivates HMGCoA reductase activity?

Answer 13

• 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

Question 14

how does high cholesterol impact HMGCoA Reductase activity

Answer 14

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)

Question 15

how does low cholesterol impact HMGCoA reductase activity

Answer 15

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

Question 16

function of LDL

Answer 16

transports high amounts of cholesterol and cholesterol esters in the blood

Question 17

how does LDL receptor work

Answer 17

cholesterol binds to LDL receptors

receptor-mediated endocytosis occurs

lysosomal degredation of the choelsterol

Question 18

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

Answer 18

downregulates LDL receptor synthesis

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

Question 19

what do mutations in the LDL receptor cause

Answer 19

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

Question 20

what are foam cells? what do they cause?

Answer 20

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

Question 21

besides statins, what treatments can lower cholesterol?

Answer 21

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

Question 22

why is HDL / LDL “good” / “bad” cholesterol

Answer 22

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

Question 23

where are chylomicrons produced?

what is their function?

what do they contain?

Answer 23

produced in GI tract

carry triglycerides to liver & adipose, NOT much cholesterol

contain triglycerides/lipids

Question 24

where is VLDL produced?

what is its function?

what does it contain?

Answer 24

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

Question 25

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

Answer 25

produced in blood from VLDL

function is endocytosed by liver or converted to LDL

contain high cholesterol, intermediate triglycerides

Question 26

where is HDL produced? function? contains?

Answer 26

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

Question 27

where is LDL produced?

function?

what does it contain?

Answer 27

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