Biochemistry 34: Cholesterol, Absorption, Synthesis, Metabolism And Fate

Front 1

How is cholesterol transported in the blood? Why is it done this way?

Back 1

using lipoproteins (chylomicrons); it is insoluble in water and needs to be with lipoprotein

Front 2

Cholesterol synthesis begins with what precursor condensing to form HMG CoA?

Back 2

Acetyl Co-A + Acetyl Co-A condense to form Acetoacetyl Co-A. Another Acetyl Co-A is added by condensation to form HMG Co-A

Front 3

In cholesterol synthesis, HMG CoA is reduced to form ...

Back 3

mevalonate

Front 4

The rate-limiting step of cholesterol synthesis involves what reaction and enzyme?

Back 4

reduction of HMG CoA by HMG CoA reductase

Front 5

In cholesterol synthesis, how is squalene formed?

Back 5

isoprene units (from mevalonate) condense

Front 6

Synthesis of LDL receptors is decreased when ...

Back 6

there is enough cholesterol in the cells and they are being stored as cholesterol esters. the cell doesn't need to take up more LDL + cholesterol

Front 7

HDL function

Back 7

transport apoE and apoCII to chylomicrons and VLDLs; reverse cholesterol transport (take cholesterol to the liver)

Front 8

Bile is stored in ...

Back 8

gall bladder

Front 9

Bile function

Back 9

emulsify fats to aid in digestion

Front 10

How is cholesterol excreted?

Back 10

as bile

Front 11

Formula to calculate LDL cholesterol. LDL =

Back 11

LDL = total cholesterol - ((HDL +(triglycerides/5))

Front 12

How is cholesterol absorbed into the enterocytes from the gut lumen?

Back 12

diffusion

Front 13

What is the function of ABC proteins (ATP Binding Cassette)?

Back 13

transport of excess cholesterols from enterocytes back into the gut lumen

Front 14

What is the disorder, sitosterolemia?

Back 14

defect in ABC proteins so excess cholesterols are absorbed into enterocytes, then blood. ABC is unable to put excess back into the gut lumen for excretion. patients have hypercholesterolemia

Front 15

How does the drug Ezetimibe work? What does it do?

Back 15

this drug lowers serum cholesterol by blocking absorption by NPCLI protein into enterocytes. leads to lower LDL eventually

Front 16

Cholesterol is formed as HMG CoA is reduced. What reduces HMG CoA? What enzyme creates this reducing agent?

Back 16

NADPH is the reducing agent. it comes from G6PD (glucose 6 phosphate dehydrogenase) activity

Front 17

Where is HMG Co-A reductase found in the cell?

Back 17

ER membrane

Front 18

How does Acetoacetyl CoA become HMG CoA?

Back 18

another Acetyl Co-A is added via HMG CoA synthase

Front 19

Binding of SREBP to SCAP has what effect on cholesterol synthesis?

Back 19

decreases synthesis; SCAP prevents SREBP from working as a transcription factor for HMG CoA reductase

Front 20

Elevated glucagon levels have what effect on cholesterol synthesis?

Back 20

glucagon phosphorylates HMG CoA reductase = inhibited = less cholesterol synthesis

Front 21

What effect do high ATP levels have on cholesterol synthesis?

Back 21

high ATP levels = less AMP = less AMP activated kinase = less phosphorylation of HMG CoA reductase = more HMG reductase activity

Front 22

How does Mevalonate become isoprene?

Back 22

phosphate groups are added from ATP to the mevalonate structure

Front 23

How does isoprene become squalene?

Back 23

condensation of 6 5-carbon isoprene = 30-carbon squalene

Front 24

Linear squalene become a ring by the action of which enzyme?

Back 24

squalene monooxygenase; oxidizes and forms epoxide and will lead to ring formation = lanosterol

Front 25

Function of Acyl CoA Acyl transferase (ACAT)

Back 25

formation of cholesterol esters

Front 26

On a high cholesterol diet, rate of cholesterol synthesis is (high or low)?

Back 26

low due to feedback suppression

Front 27

Cholesterol begins forming bile salts by what rate-limiting step?

Back 27

hydroxylation by 7a-hydroxylase

Front 28

Which cholesterol derivative has more Oh gropus? (Cholate or Chenocholate)

Back 28

Cholate has 3 OH; Chenocholate has 2 OH

Front 29

pH of the intestinal lumen

Back 29

6

Front 30

pKa of bile acid

Back 30

6

Front 31

Why does 50% of bile acid exist in the de-protonated salt form?

Back 31

pH = pKa (6=6). according to Henderson-Hasselbach, half is still acidic (bile acid), and half is de-protonated (bile salts)

Front 32

Conjugated bile salts contain one of which 2 amino acids?

Back 32

glycine or taurine (from cysteine)

Front 33

Bile salts are conjugated with either glycine or taurine. Which amino acid, when conjugated with chenocholate, will give a stronger acid?

Back 33

taurine + chenocholate = pKa 2. stronger acid = more bile in salt form rather than acid form.

Front 34

How is lithocholic acid different from cholic acid?

Back 34

lithocholic acid is missing 2 OH groups (from carbon 7 and 12)

Front 35

Are cholesterol esters hydrophobic or hydrophillic?

Back 35

hydrophobic

Front 36

What allows for a hydration shell to form around the triglycerides and cholesterol esters inside a chylomicron?

Back 36

polar proteins (apoproteins) on the outer shell

Front 37

Name 4 function of apoproteins on the outer shell of a chylomicron/VLDL

Back 37

chylomicron outer shell stability, create chylomicron hydration shell, activate enzymes for metabolism, ligand for receptors on tissues that chylomicrons are delivered to

Front 38

What is less dense? Chylomicron or VLDL.

Back 38

chylomicrons are the least dense lipoproteins since they have the highest triglyceride content

Front 39

What has a higher concentration of triglycerides? chylomicrons or VLDL

Back 39

chylomicrons

Front 40

LPL is activated by binding to which apoprotein on chylomicrons?

Back 40

apoCII

Front 41

Uptake of VLDL into the liver is mediated by which receptor apoprotein?

Back 41

apoE

Front 42

How does IDL become LDL?

Back 42

removal of triglycerides by hepatic triglyceride lipase

Front 43

Uptake of LDL into the liver is mediated by which receptor apoprotein?

Back 43

apoB-100

Front 44

What happens if there is an excess of LDL and it is not all endocytosed by the liver?

Back 44

it remains in blood and will eventually get taken up by macrophages in the endothelium = atherosclerosis

Front 45

3 ways HDL can be formed

Back 45

from scratch in the liver, from VLDL apoprotein remnants that accumulate lipid, free apoA1 collects lipids

Front 46

How does a nascent HDL become mature?

Back 46

collecting cholesterol from endothelium (this is why it is good in preventing atherosclerosis)

Front 47

Why does a defect in ABC1 (ATP-binding cassette) lead to low HDL (and high risk of atherosclerosis)?

Back 47

ABC1 is expressed on cells to use ATP to move cholesterol from inner to outer leaflet of plasma membrane. defect = unable to move cholesterol to outer leaflet = HDL cannot pick-it up = HDLs don't mature

Front 48

What does the enzyme LCAT do?

Back 48

converts cholesterol into a cholesterol ester that migrates into the HDL core

Front 49

Where does a mature HDL particle go? What does it do once it has accumulated triglycerides?

Back 49

can bind to liver (using apoE receptor) or can have the triglycerides cleared by macrophages (using SR-B1 receptor)

Front 50

Function of CETP

Back 50

cholesterol ester transfer protein mediates the exchange between VLDL and HDL (cholesterol ester from HDL goes to VLDL & triglyceride from VLDL goes into HDL)

Front 51

What type of interaction occurs between HDL and chylomicrons/VLDL?

Back 51

HDL can give them apoproteins

Front 52

When there are high levels of VLDLs, how does most cholesterol get to the liver? using VLDL or HDL? Why?

Back 52

by the VLDL.

Front 53

When LDL is endocytosed, cholesterols are quickly converted into esters. Why?

Back 53

free cholesterol is dangerous to the membranes of endocytosis or lysosomes.

Front 54

What does the enzyme ACAT do?

Back 54

creates cholesterol esters in a lysosome to prevent accumulation of free cholesterol that would damage the membranes

Front 55

When sterol levels are high, what happens to LDL receptor synthesis?

Back 55

decreases. we don't need more cholesterol to be endocytosed into cells if there are high sterol levels already. decreased LDL receptors = regulate the amount of cholesterol taken up

Front 56

When cholesterol levels fall, what happens to the rate of LDL receptor formation?

Back 56

increases so more LDL is taken into the cells

Front 57

What receptor is used by macrophages to uptake LDL and become foam cells in atherosclerosis?

Back 57

SR-B1 scavenger receptor

Front 58

Why are uncontrolled diabetics likely to have high VLDL/LDL levels?

Back 58

diabetes = high blood glucose = glycation of LDL receptors= less LDL binding = more LDL in the blood. also high free fatty acids (since the cells can't take in glucose for energy) = more VLDL formation

Front 59

What is the vasa vasorum?

Back 59

blood vessels in the outer 2/3 of the media/adventitia of the blood vessel

Front 60

What is a "fatty streak"?

Back 60

beginning of accumulation of lipids in the intima of a blood vessel

Front 61

Why might aspirin be helpful in treating atherosclerosis?

Back 61

reduce inflammation since atherosclerosis is considered inflammatory (due to migration/proliferation of macrophages)

Front 62

How do statins help patients with atherosclerosis?

Back 62

prevents LDL formation by inhibiting HMG CoA reductase

Front 63

Why are strokes more likely with atherosclerosis?

Back 63

formation of a thrombus in a blood vessel = fibrous cap = portions can rupture/dislodge and get caught in other arteries

Front 64

What is lipoprotein A?

Back 64

LDL attached to apoprotein a

Front 65

What is a mural thrombus?

Back 65

a plaque that is not fully occluding the vessel

Front 66

Where is testosterone made?

Back 66

Leydig cells of testes

Front 67

Cholesterol becomes corticoids. What is the first step of this synthesis?

Back 67

cholesterol to pregnanolone by desmolase (p450scc)

Front 68

A defect in 17-a-hydroxypregnenolone would lead to low levels of what corticosteroid group?

Back 68

sex steroids

Front 69

A defect in 17-a-hydroxyprogesterone would lead to low levels of what corticosteroid group?

Back 69

glucocorticoids

Front 70

A defect in 11-deoxycorticosteroid would lead to low levels of what corticosteroid group?

Back 70

mineralocorticoids

Front 71

Where is cortisol released from?

Back 71

adrenal cortex (zona fasciculata)

Front 72

What is primary aldosteronism?

Back 72

excess aldosterone due to tumor of zona glomerulosa of adrenal cortex; high fluid retention

Front 73

A patient with a defect in 11-hydroxylase may have high levels of what corticosteroid?

Back 73

DOC (deoxycorticosterone), precursor to aldosterone since it cannot be formed; it is a weak mineralocorticoid

Front 74

2 most important stimuli for aldosterone release

Back 74

hyperkalemia (aldosterone puts potassium into the cells); angiotensin 2 (from low blood volume renin pathway)

Front 75

Why would a 21-hydroxylase defect lead to excess testosterone formation?

Back 75

in Congenital Adrenal Hyperplasia, since we cannot make aldosterone or cortisol all the pregnenalone become testosterone

Front 76

Testosterone formation is stimulated by what hormone?

Back 76

LH

Front 77

Estrogen formation is stimulated by what hormone?

Back 77

FSH

Front 78

What are rickets?

Back 78

low vitamin D in children

Front 79

Testosterone become estradiol by what enzyme?

Back 79

p450 aromatase

Front 80

Vitamin D is made from what precursor?

Back 80

cholesterol

Front 81

What is the most potent form of vitamin D?

Back 81

calcitriol

Front 82

What is transcalciferin?

Back 82

vitamin D binding transport protein

Front 83

What is the drug cholestyramine?

Back 83

bile acid sequesterant = less bile to help digest/emulsify fats = less fat absorption = more fat excretion

Front 84

How does niacin help patients with high cholesterol?

Back 84

activates LPL, reduces VLDL synthesis, reduces HDL breakdown