40 Cholesterol Metabolism and Blood Lipoproteins

Question 1

what are the functions of cholesterol?

Answer 1

stabilizes cellular membranes primarily the plasma membrane

precursor for bile salts and steroids

precursor of cholesterol can be used for making ubiquinone, dolichol, cholecalciferol

Question 2

what is ubiquinone used for?

Answer 2

isoprene antioxidant

Question 3

what is dolichol used for?

Answer 3

glycoprotein synthesis

Question 4

what is cholecalciferol?

Answer 4

the active form of vitamin D

Question 5

what are the sources of cholesterol?

Answer 5

synthesized by most cells in the body like the liver and intestine

Question 6

what is the starting material for cholesterol?

Answer 6

acetyl CoA

Question 7

what are the dietary sources that contain cholesterol?

Answer 7

animal products like egg, red meat and liver

Question 8

in cholesterol synthesis where do the carbons come from?

Answer 8

acetyl CoA

Question 9

where do the first two stages of synthesis occur? where and what are the enzymes used in cholesterol synthesis?

Answer 9

in the cytosol; ER and the two enzymes are HMG CoA reductase and squalene synthase located on the cytoplasmic face of the ER

Question 10

during cholesterol synthesis, how does the final stage occur?

Answer 10

with ER bound enzymes

Question 11

where is the acetyl CoA for cholesterol synthesis formed?

Answer 11

in the mitochondrial matrix following glycolysis and it is transported to the cytosol by the citrate transport system

Question 12

in the Fed state, what is made?

Answer 12

FAs and cholesterol and are transported using a citrate shuttle to get acetyl CoA out to the cytoplasm under insulin signaling

Question 13

why is HMG CoA reductase important?

Answer 13

because of regulation the body will use and because its a target of drug therapy

Question 14

what enzyme is used to form Acetyl CoA from Citrate?

Answer 14

citrate lyase and so note that acetyl CoA is the starting product for cholesterol synthesis

Question 15

where do we see HMG-CoA reductase? where is it located?

Answer 15

in the first committed step of cholesterol synthesis which is also the site of regulation for cholesterol synthesis; it is located on the cytoplasmic face of the ER with catalytic domain and regulatory membrane domain

Question 16

what is the effect of limiting HMG-CoA reductase?

Answer 16

Mevalonate cannot be produced but liver can use the HMG CoA to make ketone bodies during a fast

Question 17

what is the only thing Mevalonate can be used to make?

Answer 17

cholesterol

Question 18

liver synthesizes bile salts and the gallbladder holds and releases them, T/F?

Answer 18

T

Question 19

what regulates HMG CoA reductase activity?

Answer 19

insulin dependent process and so cholesterol is made in addition to fatty acids by the liver, so for it to be activated under insulin it is dephosphorylated and phosphorylated when glucagon comes along shutting this pathway down

also note that DNA reductase under influence from bile salts and cholesterol turns on and off HMG-CoA reductase

Question 20

what enzymes are responsible for the transcriptional control of cholesterol synthesis?

Answer 20

SREBP: sterol regulatory element binding protein
-enables gene transcription to take place

SCAP: SREBP cleavage-activating protein AND S2P: site 2 protease

Question 21

how does transcriptional control of cholesterol synthesis work?

Answer 21

When cholesterol is high, cholesterol binds to SCAP. SREBP protein is intact and quiescent. When cholesterol is low, SCAP does not bind cholesterol, SREBP is activated, and S2P cleaves the DNA binding domain of SREBP. This signals DNA transcription.

Question 22

what is the effect of cholesterol esterification? what part of the molecule is modified?

Answer 22

Increases the hydrophobicity of cholesterol, which increases is solubility in lipoprotein particles an in lipid droplets in the cytosol of cells.

The hydroxyl group at C-3 can be esterified with a fatty acid

Question 23

what are the two main enzymes that esterify cholesterol?

Answer 23

Lecithin:cholesterol acyltransferase (LCAT) in blood
-esterifies cholesterol associated with HDL

Acyl:cholesterol acyltransferase (ACAT) in cells
-concentrated in cells that need to store cholesterol for steroid synthesis.

Question 24

what is cholesterol a precursor for?

Answer 24

bile salts
vitamin D
steroid hormones

Question 25

how often is cholesterol degraded?

Answer 25

a precursor for so many other molecules, that it is very rare that it ever needs to be degraded and eliminated.

One of the main “losses” of cholesterol occurs in the digestive tract with bile salts that are not resorbed properly.

Question 26

what kind of effect does salt metabolism have on cholesterol metabolism

Answer 26

direct effect

Question 27

what happens to patients who do not efficiently resorb bile salts?

Answer 27

must constantly resynthesize them from cholesterol.

These patients often have upregulated cholesterol synthesis.

Question 28

what is Cytochrome P450 monooxygenase (7α-hydroxylase)?

Answer 28

first enzyme that takes a cholesterol molecule and moves it toward a bile salt by incorporating an -OH group first; also a rate limiting step in bile synthesis

also implicated in lipid digestion disorders because they are missing bile salts

Question 29

what are primary bile salts?

Answer 29

first ones formed and so once released into digestive tract, they can be modified, forming the secondary bile salts.

OHs added to help make the molecule more soluble

Question 30

what do bile salts do?

Answer 30

emulsifier that gelatinizes it; primary and secondary forms, resorbed in the colon (95%), cholesterol is the starting material with 7α-hydroxylase as key enzyme

Question 31

know that testosterone, aldosterone, estradiol are examples of?

Answer 31

steroid hormones and note cytochrome P450 families named for location of where they put the oxygen

Question 32

what are the two major classes of steroid hormones?

Answer 32

Corticosteroids: adrenal cortex

Sex steroids: gonads (and placenta during pregnancy)

Question 33

what are five fundamental types of steroid hormones?

Answer 33

Glucocorticoids
Mineralocorticoids
Androgens
Estrogens
Progestogens

Question 34

what are the major functions of steroid hormones?

Answer 34

Control metabolism
Inflammation
Immune function
Salt and water balance
Development of sexual characteristics
Ability to withstand illness and/or injury