Lipids (Lecture 22)

Question 1

what disease can occur with the accumulation of LDL/VLDL/chylomicrons?

Answer 1

atherosclerosis

Question 2

if there’s a deficiency in LDLR, then…

Answer 2

too much LDL will accumulate

high risk for cardiovascular disease

Question 3

if there’s a deficiency in ABCA-1, then…

Answer 3

too little HDL, thus the cholesterol will accumulate within the cell

high risk for cardiovascular disease

this is the case for Tangier Disease

Question 4

cholesterol is composed of multiple units of…

Answer 4

isoprene

Question 5

what type of reaction is the synthesis of cholesterol?

Answer 5

anabolic

Question 6

what is the source of protons/ e- in the reducing reactions involved int he synthesis of cholesterol?

Answer 6

NADPH

Question 7

describe the mevalonate pathway.

Answer 7

2 acetyl Coa are combined to make acetoacetyl-CoA.

CoA is removed to make HMG-CoA (this can be used for ketogenesis)

HMG CoA is reduced via HMG CoA reductase (rate limiting step) to form mevalonate

with the investments of ATP (3 ATP) and the removal of CO2 to generate isoprene looking molecules.

farnesyl phosphate will act as a lipid anchor

eventually, NADPH will generate squalene

many other steps generate cholesterol

Question 8

how many ATPs and NADPHs are required for the synthesis of one cholesterol molecule

Answer 8

36 ATP

16 NADPH

Question 9

how is cholesterol regulated (2)

Answer 9

level of the body:
control cholesterol intake

level of the cell:
control cholesterol at the surface (to affect cell signalling)

1. regualte uptake of LDL by regulating LDLR (decrease uptake, then decreases the intracellular concentration)
2. efflux more cholesterol of ABCA1, then this depletes the amount of cholesterol in the cell
3. control regulation of endogenous production of cholesterol, control HMG CoA reductase

Question 10

how is HMG CoA regulated

Answer 10

energy state. with a lot of energy, it can synthesize cholesterol, since it takes a large investment of ATP to follow through with this process (36 ATPs)

[choelsterol] via gene regulation

Question 11

what is the transcription factor that regulates HMG CoA reductase and LDL-R

Answer 11

SREBP, a sterol response binding element

transcription factor for sterol responsive genes

Question 12

what occurs when SREBP binds to the promoter of the HMG CoA reductase gene

Answer 12

it induces its transcription

Question 13

how does the cell generate more cholesterol with gene transcription

Answer 13

upregulate HMG CoA reductase to increase cholesterol synthesis

upregulating LDLR synthesis will upregulate LDL uptake (uptake cholesterol form circulation)

Question 14

where is SREBP and what protein does it interact with

Answer 14

ER membrane

Scap (has a cholesterol sensing domain)

Question 15

what occurs when Scap is not interacting with cholesterol?

Answer 15

Scap takes the complex of bHLH and will travel to the Golgi apparatus in the absence of cholesterol

in the golgi, there’s an S1P. SIP will cleave the SREBP molecule to generate bLHL.

bHLH becomes a substrate for S2P, which cleaves a part of the protein to release the nuclear transcription factor that will enter the nucleus to bind to the sterol responsive element and activate the set of genes that will increase the synthesis or uptake of cholesterol

Question 16

what occurs with SREBP in the presence of cholesterol (high cholesterol concentration)?

Answer 16

Scap will interact with cholesterol and SREBP will not travel to the Golgi, thus preventing the modification at the gene level.

Question 17

how can cholesterol synthesis be pharmacologically regulated?

Answer 17

HMG-CoA reductase inhibitors (statins)

prevents cholesterol synthesis.

Question 18

cholesterol is a derivative of:

Answer 18

cholesterol esters

bile salts

hormones

vitamine D

Cholesterol is transformed and not degraded (because it is costly to make)