Cholesterol rich lipoproteins and Cholesterol Homeostasis

Question 1

How do CE-rich LPs modify atherclerosis risk?

Answer 1

Serum LDL –> arterial wall MACROPHAGE CE storage –> conversion from macrophage to foam cell –> conversion from foam cell to fatty streak

Question 2

How does the liver regulate serum LDL?

Answer 2

hepatic intracellular [Chol]

Question 3

What does hepatocyte IC [chol] regulate?

Answer 3

Chol input - de novo synth & LDL uptake

Chol output - CE & BA synth

Question 4

Acetyl CoA

Answer 4

Precursor to FA, chol, & KB

chol is from cytosolic acetyl CoA

Question 5

Cholesterol synth

Answer 5

1. Glucose –> cytosolic acetyl CoA
2. Synth and reduce HMG CoA
3. Assemble ring structure and tail to –> Chol

Question 6

HMG CoA reductase

Answer 6

converts HMG CoA to chol in smooth ER

Question 7

ATP citrate lyase (ACLY)

Answer 7

Converts citrate to acetyl CoA

Question 8

Hormonal regulation of HMG CoA reductase

Answer 8

(-) by glucagon

(+) by Insulin

Question 9

Other HMG CoA Reductase regulation

Answer 9

intracellular [chol]

Question 10

LDL-R synth

Answer 10

Regulated by intracellular [chol]

In RER –> processed in golgi –> secretory vesicle –> plasma membrane

Question 11

LDL-R degradation

Answer 11

regulated by intracellular [chol] & by PCSK9 protein secreted by hepatocytes

Question 12

PCSK9 regulation of LDL-R

Answer 12

binds LDL to LDL-R -> no LDL-R recycling –> inc LDL-R degradation –> dec LDL-R expression

Question 13

Which lipoproteins can cross endothelial

Answer 13

HDL (normal levels)
LDL (high levels)

Intermeds (only at very high serum levels):
IDL
CMR

Cross into arterial wall connective tissue and interact w macrophages

Question 14

Macrophages use ___ to take up ___ in connective tissue

Answer 14

LDL-R

LDL, IDL, or CMR

Question 15

Macrophages use ___ to convert ___ to ___ for storage

Answer 15

Macrophages use ACAT to convert chol to CE for storage

Question 16

Macrophages use _____ to efflux ___ onto ____

Answer 16

Macrophages use ABCA1 to efflux chol onto HDL

Question 17

Scavenger receptors (SR)

Answer 17

• expressed by macrophages
• recognize various ligands so macrophages can clear shit up
• not downreg by high IC [chol]

Question 18

Macrophages take up enough chol from apoptotic bodies to _____ the LDL-Rs at normal LP levels

Answer 18

downregulate

Question 19

At normal serum LP levels, little ___ is modified and taken up by ____

Answer 19

LDL

SRs

Question 20

How can macrophages prevent excessive CE accumulation?

Answer 20

By effluxing chol onto HDL

Question 21

What happens to LDL that remains in arterial walls?

Answer 21

Oxidation, acetylation, etc.

Becomes a target for SRs

Question 22

How does high serum [LDL] affect SR?

Answer 22

High serum LDL –> inc LDL transport –> inc modified LDL –> IC chol –> dec LDL-R

but does NOT dec SRs

Question 23

What causes a macrophage to turn into a foam cell

Answer 23

Very high [CE] activates secretion of cytokines that convert it and also recruit more macrophages to become foam cells –> fatty streaks –> atherosclerosis

Question 24

Which of the following increase early risk of atherosclerosis:
VLDL, LDL, IDL, CMR, or CM?

Answer 24

High LDL, IDL, and CMR; CM do not

Question 25

What contributes to macrophage CE storage?

Answer 25

High serum LDL (major contributor), IDL, CMR Low HDL

Question 26

Key initiator of athersclerosis?

Answer 26

Excess macrophage CE storage

Question 27

Sterol-responsive transcription factors

Answer 27

How IC [chol] regulates cell processes

Question 28

SREBP

Answer 28

Inc transcription of LDL-R and HMG CoA Is inhib by IC [chol]

Question 29

LXR/RXR

Answer 29

``` Inc transcription of: ABCA1 ACAT 7alphaOHase PCSK9 secretion ``` Stim by IC [chol]

Question 30

What is the major cause for an inc in IC [chol] in liver?

Answer 30

HMG CoA reductase

Question 31

What is a major cause for dec in IC [chol] in liver?

Answer 31

7alpha-OHase (chol--> BA)