Cholesterol synthesis

Question 1

Function

Answer 1

structural component of cell membrane
precursor for bile acids, steroid hormones, vitamin D
component of plasma lipoproteins

Question 2

Location

Answer 2

liver
intestines
adrenal cortex
reproductive organs

Question 3

1. Acetyl CoA + Acetyl CoA -> Acetoacetyl CoA

Answer 3

• CoASH
• enzyme: THIOLASE
• in cytosol

Question 4

2. Acetoacetyl CoA + Acetyl CoA -> HMG CoA

Answer 4

• CoASH
• enzyme: HMG CoA SYNTHASE
• in cytosol

Question 5

3. HMG-CoA -> Mevalonate

Answer 5

• reduction 2NADPH-> 2NADP+
• CoASH
• enzyme: HMG-CoA REDUCTASE
• COMMITTED STEP, RATE LIMITING
• in ER

Question 6

Regulation of HMG CoA reductase

Answer 6

inhibited by: 
high cholesterol
phosphorylation
AMP
glucagon
glucocorticoids
statins (comp. inhibitor)
bile salts

Activated by:
low cholesterol
dephosphorylation
ATP
insulin
thyroxine

Question 7

4.Mevalonate -> 5-phosphomevalonate

Answer 7

• ATP->ADP

- enzyme: MEVALONATE KINASE

Question 8

5. 5-phosphomevalonate -> 5-pyrophosphomevalonate

Answer 8

• ATP->ADP

- enzyme: PHOSPHOMEVALONATE KINASE

Question 9

6. 5-pyrophosphomevalonate -> 3-phospho-5-pyrophosphomevalonate

Answer 9

ATP->ADP

-enzyme: MEVALONATE 5 PYROPHOSPHATE DECARBOXYLASE

Question 10

7. 3-phospho-5-pyrophosphomevalonate -> Isopentenyl pyrophosphate

Answer 10

• CO2

- enzyme: MEVALONATE 5 PYROPHOSPHATE DECARBOXYLASE

Question 11

8. IPP -> Dimethylallyl pyrophosphate

Answer 11

• reversible

- enzyme: IPP ISOMERASE

Question 12

9. IPP + DPP -> Geranyl pyrophosphate

Answer 12

• ppi

- enzyme: PRENYL TRANSFERASE

Question 13

10.GPP + IPP -> Farnesyl pyrophosphate

Answer 13

• ppi

- enzyme: PRENYL TRANSFERASE

Question 14

11. FPP + FPP -> Squalene

Answer 14

• ppi
  NADPH->NADP+
  -enzyme: SQUALENE SYNTHASE

Question 15

12. Squalene -> Squalene Epoxide

Answer 15

+O2
-H2O
NADPH-> NADP+
-enzyme: SQUALENE MONOOXYGENASE

Question 16

13. Squalene Epoxide -> Prosterol Cation

Answer 16

+ H+

-enzyme: LANOSTEROL SYNTHASE

Question 17

14. Prosterol Cation -> Lanosterol

Answer 17

enzyme: LANOSTEROL SYNTHASE

Question 18

15. Lanosterol -> Cholesterol

Answer 18

• formic acid
• 2 CO2
  19 steps

Question 19

Long term control

Answer 19

1.Transcription level: control rate at which HMG CoA reductase mRNA is made
2. Translational level
dietary cholesterol inhibits
3. Proteolytic level

Question 20

ACAT

Answer 20

acyl coA cholesterol acyltransferase
ACAT1: macrophages
ACAT2: intestines, liver
cholesterol -> cholesterol ester

Question 21

NPC1L1

Answer 21

Riemann Pick C1 Like 1
in GI epithelial cells + hepatocytes
absorbes cholesterol
inhibition: ezetimibe

Question 22

HSL

Answer 22

hormone sensitive lipase
cholesterol ester -> cholesterol
TAG -> free fatty acids

Question 23

ABCA1

Answer 23

ATP-binding cassette transporter (CERP)
regulator of efflux of cellular cholesterol + phospholipid homeostasis
transports to apoA1 + apoE

Question 24

LXR

Answer 24

liver X receptor
ligand: oxysterol
effects: CYP7A1, ABCA1,IDOL
increase in bile synthesis, cholesterol efflux
decrease in LDL repectors

Question 25

FXR

Answer 25

farnesoid X receptor

ligand: bile acid
effects: IBAT, IBABP, FGF19, BSEP, PCSK9. SHP
increase: bile acid reabsorption (auto/endocrine), LDL receptor, gene expression

Question 26

SHP

Answer 26

small heterodimer protein
no ligand
effects: CYP7A1
bile acid synthesis decrease