Human metabolism lecture 8 Flashcards
1
Q
Role of cholesterol
A
- Regulates membrane fluidity
- Precursor for bile acids, vitamin D, steroid hormones
2
Q
Cellular cholesterol status
A
Sources of cellular cholesterol
- De novo synthesis
(20-30 E, mevalonic A = 1st unique E, similar to ketone body synthesis, 2NADPH/H+, HMG coa reductase that response to [cholesterol] - Circulating cholesterol carried by LDL
- ↑ LDL receptor = ↑ capacity for uptake
- Receptor mediated endocytosis, Cathrin coated pits, proton pump, pH optimum
3
Q
NPC1/2
A
- NPC2 binds esterified cholesterol in lumen of ER + transfers to membrane bound NPC1
4
Q
Transcriptional regulation
A
- LDL receptor + HMG CoA reductase have TF SREBP2
- ER [cholesterol] ↑, SREBP2 binds INSIG + stays in ER
- ” “ ↓ , SREBP2 goes to Golgi by COPII where activated by S1P/S2P, moves to nucleus
- SCAP has sterol sensing domain + binds INSIG
- ↑ cholesterol, SCAP binds cholesterol, x bind COPII, SCAP/SREBP retained in ER by INSIG
- ↓ cholesterol, SCAP binds COPII, SCAP/SCREBP move to Golgi
5
Q
Endocytic cholesterol metabolism
A
- Free cholesterol enters enterocyte via NPC1L1
- Some cholesterol returns to lumen via ABCG5/8 in TICE
- Remaining cholesterol is esterified by ACAT
6
Q
Cholesterol disposal
A
- Excess cholesterol excreted
- RCT, efflux of cholesterol on HDL to liver
- In liver, secreted into bile, portion reabsorbed
7
Q
Cholesterol efflux from tissues
A
- 4 pathways from a macrophage (2 need diffusion by SR-B1, 2 need ATP)
- Liver + intestine make apoA1
- ApoA1 gathers cholesterol from 2 diffusion pathways
- As ApoA1 gets cholesterol, matures to HDL + LCAT
8
Q
Good vs bad cholesterol
A
- Were cholesterol reaches
- Cellular cholesterol is safe
- Most carried by LDL (bad), minority by HDL (good)
- If endothelial layer damaged, LDL taken up into sub-endothelial space + oxidised (bad)
- Statins inhibit HMG CoA reductase
- ↑ LDL receptor no. → ↑ capacity for cholesterol uptake, ↓ circulating LDL
- Epidemiological studies
