Cholesterol

Front 1

What is cholesterol?

Back 1

-4 ring structure
-has an OH at the 3' position
-has a bit of a hydrocarbom chain

Front 2

Properties of cholesterol, where is it found?

Back 2

-Amphipathic
-Found in biological mb

Front 3

How is cholesterol made?

Back 3

From acetyl CoA or acetate
*Note all the lipids (phospholipids, sphingolipids etc) and cholesterol are mae from acetyl CoA

Front 4

What are the steps of cholestrol synthesis?

Back 4

1)Combine 2 acetyl CoAs
2)Add 3rd acetyl CoA to form HMG-CoA, using HMG CoA synthase
3) HMG-CoA Reductase, reduce HMG-CoA to Mevalonate
4)Series of P using ATP to convert Mevalonate (6C) to Isoprene (5C)
5)Synthesize Geranyl (10C), Farnesyl (15C), Geranyl-Geranyl (20C) starting with isoprene (5C)
6)Squalene synthase is used to synthesize squalene (30C) from 2 Farnesyls
7) 3 decarboxylations to produce cholesterol (27C) from squalene

Front 5

What is the rate limiting enz in cholesterol synthesis?
Which drugs target it?

Back 5

-HMG-CoA Reductase
-Statins target it

Front 6

What can isoprene and its subsequent products be used to build?

Back 6

-Gernayl (10C)
-Farnesyl (15C)
-Gernaylgeranyl (20C)
-Squalene (30C)

Front 7

Why would you target squalene synthase over HMG-CoA reductase?

Back 7

Reduce side-effects cuz farnesyl/geranylgeranyl are used as hydrophobic anchors/tags for ptn. If you inhibit HMG-CoA reductase, don't make these products but if you inhibit Squalene synthase, make them and don't get side effects

Front 8

What are some derivatives of the cholesterol path/isopropene units?

Back 8

Vitamin A
Vitamin K
VitaminE
Farnesyl
Geranyl

Front 9

What can cholesterol be converted to?

Back 9

-Ble acids
-Vitamin D
-Steroid hormones:progesterone, testosterone, estradil aldosterone, cortisol

Front 10

What are statins?

Back 10

-Inhibitors of HMG-CoA reductase
-resemble mevalonate and are .: competitive inhib. of HMG-CoA reductase

Front 11

How are cholesteryl esters formed?

Back 11

By PC + cholesterol, through the action of LCAT (transfers fatty acyl gp from PC to cholesterol)

Front 12

What are cholesteryl esters used ofr?

Back 12

Storage form of cholesterol cuz its no lonnger amphipathic. Stored in the same area as triacylglycerols

Front 13

Cholesterol formation in the cell?

Back 13

Combine Acyl CoA and cholesterol. Use ACAT to transfer acyl group from acyl CoA to cholesterol to fomr the cholesteryl ester and CoA

Front 14

What is the difference between ACAT and LCAT?

Back 14

ACAT: in the cell. gets its acyl group from Acetyl CoA
LCAT: in the plasma. gets its acyl group from PC

Front 15

Important points about cholesterol.

Back 15

-Amphipathic
-Very stable: no enzymes can degrade cholesterol, only convert it
-small amounts used for steroid hormnes, bile acids, vitamins, isoprenes etc
-important in bio. mbs
-plasma mb where most of cholesterol located
-can be converted to cholesteryl ester for storage
-can be converted to vitamin D

Front 16

Differences between cholesterol and bile acids?

Back 16

-Bile acids have many more OH gps and are more hydrophilic
-They help emulsify fats

Front 17

How do you target proteins?

Back 17

Target protein to a mb by making thm very hydrophobic.
i.e.: add fatty acyl group of farnesyl/geraylgeranyl gp

Front 18

What is HMG-CoA reductase ?How is it regulated? (Inhibitors/activators)

Back 18

-Rate limiting enz of the cholesterol synthesis path
-Inhibitors: Glucagon, cholesterol (also stimulates ACAT to make cholesteryl esters to be stored in lipid droplets)
-Activators: Insulin

Front 19

What are two ways to get cholesterol into the cell?

Back 19

1) Make it in the cell (using ACAT)
2) Endocytosis of cholesterol carrying poteins (LDL)

Front 20

What is a lipoprotein?

Back 20

Complex of phospholipid, ptns, cholesterol and sometimes FA

Front 21

What are lipoproteins used for?

Back 21

Carriers of cholesterol

Front 22

How are cholesterol transported?

Back 22

1)Cholesterol is present in LDL (;cholesterol carrier) in the form of cholesteryl ester
2) LDL binds the LDL receptor
3)This complex is engulfed when the invaginates, forming a clathrin coated pit (Receptor mediated endocytosis)
4)LDL is separated from the LDL receptor so that it can be recycled to the cell surface
5)LDL is degraded inside the lysosome (everything inside is degraded to its basic subunits, except cholesteryl ester which is only degraded to cholesterol, which cannot be further degraded)
6)Cholesterol is transported to the ER mb

Front 23

Three regulatory steps when cell needs cholesterol?

Back 23

1)Express LDL receptor
2)Make cholesterol (express more HMG-CoA reductase)
3)Liberate cholesterol from lipid droplet

Front 24

Three regulatory steps if cell has too much cholesterol?

Back 24

1)Stop making LDL receptors and reduce them if possible
2)Stop making HMG-CoA reductase (degrade if req'd)
3)Store cholesterol as cholesteryl ester in the lipid droplets

Front 25

How is cholesterol regulated?

Back 25

-On the basis of SCAP and SREBP binding
-SCAP has a STEROL sensing domain (SSD)
-When SCAP binds cholesterol, it bind to SREBP.
-If no cholesterol, SCAP does not bind SREBP and SREBP is free to go wherever it wants.

Front 26

What happens when there is no cholesterol in the cell?

Back 26

-No cholesterol in the cell then no cholesterol in the ER mb.
-SCAP doesn't bind SREBP .: it is free to go to the golgi through a secretory mechanism
-In the golgi, SEBP is cleaved by 2 proteases, forming a soluble ptn
-Soluble ptn gos to nucleus and acts as a TF
-Stimulates LDL receptor an HMG-CoA reductase

Front 27

What happens when cholesterol lvl in the cell is high?

Back 27

-SCAP binds cholesterol
-This binding prevents release of SREBP .: it can't go to the golgi or nucleus and it can't upregulate the target genes, .: won't actto increase transcription of cholesterol

Front 28

How can you regulate cholesterol lvls in the cell?

Back 28

-ACAT
-Mb of ER (using SCAP and SREBP)

Front 29

3 shapes of phospholipids?

Back 29

-Micelle (hydrophobic interior)
-Bilayer
-Liposome (core is water, has a bilayer)
*most organelles are liposomes

Front 30

What are the components of the mb? Why do the component proportions vary?

Back 30

-Protein, phospholipids, sterols
-Composition varies depending on how stiff/fluid you want the mb to be

Front 31

Which has higher affinity for cholesterol: sphingolipids or phospholiids?

Back 31

Sphingolipids

Front 32

What are lipoproteins composed of?

Back 32

Proteins, phospholipids, free cholesterol, cholesteryl esters and triacylglycerols

Front 33

How do you separate diferent lipoproteins from each other?

Back 33

Density ultracentrifugation
(Fattest one float to the top and least fat ones sink to the bottom)

Front 34

What is the order of density of the different lipoptns?

Back 34

Chylomicron< VLDL<LDL<HDL
-lower the density, higher the concentration of TAG, lower the concentration of ptn

Front 35

Which organ regulates the body's cholesterol metabolism?

Back 35

Liver

Front 36

What are the steps of the forward cholesterol path (path from diet to liver to tissues)?

Back 36

1)Chylomicron containing CE and TG, has intergral ptn Apo-B48. As it travels through the the blood, it is acted on by lipases: releases FFA.
(the Remnant is wtv is left of the chylomicron, but it still contains CE and Apo-B48)
2) Apo-E binds remnant receptor on the liver and mediates endocytosis of the remnant
3)Once FC and CE in theliver, can package it into VLDL (has Apo-B100)
4)The VLDL has FFA, TG and CE in it. As it travels through the blood, it is acted on by lipases, releasing FFA=> lef with another remnant: LDL
5)LDL only has CE in it. LDL interacts with the LDL receptor of a cell, via Apo-B100
=>mediates endocytosis to release FC and CE inside the cell

Front 37

What happens when cells have too much cholesterol?

Back 37

-Cells downregulate LDL receptor
--If all cells downregulate the receptor, LDL just floating around in the body, becomes a target for oxidation
-LDL is targeted by macrophages, binds through the scavenger receptor (SR)=> eventually macrophages will die
-cholesterol that accumulates can casue a heart attack

Front 38

What is reverse cholesterol transport?

Back 38

-ApoA1 interacts with ABCA1 (transporter) on cells.
-ApoA1 will pick up cholesterol and phospholipids from the cell
-ApoA1 will then begin to make HDL cells, with the help of LCAT, which will make the LDL particles spherical and convert the cholesterol into CE
-HDL can transport cholesterol back into the liver

Front 39

What is Apo-A1?

Back 39

-Main ptn of HDL
-Interacts with ABCA1 transporter and activates LCAT (which converts FC to CE)

Front 40

What is Apo-B100?

Back 40

-Present on VLDL and LDL
-It contains the region that binds the LDL receptor

Front 41

What is Apo-B48?

Back 41

-Present on chylomicrons
-Does NOT contain the region that binds the LDL receptor

Front 42

What is Apo-E?

Back 42

-Mediates uptake of remnants to the liver by binding the chylomicron remnants

Front 43

What can the liver do with FC and CE?

Back 43

-Store it
-Allow it to be regulatory
-Transform it to VLDL

Front 44

Which apolipoptns are exchangeable and which are integral?

Back 44

Integral: Apob48 and ApoB100
Exchangeable: ApoA1 and ApoE

Front 45

What happens to the mb when LDL is taken up?

Back 45

When LDL is taken up, cholesterol is also taken up by the cell, gt inc of cholesterol in the ER mb
-SCAP binds cholesterol, won't release SREBP, .: no upregulation of LDLR and HMG-CoA reductase