Cholesterol and Bile Acid Metabolsim

Question 0

Layers of a healthy artery

Answer 0

Endothelial cells: form the lumen where blood flows thru
Intima: consistent of structural proteins and molecules like collagen and proteoglycans, give the 3D form
Media: smooth muscle cells, contraction of arteries
Adventitia: outermost connective tissue

Question 1

Heart attack

Answer 1

Coronary arteries are occluded by plaque in blood clots
Plaque builds up over the years and if there is a rupture there will be blood clots that occlude the arteries
If heart does not eat any more blood in a certain part, that part will die

Question 2

Cholesterol enters a cell

Answer 2

LDL enters the arterial intima through the endothelial lining
ROS are generated by macrophages, smooth muscle cells and endothelial cells oxidizes LDL
Oxidized LDL damages endothelial cells and causes them to release chemotactic factors
MCP-1: attracts circulating monocytes which clean up bacteria invaders or debris
M-CSF: converted monocytes to macrophages, generate even more ROS

Question 3

Fate of OxLDL

Answer 3

OxLDL is taken p by scavenger receptor, cholesterol is now in a macrophage
Scavenger receptor is not regulated—cholesterol uptake is not limited and the macrophage becomes bigger and bigger
As cholesterol and TG accumulate, macrophage is converted to a lipid-laden foam cell
When foam cell dies, it leads behind a fatty streak. If this ruptures it will form a clot and there is no flow, can lead to a heart attack

Question 4

ABC1

Answer 4

ABC1 mediates efflux of cholesterol from macrophage to HDL particles, balance
OxLDL accumulates when high levels of LDL remain in circulation for a long time
Vitamin e supplementation necessary to reduce ROS toxicity
NOT effective in reducing risk of a heart attack

Question 5

Drugs to treat heart disease

Answer 5

Lipitor and plavix
2 best selling drugs in the world
Death due to heart disease has increased a lot since the 1900s, people living long and eating differently
75% of deaths from cv disease due to atherosclerosis and subsequent complications

Question 6

Cholesterol

Answer 6

27 carbons long, 4 fused hydrocarbon rings
Precursor to steroid
OH group on C3 of A group
Steroid alcohol is more polar and more soluble
Very hydrophobic due to hydrocarbon tail, live in vicinity of lipids not aqueous solution
If removed the OH group and add a long chain fatty acid—cholesterol ester which is the transport version

Question 7

Cholesterol properties

Answer 7

Low solubility in water
Present in plasma bound to lipoproteins
30% of cholesterol is unesterified, 70% is esterified
Cholesterol esters are even less water soluble
Cholesterol esters are interiors of lipoproteins, free cholesterol on surface

Question 8

Cholesterol roles

Answer 8

Component of all membranes especially myelin
Important for signal transduction in cells
Precursors for bile acids, steroid hormones and vitamin D
essential for embryo formation
Defects in synthesis are lethal in mic

Question 9

Cholesterol biosynthesis

Answer 9

Synthesized by all cells in the body, greatest in intestine. Liver and cells that produce steroid hormones
80% of cholesterol synthesis occurs in the liver
Synthesized from HMG CoA reductase in the cytosol
Unique rate limiting step = HMG CoA reductase
Fed state: make acetyl-CoA into cholesterol
Fasting state: turned into ketone bodies
Statin drugs are analogs of HMG CoA, blocks synthesis of cholesterol

Question 10

Intermediates in cholesterol synthesis

Answer 10

From a six C mevalonate to a 27 C cholesterol

See slides

Question 11

HMG CoA reductase regulation

Answer 11

Rate limiting step
SREBP-2 is important to upregulate the amount of HMG CoA reductase and modifies HMG CoA synthase
Has to move SREBP-2 from the ER to the Golgi, then to the nucleus which induces transcription
SCAP protein s essential in this transport from the ER to the Golgi. If the is a lot of cholesterol, will trap SCAP in the ER then cannot move SREBP-2 to the Golgi, down regulate the amount of cholesterol produced
Negative feedback loop

Question 12

Cholesterol biosynthesis regulation summary

Answer 12

HMG CoA reductase — rate limiting step
HMG CoA reductase — inhibited by free Cholestid
HMG CoA reductase — activated by insulin (fat and cholesterol both made in the fed state and incorporated into lipoprotein VLDL particles)
LDL receptors are down regulated by free cholestero

Question 13

Cholesterol catabolism and excretion

Answer 13

Bile acids = bile salts = end product of cholesterol catabolism in the liver
1/2 cholesterol excreted as bile acids, 1/2 excreted as cholesterol
Bile acids needed to solubize cholesterol
Excess cholesterol causes gallstones
Intracellular cholesterol in liver stimulates formation of bile acids
Bile acids inhibit formation of bile acids

Question 14

Bile acids

Answer 14

Looks similar to cholesterol
4 carbon ring and shortened hydrocarbon gal
Adding more OH groups to add charge and make more water soluble
7alpha-hydroxylase is the rate limiting step
Primary bile acids: cholic and chenodeoxycholic acids

Question 15

Functions of bile acid

Answer 15

Emulsify the dietary fats so they can be absorbed and digested, essential for fat digestion
Facilitate the absorption of fat soluble vitamins
Eliminate cholesterol
Prevent precipitation of free cholesterol out of solution in the gall bladder

Question 16

Regulation of bile acid metabolism

Answer 16

7alpha-hydroxyalase is the rate limiting step
Activated by cholesterols
Inhibited by bile acids

Question 17

Enterohepatic circulation of bile acids

Answer 17

The livers ability to produce bile acids is limited, but they are essential for digestion of fats
Thus, 99% of bile acids are reabsorbed, enter the portal circulation and are returned to the liver: enterohepatic circulation
Also true for cholesterol
Small % of bile salts that are not reabsorbed represent the only mechanism for elimination from the body. Regulation of bile acid synthesis and reabsorption is very important

Question 18

Uptake and cellular fate of LDL

Answer 18

Bad cholesterol
Can store cholesterol using ACAT (acetyl-CoA acetyltransferase)
Can make cholesterol ester, very hydrophobic,lipid core around them and not accessible. Does not affect cell

Question 19

ACAT

Answer 19

Storage of cholesterol

Question 20

Cholesterol uptake

Answer 20

Passive diffusion
Receptor independent, non-saturable, unregulated
Most cholesterol in liver = receptor dependent
Most cholesterol in other tissues = receptor independent
90% receptor mediated LDL uptake occurs in the liver
Liver is the MAJOR site for regulating ldl levels
Regulation is designed to normalize cholesterol levels in the cell, not the blood

Question 21

LDL delivery into cell

Answer 21

LDL binds to LDL receptor
Clusters in Clathrin coated pits
Endocytosed and delivered to lysosomes
Free cholesterol released into cytosol
Receptors recycled to membrane

Question 22

Cholesterol effect positive and negative

Answer 22

Engine effect on uptake and production of LDL

Positive effect on 7alpha-hydroxylase (bile acids) and ACAT cholesterol esters (storage)

Question 23

High Cholesterol diet

Answer 23

Lots of LDL coming to the liver and netting the cell, cell cholesterol levels go up
LDL receptors will go down
Bad cholesterol floating around for a longer time in the blood as plasma ladled
Can cause heart attacks

Question 24

High saturated fat diet

Answer 24

Screw up cholesterol storage, ACAT
ACAT needs unsaturated FA to store cholesterol
Cholesterol in the cell goes up, LDL receptors down and more plasma ldl
Saturated fats reduce membrane fluidity

Question 25

Low fiber diet

Answer 25

Most bile acids and salts will be recirculated into the liver
Not getting rid of cholesterol, increasing cholesterol uptake into the cell and LDL receptors down
Plasma ldl up

Question 26

American diet

Answer 26

3 of 4 pathways that lower plasma LDL cholesterol are compromised
Cannot store, get rid of or take up
Plasma ldl through the roof–>atherosclerosis
Low fiber. High saturated fats. High cholesterol

Question 27

Myth of low fat diet

Answer 27

Fat known as bad so reduced both the good and bad
Replaced with fag carbs which increase blood glucose and insulin which increased TG/cholesterol production and higher LDL blood levels

Question 28

Drug treatment for high cholesterol

Answer 28

Statins: controls cholesterol biosynthesis, inhibits HMG CoA reductase

Eztetimibe: inhibits cholesterol absorption in small intestine, affects uptake

Cholestryamin: binds bile in the intestine and controls excretion