Cholesterol 6 Flashcards
What cholesterol metabolism occurs in the liver?
0.5g of cholesterol/day is converted to bile acids
These can then be conjugated to glycine or taurine leading to the bile salts being able to be secreted into the gall bladder and then via the bile duct into the intestine
What are the functions of bile acids?
Can emulsify dietary lipids and fat soluble vitamins
Can act as a disposal system for cholesterol
What is the role of the intestinal enterocyte in cholesterol metabolism?
Has a bile acid transporter that retrieves most (95%) of the bile acids and returns them to the liver
Roughly 5% of bile acids are therefore secreted this is replaced by the liver which has a resynthesis rate of 0.5g/day
How can the liver directly excrete cholesterol into the bile?
Cholesterol is almost insoluble but very soluble in phosphatidyl choline
Both phospholipids and cholesterol are exported into the bile
Bile is an aqueaous fluid containing phospholipids and, cholesterol and bile acids
Alteration of biliary metabolism can be used to prevent heart attacks
How is Bile formed?
The liver hydroxylates cholesterol to form bile acids
ABCB11 pumps bile salts out of liver
ABCB4 Pumps phospholipids out of the liver
ABCG5/8 pumps cholesterol out of the liver leading to micelle formation
Bile is excreted into the intestines
In the intestine the IBAT transporter takes up bile acid with sodium using I-BABP as a protective binding protein, the bile acid is transported across the cell to a bile acid efflux pump returning the bile acid to the blood where it is taken up by the liver through NTCP
What are the transporters for cholesterol and bile salts in the liver?
ABCB4 which flips phosphatidylcholine to the outer leaflet of the hepatic apical membrane
ABCB11 which is a bile salt export pump
ABCG5/8 which exports sterols
NTCP which is Na-dependent bile acid transporter
What are the transporters for cholesterol and bile salts in the intestine?
IBAT- Na Dependent Intestinal Bile Acid Transporter
IBAP- Bile Acid Binding Protein
ABCG5/8 Exports sterols/bile salts to blood
What is the Liver X receptor?
Receptor which senses oxysterols which are present during high levels of cholesterol and stimulate CYP7A cholesterol-7-hydroxylase, as well as expression of the ABC transporters that export cholesterol into the bile or onto lipoproteins
This results in a promotion of lipoprotein production
What is FXR?
Receptor which binds bile acids found in both liver and intestinal epithelial cells
Represses synthesis of cholesterol 7 alpha hydroxylase (CYP7A gene)
Stimulates expression of IBABP binding protein and transporters which mediate cellular export of bile
Also represses NTCP so more cholesterol is not taken up by the cell
How is cholesterol regulated in the hepatocyte?
Cholesterol is taken up via LDL-R
LXR induces CYP7A1 and bile acids are secreted by ABCB11
Bile acids are then extracted from portal blood by basolateral NTCP these activate FXR which decreases NTCP and increases ABCB11 (reducing uptake and increasing secretion)
FXR increases SHP-1 which antagonizes LRH-1 effect on CYP7A1
How is cholesterol regulated in the intestinal epithelium?
Dietry cholesterol made soluble by bile salts enters the cell
Formation of oxy sterols activates LXR
Which promotes cholesterol efflux into the intestinal lumen
Bile acids enter through IBAT and activate FXR
FXR increases IBABP and bile acids export to the blood through ABCC3
What lessons have been learned about cholesterol regulation from gene knockouts?
LXR mice knockouts accumulate enormous amounts of cholesterol in the liver
FXR mice knockouts cannot repress CYP7A1 gene
CYP7A1 mice knockouts die in the first 3 weeks of life due to liver failure and deficiencies in fat-soluble vitamins
What are two treatments for atherosclerosis based of cellular cholesterol metabolism?
Statins which inhibit HMG-coA reductase to decrease cholesterol synthesis, insig1/SCAP interaction, plasma LDL cholesterol while increasing nuclear SREBP and LDLR
Bile Acid Binding resins which increase loss of bile acids through preventing absorption from the intestine this results in increased bile acid synthesis and LDL uptake by the liver to help clear cholesterol
