Cholesterol and bile acid Metabolism & Function Flashcards
What is the structure/characteristic of cholesterol
- fused rings
- very non-polar
- even more non-polar when esterified to fatty acid
- extremely water insoluble
- stabilizing component of cell membranes
What is cholesterol synthesized out of?
acyl-CoA
What are the major sites of cholesterol synthesis?
Liver
Intestine epithelial
What is cholesterol a precursor of?
Bile salts (liver) steroid hormones (endocrine glands)
Can cholesterol be degraded?
No.
There are no enzymes that degrade cholesterol
Why sis cholesterol associated with vascular disease?
- Can’t be degraded
- High non-polarity
is cholesterol synthesized in plants?
no
how is cholesterol transported?
In the blood in lipoproteins
How is cholesterol excreted from the body?
by converting it to bile salts
this is why it is essential to transport cholesterol from peripheral tissues to the liver
What are the 4 phases in the pathway of cholesterol synthesis?
- Acetyl-CoA units condense to form mevalonate
- Mevalonate is converted to 5C isoprene units
- Six C5 isoprene units condense to form the C30 squalene
- Squalene cyclizes to form the 4 ring lanosterol. Carbons are released to convert lanosterol to 27C cholesterol
What are the 3 ways HMG-CoA reductase is regulated?
- Transcription control
- Regulation by proteolysis
- Regulation by phosphorylation
How is HMG-CoA reductase regulated by transcription control?
High levels of cholesterol negatively regulate the rate of synthesis of HMG-CoA mRNA via repression of transcription of HMG-CoA gene
How is HMG-CoA reductase regulated by proteolysis?
Rising level of cholesterol and bile salts (in the liver) makes enzyme more susceptible to proteolysis
How is HMG-CoA reductase regulated by phosphorylation?
Phosphorylated HMG-CoA reductase is inactive
Dephosphorylated HMG-CoA reductase is active
How is cholesterol esterified?
Cholesterol OH at position 3 is esterified to form cholesterol ester (CE)
Where does the enzyme LCAT esterifies cholesterol?
in HDL particles
LCAT is located in the blood
Where does the enzyme ACAT esterifies cholesterol?
In cells
Which enzyme hydrolyzes CE?
CEH - cholesterol ester hydrolase
What is the purpose of esterification?
- Causes cholesterol to become more hydrophobic to facilitate incorporation into lipoproteins
- Contributes to govern free cholesterol levels in blood and cells
What is the fate of chylomicron cholesterol from the diet to the liver?
- Dietary cholesterol is absorbed from bile salts micelles into intestinal epithelial cells
- It is packaged into nascent chylomicrons
- Nascent chylomicrons enter the blood via the lymph system and are converted into chylomicrons by obtaining apoCII & apoE from HDL
- In the blood, chylomicrons TGs are digested by LPL
- Chylomicrons remnants bind to liver receptors and are internalized by endocytosis
- In the liver cells, chylomicrons remnants are digested in lysosomes where proteins are degraded, FA cleaved from CE and free cholesterol enters the cholesterol pools in liver cells
What is the fate of VLDL cholesterol?
- Liver cholesterol, TG, phospholipids and apoB-100 are packaged to VLDL and secreted to blood
- In the blood, HDL transfers CE, apoCII and apoE to VLDL
- TG carried in VLDL are metabolized by LPL and converted to IDL
Fate of VLDL:
- IDL either endocytosed into liver cells thus returning VLDL cholesterol back tot the liver
- IDL TG degraded to produce LDL which delivers VLDL cholesterol to peripheral cells or liver
What is the fate of LDL (bad) cholesterol?
- LDL produced in blood from IDL
- Major role of transporting cholesterol to several tissues including liver, peripheral tissues
- Uptake of oxidized LDL into macrophages plays a major role in atherosclerosis - thus “bad” cholesterol
Describe the uptake of LDL by the LDL receptor?
- LDL receptors synthesized in the ER and golgi travel to the cell surface
- Membrane LDL receptor brings LDL into cell by endocytosis. Receptors recycled to the surface
- In the endosome, decreased pH, LDL dissociate from receptor
- Endosomes fuse to lysosomes containing hydrolytic enzymes that digest lipoproteins releasing AA, FA, CE
- CE further hydrolyzed to cholesterol, joining intracellular pool
What is the effect of cholesterol on HMG-Co reductase?
elevated cholesterol reduces synthesis of HMG-Co reductase
What is the effect of cholesterol on ACAT?
elevated cholesterol stimulates the activity of ACAT converting C to CE
What is the effect of cholesterol on HLDL receptors?
elevated cholesterol reduces synthesis of LDL receptors
Where is HDL synthesized?
liver and intestinal cells
How does HDL transport cholesterol? “Reverse C transport
- HDL picks up cholesterol from cell membranes,
- Cholesterol is converted to CE by LCAT
- HDL transfers apoCII/apoE to chylomicrons & VLDL
- HDL transfers CE to VLDL in exchange for TG, mediated by CETP
- Hepatic lipase hydrolyzes HDL, allowing release of CE to liver
- VLDL degraded by LPL are converted to IDL/LDL endocytosed by liver
Why is HDL-C good cholesterol?
Because HDL-C from peripheral cells is returned to the liver by “reverse C transport”. It’s then converted to bile salts and eliminated from the body as feces
How does the body get rid of cholesterol
converting it to bile salts
Where does the conversion of cholesterol to bile salts occur (synthesis of bile salts from cholesterol)
In the liver
How is cholesterol transferred from peripheral tissue to the liver?
HDL
How is bile salts synthesized?
- An a-hydroxyl group is added to C7.
- Double bond is reduced
- Hydroxylation of 2 sets of compounds
- # C removed by oxidation - remaining 5C is attached to ring structure and carboxyl
What rate limiting step of bile salt synthesis?
a-hydroxyl group is added to C7 catalyzed by 7a-hydroxylase
How is the rate limiting step of bile salt synthesis regulated (7a-hydroxylase)
activity of the enzyme is decreased by bile salts
ie bile salts negatively regulate biosynthesis
What are bile salts conjugated to?
glycine or taurine (derived from cysteine)
What is the role of conjugation of bile salts?
Conjugation lowers the pH of bile salts so that a greater percentage of the molecules are ionized in the lumen of the gut, making them better detergents for lipid digestion
What is the importance of ionized bile salts?
Only ionized bile salts have sufficient polarity to function as a natural detergent that emulsifies (as micelles) dietary fat so that it can be digested by pancreatic enzymes
How are bile salts conjugated?
- The carboxyl at the end of the side chain reacts with CoA- reaction requires ATP
- The acetyl CoA derivatives react with either glycine or taurine forming amides
What is the enterohepatic system?
Bile salts circulate from the liver to the intestine and back with 95% efficiency
After secretion into the intestine, what happens to primary bile salts?
they are deconjugated and dehydroxylated forming secondary bile salts
How does bile salt deficiency occur?
prolonged obstruction of common duct that carries secretions from the gallbladder into the intestine
What are some consequences of bile salt deficiency?
- Decreased fat soluble vitamin (A,D,E,K) uptake –> vitamin deficiency
- Decreased fatty acid uptake –> calorie uptake
- increased passage of FA into colon (steatorrhea ie fatty stools)
- induced water secretion
- diarrhea
How do statins lower cholesterol & TG levels?
eg Lipitor
HMG-CoA reductase inhibitors that inhibit cholesterol biosynthesis
How do bile acid resins lower cholesterol & TG levels?
eg cholestyramine
bind bile acid in the intestine causing increased excretion of bile salts in feces and consequently increase in cholesterol elimination
How do ezetimibe lower cholesterol & TG levels?
by inhibiting intestinal cholesterol absorption
How do niacin lower cholesterol & TG levels?
activates LPL;
reduces hepatic production of VLDL;
reduces catabolism of HLDL;
suppresses mobilization of FA from adipose tissue
How do fibrates lower cholesterol & TG levels?
Increase LPL activity thereby increasing VLDL turnover
Inhibit VLDL secretion from the liver
