Flashcards in Cholesterol and Steroid Metabolism Deck (72):
What are the important functions of cholesterol?
1)Component of all cell membranes
2)Precursor of Bile Acids
3)Precursor of steroid hormones and Vitamin D
Describe the structure of cholesterol.
4 carbon ring with a hydrocarbon tail and and OH group at other end.
Where is the site of attachment of fatty acids in cholesterol ester?
OH group on A chain on cholesterol.
What is a cholesterol ester?
Cholesterol molecule with fatty acid attached to OH group end.
What is the main organ cholesterol metabolism takes place?
If cholesterol is completely cut out of the diet, why can high cholesterol levels persist? (in theory)
De Novo Synthesis in liver
What is required for cholesterol synthesis?
What is the rate limiting enzyme in cholesterol synthesis?
HMG CoA reductase
Where is the cell does cholesterol synthesis occur?
Occurs in the cytoplasm with enzymes in cytosol and ER
Too much plasma cholesterol can lead to what?
Too much cholesterol secretion causes formation of what?
What are the two phases of cholesterol synthesis?
1) synthesis of mevalonic acid (mevalonate)
2) synthesis of cholesterol from mevalonate
How did the Acetyl CoA used in cholesterol synthesis get there?
From citrate, broken down by ATP-citrate lyase.
In the first step of cholesterol synthesis, 2 Acetyl CoA are converted to what? By what enzyme?
During the second step of cholesterol synthesis, Acetoacetyl CoA is converted to what? By what enzyme?
HMG CoA is also known as what?
HMG CoA gets converted to what? By what enzyme?
HMG CoA Reductase
HMG CoA reductase requires what reducing equivalents?
2 molecules of NADPH
In stage 2 of cholesterol synthesis, Once mevalonate is made, what is formed next?
During stage 2 of cholesterol synthesis, what is 5-pyrophosphomevalonate converted into in the 2nd step?
Isopentenyl pyrophosphate (IPP)
Isopentenyl pyrophosphate (IPP), besides beings converted into 3,3-dimethylallyl pyrophosphate (DPP), can also alternately be transformed into what?
Dolichol or ubiquinone
IPP plus DPP undergo condensation to form what?
Geranyl Pyrophosphate (GPP) -10 C
What gets added to Geranyl Pyrophosphate (GPP) to form Farnesyl Pyrophosphate (FPP -15 c)
2 Farnesyl Pyrophosphate (FPP) molecules are joined to form what?
Farnesyl Pyrophosphate (FPP) (15C) an important intermediate in cholesterol synthesis, can also be a precursor for what?
Which two intermediates in cholesterol synthesis can be considered precursors for Dolichol or ubiquinone?
Farnesyl Pyrophosphate (FPP)
Isopentenyl Pyrophosphate (IPP)
Is Squalene cyclic or non cyclic?
Squalene undergoes cyclization to form what?
HMG CoA reductase is located where??
ER - cytosolic side
AMP kinase ________ and therefore ______ HMG CoA reductase
How does cholesterol inhibit HMG CoA reductase?
-regulating gene expression of enzyme
-promoting degradation of enzyme
AMP Kinase can be stimulated by what?
Glucagon or Epinephrine
Glucagon __________ and therefore ________ HMG CoA reductase, decreasing cholesterol synthesis.
Phosphorylates (PKA Dependent);
What are statins?
-A class of drugs that cause enzyme upregulation (reversible inhibitors of HMG CoA reductase
-long term regulation
Which drugs (specifically) are statins?
- Simvastatin (Zocov)
- Pravastatin (Pravacol)
- Lovastatin (Mevacor)
- all are structural analogs of Mevalonate.
Low concentrations of intracellular cholesterol stimulates what?
SREBP = sterol regulatory element binding protein
- released from ER
What is the function of SREBP?
Moves to a specific enhancer region (SRE= sterol responsive element) in the gene for HMG CoA reductase upregulation.
Why does blocking HMG CoA reductase with statins cause an upregulation of the gene?
Cholesterol usually inhibits SCAP-SREBP (SREBP cleavage activating protein). Therefore, low levels of cholesterol cause SREBP cleavage (activation) leading to upregulation of HMG CoA gene.
Usually, giving a patient a large dose of statins accounts for any new HMG CoA synthesized
________ concentrations of cholesterol and/or mevalonate leads to _____________ of the HMG CoA reductase enzyme.
Rapid degradation (proteolysis)
When there is high levels of intracellular cholesterol, the ________ system in proteosomes leads to the degradation of ________
HMG CoA Reductase
What are the effects of low intracellular cholesterol on HMG-CoA reductase, LDL receptors, and serum cholesterol?
- HMG CoA: upregulation
- LDL receptor: upregulation
- Increased uptake of LDL from serum
- reduction in serum cholesterol
Besides HMG CoA Reductase, intracellular cholesterol is a key regulator of?
- LDL receptor endocytosis
SLOS (Smith-Lemli-Optiz Syndrome) is a _________ defect of _________.
SLOS is relatively common and leads to what?
- other embryonic malformations
What enzyme is partially deficient in SLOS? What is this enzyme needed for?
- 7-Dehydrocholesterol reductase
- needed for correct double bond formation in ring B
What is major mechanism of elimination of cholesterol?
Cholesterol into bile acids --> excreted in feces
Some cholesterol is modified by bacteria in the intestines to form what?
What forms the bulk of fecal sterols?
How do Coprostanol and Cholestanol differ?
Coprostanol: Hydrogen in B- orientation
Cholestanol: hydrogen in a-orientation
What are the most abundant organic components of bile?
Phosphatidylcholine (lecithin) and bile salts
What is another name for phosphatidylcholine?
Bile enters the _____ through the _______ or is stored in the gall bladder.
- common bile duct
What are the primary bile acids?
What is the rate limiting enzyme in the synthesis of bile acids?
What is the reaction 7-alpha-Hydroxylase catalyzes?
Catalyzes the addition of an OH group to carbon 7 on cholesterol. (making it into Cholic acid)
How is 7-alpha-Hydroxylase regulated?
Inhibited by: Cholic acid
Stimulated by: cholesterol
Bile acids that are conjugated with glycine form which bile salts before leaving the liver??
- Glycochenodeoxycholic acid
Bile acids that are conjugated with taurine form which bile salts before leaving the liver??
- Taurocholic acid
- Taurochenodeoxycholic acid
What is more effective at solubilizing lipids than bile acids?
Bile salts like:
Other intestinal bacteria convert primary bile salts into ________ by removing ___________.
Secondary bile salts;
Cholic acid, under the action of intestinal flora, becomes...
Lithocholic acid, under the action of intestinal flora, becomes...
What is cholelithiasis?
Bile salt deficiency
What are potential causes of Cholelithiasis?
-Malabsorption of bile acids from intestine
-Obstruction of the biliary tract
-Interruption of the enterohepatic circulation
- Decreased bile production (hepatic dysfunction)
- Accelerated rate of bile recycling (excessive suppression of bile synthesis)
What is Chenodeoxycholic acid used for?
Treatment of Cholelithiasis
What is another name for chenodeoxycholic acid?
One of the four physiologically significant functions of bile acids/salts is that they facilitate ________ of dietary TAGS by acting as __________ that render fats accessible to __________.
One of the four physiologically significant functions of bile acids/salts is that they facilitate the intestinal absorption of_________
What is the significance of bile acids and phospholipids solubilizing cholesterol in the bile?
It prevents the precipitation of cholesterol in the gallbladder.
Migrating gallstones that obstruct the ampulla of Vater can cause what?
Why is Pyrophosphate incorporated into cholesterol?
Without Pyrophosphate, compounds such as Squalene, Lanosterol all the downstream intermediates all the way up to cholesterol would be so hydrophobic, they would need carrier proteins to keep then soluble.