Biochemistry-Cholesterol Flashcards
What cellular membrane has the smallest amount of cholesterol?
ER. This is the site of cholesterol synthesis control (SREBP)
Structure of cholesterol
4 fused rings form the rigid backbone, large hydrophobic carbon chain, OH polar face…makes it amphipathic.
What is cholesterol’s role in the membrane?
It interferes with lipid packing and keeps the membrane fluid.
What determines the solubility of cholesterol in the bile?
Phosphatidylcholine and bile acids solubilize cholesterol in the bile.
What are many cholesterol synthesis intermediates used for?
Tethering proteins to membranes. For example prenyl groups stick G proteins on the membranes.
What intermediates are the building blocks of cholesterol synthesis? What else are they used for?
Isopentenes. These are also used for synthesis of Vitamin A, CoQ, Dolichol and Heme A.
What contributes to a healthy serum cholesterol?
*
Where does cholesterol synthesis first begin?
Cholesterol, phosphatidylcholine and bile salts are synthesized in the liver and stored in the gallbladder.
What is the role of cholesterol in helping digest a meal you just ate?
Neurohormonal signaling causes bile secretion into the duodenum, which contains cholesterol and cholesterol esters. These help to emulsify fat so pancreatic enzymes can digest the fat. Cholesteryl esterase is also release by the pancreas.
What does the intestine do with the cholesterol secreted in the bile?
ABC pumps bring it back into the enterocyte, they also secrete a small amount into the feces. In the enterocyte, the cholesterol either remains in its free form, or is esterified by ACAT. It is then packaged with ApoB-48 in the enterocyte and secreted as a chylomicron headed back to the liver.
How can you treat high cholesterol by decreasing reabsorption?
Inhibition of the ATP binding site on the Niemann-Pick C1-like-1 protein (Ezetimibe)
Deficiency in what enterocyte cholesterol pump can result in sitosterolemia and coronary heart disease?
ABC-G5 and G8 proteins, these are responsible for secretion of cholesterol and plant sterols
Where does cholesterol synthesis take place and where do the carbons come from?
Takes place in the cytosol near the RER. All carbons come from acetyl CoA.
What drives the reactions in cholesterol synthesis?
ATP and Acetyl CoA hydrolysis
Where do the reducing agents used in cholesterol synthesis come from?
Oxidative decarboxylation of Gluc-6-P
What is the committed rate limiting step in cholesterol synthesis?
HMG-CoA -> Mavalonate by HMG-CoA reductase + NADPH.
1st step in cholesterol synthesis
3 Acetyl CoA molecules combine to form HMG-CoA. 1) Thiolase adds 2 Acetyl CoAs together to form acetoacetyl CoA. 2) HMG-CoA synthase + another acetyl CoA form HMG CoA
2nd step in cholesterol synthesis
HMG-CoA is reduced to Mevalonate by HMG-CoA reductase + 2 NADPH
What enzyme is targeted by statins?
Their beta-hydroxy acid competitively binds HMG-CoA reductase and prevents HMG-CoA binding to the enzyme. Note that these drugs can be overcome by higher concentrations of HMG-CoA. Ultimately this results in a decrease in cholesterol synthesis, which causes increased expression of LDLR, which takes more cholesterol out of the blood.
3rd step in cholesterol synthesis
3 phosphates are added to 6 carbon mevalonate by mevalonate kinase, it is then decarboxylated to form a 5 carbon isoprene
4th step in cholesterol synthesis
3 five-carbon isoprenes combine to form 15 carbon farnesyl pyrophosphate. Those then combine to form 30 carbon units.
5th step in cholesterol synthesis
30 carbon unit loses 3 carbons.
How is HMG-CoA reductase regulated at the level of transcription?
SREBP is released from ER membrane by its chaperone SCAP -> delivered to golgi -> SREBP’s DNA-binding domain is proteolytically cleaved and released to nucleus -> DNA binding domain activates SRE gene in nucleus -> Increased synthesis of HMG-CoA reductase and increased expression of LDLR -> Cholesterol levels increase -> Negative feedback by sterols inhibits SREBP release by SCAP
How is HMG-CoA reductase regulated allosterically?
HMG CoA reductase is associated with the ER membrane. High levels of sterols promote proteolytic degradation of HMG-CoA reductase.
How is HMG-CoA reductase regulated by phosphorylation?
When it is not phosphorylated it is active. When its serine is phosphorylated it is inactive. Insulin works to activate phosphatases and turn on cholesterol synthesis. Glucagon works to activate AMP-activated protein kinases that phosphorylate HMG-CoA reductase and shut off cholesterol synthesis.
Enterohepatic circulation
Bile salts produced in liver -> Stored in gallbladder -> Released after a meal to emulsify fats via ABC -> 95% of salts are reabsorbed in the terminal ileum -> Other 5% allows for excretion of cholesterol
How are bile acids formed?
In the liver, cholesterol -> 7alpha-hydroxycholesterol (RDS) -> Cleaved -> Bile acid thioesterified w/CoA -> Thioester conjugated w/taurine or glycine -> Bile salts
What are the negative feedback functions in bile acid synthesis?
Chenocholic acid and cholic acid feedback to inhibit 7a-hydroxylase
How does our normal flora help keep our cholesterol levels in check?
There are normal flora that deconjugate and dehydroxylate bile salts to secondary bile salts. By doing this, bile salts are less soluble and do not return to the liver. This is why we excrete 5% of our bile salts.
