Synthesis and Transport of Cholesterol. Synthesis is Bile Acids, Bile Salts and Flashcards

Terms Definitions
What is the precursor for ketone bodies?
acetyl CoA, when in the mitochondria
What is acetyl CoA in the cytosol a precursor for?
FFA that are fated for TAGs
What is the precursor for cholesterol?
acetyl CoA
Where is cholesterol made? How is it delivered? Is it a fuel in humans? Why or why not?
a) liver… b) lipoproteins… c) No, we lack the enzymes to harvet the energy
In what state is cholesterol made?
Where does the acetyl CoA come from that is fated for cholesterol?
Citrate that gets into the cytosol
What are bile salts made from?
cholesterol byproducts
What organs makes cholesterol?
liver, adrenal cortex (cortisol) and gonads (for steroids)
What reducing agent is used in cholesterol synthesis?
Where ever you see NADPH, what pathway is also present?
Pentose pathway
What drives the rxns in cholesterol synthesis and thus what regulates cholesterol synthesis?
What is the first commited intermediate in cholesterol synthesis?
Where do statins work in the reduction of cholesterol?
Where is cholesterol synthesized?
liver/ cytoplasm
Describe the cholesterol synthesis pathway
a) Acetyl CoA --> acetoacetyl CoA… acectoacetyl CoA --> HMG-CoA (HMG CoA synthase)… b) HMG CoA --> Mevalonate (2 NADPH + HMG CoA reductase)… c) Mevalonate --> isopentenyl pyrophosphate (3 ATP)… IPP >> geranyl PP >> farnesyl PP >> Squalene >> lanosterol >> cholesterol
Which HMG CoA, cytosol or Mitochondrial is involved in cholesterol synthesis?
Where is HMG CoA acted upon by HMG CoA lyase?
in ketone synthesis
In cholesterol synthesis, what is acting on HMG CoA?
HMG CoA reductase
What is the first compound commited to cholesterol synthesis?
What regulates cholesterol synthesis?
Where do statin control cholesterol?
What effect does a high insulin:glucagon ratio have on HMG CoA reductase?
phosphatase will remove phosphate and make it more active
How is cholesterol feedback inhibited?
by sterols, which activate protein kinase, which phosphorylates HMG CoA reductase and deactivates it.
What is the mechanism by which a low ATP:AMP ratio will result in HMG CoA reductase inhibition?
Protein Kinase kinase (PKK) is activated by AMP, which will lead to the the phosphorylation HMG CoA
What is the key player in transcriptional control of HMG CoA reductase?
Steroid responsive element (SREBP), which binds or doesn't bind to DNA
Which part of the SREBP is active in migrating to the DNA?
the Amino terminal, which are cut off by proteolytic enzymes.
What are the 2 ways the amino terminal of the HMG CoA reductase domain controlled?
1) rapid degradation… 2) proteolytic enzyme SCAP and S2P (which are positively regulated by sterols)
What are some other positive benefits of statins?
a) in alzheimer's, it reduces Cholesterol depostion in vasculature and decreases risk for stroke… b) in osteoporosis, it is suspected that the rxn in the pathway reduce bone loss through a complex elimination of downstream intermediates (similar to bisphosphonates which are taken by people to reduce osteoporosis.)
What negative aspects are there in statin use?
muscle weakness
What other products are made that arise from mevalonate that may have a unfavorable side effect?
coenzyme Q, dolichol and vitamin D
What transports cholesterol synthesized in the liver?
What fate of VLDL can be detrimental?
conversion to LDLs which hang around long enough in circulation to oxidized and be taken up by foam cells --> atherosclerosis
Why is it that chylomicrons are not a problem with respect atheroslerosis?
They don't hang around, they go to the liver and are recycled.
What are two positive aspects of HDLs?
1) they can swap Apos… 2) they deliver cholesterol in plasma membranes back to the liver… thus reducing periheral cholesterol
Why are Apoproteins important?
they dictate where lipoproteins dock and what they do in the plasma
What is the relationship betweeen the % of apoproteins and the % of TAGs in lipoproteins?
it is inversely proportionate
Place the lipoproteins in order from greatest % of apoproteins to least.
What is involved in the hydroxylation cholesterol, part-one of making bile salts?
1) add hydroxyl using 7-∂-hydroxylase (multiple additions) and requires the oxidation of NADPH.. 2) oxidize the side chain giving it a negative charge (carboxyl group)
What inhibits 7-∂-hydroxyase?
bile salts and acid… feedback inhibitioin
What is the net effect of adding hydroxyl groups to cholesterol in bile synthesis?
it makes cholesterol less fatty
What is the second part of making bile salts?
Conjugating or coupling compounds to the carboxyl group.
What is the process of conjugating cholesterol in bile synthesis?
1) activate the carboxy group in the form of a CoA derivative… 2) add taurine or glyciine (increase the fraction of the compound that is negatively charged)
What is the charge on the polar part of the bile salt?
Where is the non-polar of the bile salt?
rings of the steroid nucleus
What is the significance of the low pKa for the conjugated bile salts?
it is ionized more at the gut pH ~6
What effect does intestiinal flora (bacteria) have on bile salts?
a) they deconjugate the bile salt (remove the taurine or glycine) and… b) remove the 7-∂-hydroxyl group.
Does this effect the bodies ability to use the bile salt?
What percentage of bile salts are lost each day?
Besides statins, what is a method of reducing the amount of cholesterol in the body?
since most cholesterol in bile salts is recycle, increasing the amount secreted would lower the total cholesterol
Where does much of the cholesterol used in steroid hormones (cortisol) come from?
the liver
Why, in the transport of cholesterol, are they packaged as cholesterol esters?
they are more hydrophobic and thus package better in to lipoproteins
Which enzyme removes the ester from the cholesterol?
What is the overall pathway in vitamine D synthesis?
1) 7-dehydrocholesterol --> UV light on skin --> goes to liver --> converted to 25-hydroxycholecalciferol --> goes to kidney --> converted to 1,25-dihydroxycholecalciferol by 1-∂-hydroxylase.
What positively regulates 1-∂-hydroxylase in vitamin D synthesis in the kidneys?
What would a person who is malnurished, has reduced sunlight and renal failure have? What else would cause this?
a) vitamin D deficiency… b) malobsorption of fat (vitamin D is fat soluble, thus a bile salt synthesis can cause a vitamin D deficiency)
A person with statorrhea "floaties" may also have what deficiency? Why?
a)Vitamin D… b) fat malabsorption due to bile synthesis or secretion
Done... exit this set of flash cards... the rest are repeats
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