Liver Biochemistry Flashcards
What are xenobiotic reactions?
Compounds w/no nutritional benefit but also may be toxic
What is the major role of the liver?
Monitor, synthesize, recycle, distribute, modify metabolites
How many acetyl CoAs make an IPP?
How many carbons is an IPP?
3
5
How is acetyl CoA generated and where?
In mitochondria via
Oxidative de carboxylation of pyruvate
Beta oxidation of F.A.
Breakdown of a.a.
Biosynthesis occurs in the cytosol, how is acetyl CoA transported there?
Citrate shuttle
What makes up a sterane ring?
What is it the backbone of?
6 units of IPP forms 4-ring structure
Steroids (cholesterol, estradiol, cholic acid)
Where is the hydroxyl group located in cholesterol?
Double bond?
Where are the methyl groups located?
C3
Between C5-C6
C10 and C13
How many carbons does the sterane ring have?
Where is the hydrocarbon side chain attached and how many carbons?
17
17, 8
What is cholesterol a precursor to?
Bile acids and bile salts
Vitamin D
Steroid hormones (alcohols)
Describe phase 1 of cholesterol synthesis
Acetyl CoA -> Acetoacetyl CoA -> HMG CoA -> Mevalonate -> IPP
Describe the phase 2 intermediates
6 IPP -> Squalene -> Lanosterol -> Cholesterol
What is the RLS of cholesterol synthesis and what is the substrate and product?
HMG CoA -> Mevalonate
Enzyme is HMG CoA Reductase
What enzyme catalyzes Acetoacetyl CoA to HMG CoA?
HMG CoA synthase
What enzyme catalyzes the 1st step of cholesterol synthesis?
acetyl CoA - acetyltransferase
What stimulates the formation of Mevalonate?
Insulin
Thyroxine
What inhibits the formation of Mevalonate?
Vit E high AMP glucagon sterols and statins VAGSS
How is cholesterol packaged and where does it go?
Into VLDLs and released into circulation
How is cholesterol used in the liver?
Skin?
Adrenals, ovaries, testes?
Synthesize bile acids
Synthesize Vit D
Synthesize steroid hormones
Where is cholesterol located?
What kind of density?
Local centers for what?
Lipid rafts
Low buoyant density
Signal transduction processes
Where are the sites of ubiquination of HMG-CoA Reductase
Which side does the catalytic domain face?
Lys 89 and 248
cytosol
How is HMG CoA Reductase inhibited?
What is a competitive inhibitor of it?
Free F.A., bile acids, oxysterols
FBO
statins
When is HMG CoA Reductase active?
What factors favor activation?
-What enzyme does this activator work through?
Dephosphorylated
Insulin
HMGR phosphatase
What inactivates HMG CoA Reductase?
Low energy/high AMP
Glucagon (prevents dePO4)
Where is the SRE located?
Where does it bind?
Promoter
SREBP
What does the SREBP bind to?
In the presence of cholesterol what happens to this complex?
SCAP
Retained in ER due to binding to INSIG, SLOW transcription
How is HMG CoA Reductase translationally regulated?
Reduced by gamma-tocotrienol (Vit E) and oxylanosterols
In cases of high cholesterol what happens to the HMG CoA Reductase?
Interacts with INSIG –> polyubiquination –> removal from ER and degradation by 26S protea some
How is degradation of HMG enhanced?
Sterols, methylated sterols, oxysterols, to orients, Mevalonate derivatives, Biphosphate SR-12813
How are dietary cholesterols delivered to the liver?
Chylomicron remnants
What is the liver a major source of?
What does it synthesize?
Nascent HDLs
Bile acids, eliminates cholesterol into bile
What are the side effects of statins?
What is the Ki for statins?
Myotoxic - decreased formation of ubiquonone and prenylated proteins
5-45 nM
What else can CYPs do?
Detoxify xenobiotics and statins
What do agents that inhibit CYP cause?
Examples of CYP inhibitors?
INC in statin levels -> toxic side effects
Clarithromycin, itraconozole, cycolsporine
Citrus juice, grapefruit juice
What enzyme degrades sterane ring of cholesterol?
What is cholesterol converted to?
NONE
Bile acids
Where is bile made?
What is a precursor to bile acids and salts?
Hepatocytes
Hepatic cholesterol
Fx of bile?
Lipid emulsifier, aids in lipid digestion by forming micelles
Describe the synthesis of bile acids starting with cholesterol
Cholesterol -> 7alpha-hydroxycholesterol -> 3a,7a-Diol -> Chenocholic acid
3a,7a,12a-Triol -> cholic acid
Where are the OH groups located on Chenocholic acid?
C3 and 7
Cholic is conjugated to what?
What is added?
Final end products?
Cholyl CoA
Taurine and Glycine
Taurocholic acid and Glycocholic acid
Where are the OH groups located on cholic acid?
C3, 7, 12
What are gallstone crystals made of?
What is cholelithiasis?
Bile supersaturated with cholesterol
Insufficient secretion of bile salts or phospholipids OR excess cholesterol secretion
What is the Tx of gallstones?
Oral ursodeoxcholic acid (2ndary bile acid) reduces cholesterol secretion into bile
For small-medium sized stones
How does the liver get its blood?
75% portal V via enteric circulation
25% hepatic A via periphery
CYP enzymes are needed to convert what into what?
Linear isoprenoid Squalene into cholesterol
