Liver Biochemistry-1/21/16 Flashcards
List the functions of the liver
Primary receiving, distribution, and recycling center Lipid biosynthesis and management Protein biosynthesis (albumin, IgG) Nitrogen metabolism (Urea cycle) Waste management (xenobiotic rxns) Bilirubin metabolism Fuel management
___ acetyl coa are used to generate IPP
___ serves as the building block for the synthesis of all isoprenoids, including steroids and lipid-soluble vitamins
3
Isopentenyl pyrophosphate (IPP)
Acetyl CoA is generated in the mitochondria from these various pathways:
How is acetyl coa transported into the cytoplasm?
Oxidative decarboxylation of pyruvate; B-oxidation of FA’s; Breakdown of AA’s
Via citrate shuttle
The ___ is the backbone of most steroids
Sterane ring
The hydroxyl group on cholesterol is located at ___
The sterane ring has ___ carbons
The double bond in cholesterol is located between ___
Where is the 8-member hydrocarbon chain attached on the cholesterol molecule?
C3
17
C5 and C6
C17
Cholesterol is the precursor of these biologically active compounds:
Bile acids and bile salts
Vitamin D
Steroid hormones
What is the reaction to generate Cholesterol?
18 ACoA + 18 ATP + 16 NADPH + 16 H+ + 4O2 —–>
1 Cholesterol + 16 NADP+ + 18 ADP + 18 Pi
Acetyl CoA ——> Acetoacetyl CoA
acetyl co-a acetyltransferase
Acetoacetyl Coa ———-> HMG CoA
(Name this enzyme)
HMG CoA —————> Mevalonate
(Name this enzyme)
HMG CoA Synthase
HMG CoA Reductase (rate-limiting)
What is the rate-limiting enzyme, substrate, and product for cholesterol synthesis?
Enzyme-HMG CoA reductase
Substrate-HMG CoA
Product-Mevalonate
What hormones can stimulate the production of Mevalonate from HMG CoA?
What hormones can inhibit the production of Mevalonate from HMG CoA?
+=insulin, thyroxine
-=Glucagon, sterols, high [AMP], vitamin E, statins
List 2 compounds derived from intermediates in cholesterol synthesis:
Quinol form of Ubiquinone (CoQ10) Heme A (in cytochromes)
How is cholesterol utilized in ALL TISSUES?
Liver?
Adrenal glands, ovaries, testes?
Skin?
ALL TISSUES–> incorporated into cell membranes
LIVER–> Used to synthesize bile acids
ADRENALS, OVARIES, TESTES –> synthesize steroid hormones
SKIN –> Synthesize vitamin D
____ are plasma membrane microdomains enriched in cholesterol, sphingolipids, and gangliosides. They are detergent-insoluble, have low buoyant density, and local centers for signal transduction processes. They are also sites for abnormal processing of proteins in neurodegenerative disorders
Lipid rafts
What are the sites of Ubiquitination on HMG CoA Reductase? Where is the site of Insig binding on HMG CoA reductase?
Ubiquitination–> Lys 89 and Lys 248 (cytosol)
Insig binding –> Membrane domain (lumen)
____ is inhibited by free FA’s, bile acids, and oxysterols. Can also be inhibited by statins (act as competitive inhibitors)
HMG CoA reductase-Statins compete with HMG CoA for binding to active site
This is a form of DIRECT INHIBITION
HMG CoA reductase will be active when ____
HMG CoA reductase will be inactive when ____
Active=DEPHOSPHORYLATED
Inactive=PHOSPHORYLATED
____ inhibits HMG COA by preventing dephosphorylation
____ activates HMG COA by promoting dephosphorylation
Glucagon
Insulin
___ levels of [cholesterol] triggers translocation of SREBP-SCAP complex to Golgi and SREBP transcription factor dimer binds to SRE on HMG CoA reductase promoter
Low –> Low sterol promote release SREBP-SCAP complex from ER to Golgi where SREBP undergoes proteolysis to release the mature form of SREBP which dimerizes and translocates to nucleus to promote the transcription of the rate-limiting enzyme
High [cholesterol] levels retain SREBP in ER membrane via binding of SCAP to INSIG
Translation of HMG CoA Reductase is reduced by ___
Gamma-tocotrienol (Vitamin E family) and oxylanosterols
After cholesterol is synthesized in the liver, the liver packages it into ___ and releases it into the blood. It is then metabolized to ___ by peripheral tissues
VLDL
LDL
Statins have a ____ action due to increase in SREBP maturation which leads to transcription of LDL receptor and subsequent enhanced clearance of cholesterol via LDL-receptor mediated endocytosis and leads to an overproduction of ___ protein
Hypocholesterolemic
HMG CoA reductase protein
What are 2 supplements that should go alongside statin use?
Ubiquinone and prenylated proteins
___ enzymes convert linear isoprenoid squalene into cholesterol and detoxifies xenobiotics and pharmacological agents (including statins)
Cytochrome P450
Agents that inhibit CYP will cause an ____ in statin levels leading to toxic side effects (myopathy and rhabdomyolysis).
Agents that induce CYP will ___ levels of statin in plasma
Increase–> inhibitors includes itraconozole, clarithromycin, and cyclosporine. Citrus juices and grapefruit juice
Decrease –> inducers include rifampicin, carbamazepine, and st johns wort
