Liver Biochemistry Flashcards
What supplies most of the blood to the liver?
protal vein
What do hepatic stellate cells do?
store lipids and vitamin A
What are some functions of the liver?
- recycling center
- lipid biosynth and management
- make Albumin and IgG
- N metabolism , Urea cycle
- waste management: seonobiotic reactions
- bilirubin metabolism
- fuel management
What characteristics of the liver allow for greater access and increased contact b.w theliver and blood?
- no basement membrane between endothelial cells and hepatocytes
- gaps b/w endothelial cells
- fenestrations in endothelial cells
- low portal blood pressure
What are hepatocytes like?
well developed pasma membrane and ER, lots of mitochondria, lots of lysosomes
What is the building block of all isoprenoids and what is used to make it?
IPP
-3 acetyl coA’s go into it
What are some sources of Acetyl CoA?
generated in mitochondria from:
- oxidative decarboxylation of pyruvate
- B ox of fatty acids
- breakdown of aa’s
how is Acetyl CoA transported into the cytoplasm?
via citrate shuttle
What is the backbone of most steroid?
the tetracyclic sterane ring
-made up of six IPP’s
What is one important characteristic about the structure of cholesterol?
the OH group at C3
What does cholesterol make?
Bile acids and salts
Vit D
Steroid hormones
How many ATP go into making one Cholesterol?
18
that’s a lot of energy
What are the 2 phases of Cholesterol synthesis?
- Generation of IPP from Acetyl CoA
- Generation of cholesterol from IPP
What does HMG CoA synthase do?
Acetoacetyl CoA —> HMG CoA
*uses an Acetyl CoA here
What do HMG CoA reductase do?
HMG CoA—–> Mevalonate
*uses 2 NADPH’s… and a CoA pops off in this step
What is the rate limiting step?
The one involving HMG CoA reductase
- HMG CoA—–> Mevalonate
What enhances the rate limiting step of cholesterol synthesis?
Insulin and thyroxine
What inhibits the rate limiting step?
Glucagon, sterols, high AMP, Vit E, and Statins
What are some compounds derived from intermediates in cholesterol synthesis?
Quinol from ubiquinone
Heme A
List the intermediates in order in cholesterol synthesis.
Acetyl CoA, Acetoacetyl CoA, HMG CoA, Mevalonate, IPP, Squalene, Lanosterol, cholesterol
What happens to cholesterol after it is made?
gets packaged into VLDL and released into circulation
How is Cholesterol cynthesis mainly regulated?
HMG CoA reductase
- the rate limiting enzyme
- can happen by direct inhibition, covalent mod, transcriptional control, translational control, or post-translational control- protein turnover
How does direct inhibition go?
- HMG CoA reductase inihibited by Free FA’s , buile acids, and oxysterols
- also inibited by statins
What are statins,
competitive inihibitors of HMG CoA reductase
- compete w. HMG coA for binding to active site
- statin lacks the Methyl group*
- these are cholesterol lowering drugs
- bind more tightly to the active site
How does covalent modification go?
HMG CoA reductase is active when DEPHOSPHORYLATED
-inactive when P’ed
What marks a low energy condition?
High AMP levels (result of low ATP)
-this stimulates AMPK which P’s and inactivates HMG CoA reductase
How does glucago inhibit HMG CoA reductase?
by preventing deP
-insulin just does the exact opposite
How does transcriptional control work?
HMG CoA reductase has a sterol regulatory element (SRE) in its promoter
- that binds SREBP proteins
- SCAP cleaves inactive SREBP to make it active
- if we already have cholesterol or oxysterols, SREBP-SCAP is kept in the ER due to binding to INSIG
- That slows transcription (makes sense)
What happens with the transcriptional control when we have low sterol conditions?
- SREBP-SCAP gets released from ER to Golgi
- SREBP gets cut… now it’s mature
- it dimerizes and goes to nucleus
- binds to SRE and promotes transcription of HMG CoA reductase and others (like LDL receptor :D)
How does translational and post-translational control work?
- translation reduced by gamma-tocotrienol and oxylanosterols
- in presence of cholesterol, HMG CoA interacts with INSIG
- then, it gets ub’ed and degraded
- things with “ol” at the end of them enhance this
Describe cholesterol homeostasis.
liver packages it into VLDL, released into blood, metabolized into LDL by peripheral tissues
- Liver is major source of HDL’s, help to clear lipoptns from blood
- synthesizes bile acids and elminiates cholesterol into bile
What is the main side effect with a statin?
myotoxic
-decreased formation of ubiquinone and prenylated proteins
What is the significance of Cytochrome P450 (CYP)
these enzymes convert squalene into cholesterol
-also detoxify xenobiotic and pharmacological agents (statins!)
What happens if we inhibit CYP?
statin levels will rise (and vice versa)
-leads to toxic side effects
Can any enzyme degrade the sterane ring of cholesterol?
No
When making bile acids, what is the first thing that cholesterol is converted to?
7-alpha-hyroxycholesterol
What 2 things do we end with in bile synthesis?
Chenocholic acid and cholic acid
What happens after we make cholic and chenocolic acid?
we either add taurine to make taruocholic acid or glycine to make glycocholic acid (just add cheno in there if other one)
What do bile salts get inserted into after they’re made?
mixed micelles
What are gallstones?
crystals made up of bile supersaturated with cholesterol
What is cholelithiasis?
insufficient secretion of bile salts or phopholipids or excess cholesterol secretion
What is used to dissolve small-medium sized stones?
oral administration of ursodeoxycholic acid
-it reduces cholesterol secretion into bile
