Liver Biochemistry Flashcards
What is the blood flow to the liver?
75% portal vein
25% hepatic artery
What are the biliary components of the liver?
bile ducts
gall bladder
What cells are metabolically active and rich in ER?
hepatocytes
Which cells are lined with sinusoids and allow things to enter hepatocytes?
endothelial cells
Which cells break down foreign substances and have phagocytic activity?
Kupffer cells
Which cells act as storage cells for lipids and vitamin A?
Hepatic stellate cells (ITO)
What cells are natural killer cells and protect against virus and tumors?
Pit cells (lymphocytes)
What are the primary functions of the liver?
receiving nutrients, distributing and recycling center
Retrieves useful items for reuse
Monitoring, synthesizing, recycling, distributing and modifying metabolites
What is the liver’s role with lipids?
lipid biosynthesis and management of triacylglycerol, phospholipids and steriods
What is the liver’s role with proteins?
protein biosynthesis of albumin and IgG
Blood coagulation proteins (fibrinogen, prothrombin)
C-reactive protein
What is the liver’s role with nitrogen?
nitrogen metabolism with the urea cycle
converts harmful product into safe product
What is the liver’s role with waste?
waste management in drug metabolism
Xenobiotic reactions: removal of food additives, dyes and other toxins
What is the liver’s role in getting rid of old RBC?
heme degradation - rid the body of bilirubin
Describe the structural features of enteric circulation
lack of BM btwn endothelial cells and hepatocytes
gaps btwn endothelial cells
fenestration in endothelial cells
low portal blood pressure
*allow greater access and increased contact btwn liver and blood
Describe the structural features of hepatocytes
well developed PM with endocytic and exocytic system Well developed ER Metabolically active cells lots of mitochondria lots of lysosomes
Describe the formation of the building block for the synthesis of all isoprenoids
three acetyl CoA used to generate isopentenyl pyrophosphate (IPP)
What are the sources of acetyl CoA?
Generated in mitochondria
- oxydative decarboxylation of pyruvate
- beta oxidation of fa’s
- breakdown of AA’s
How does Acetyl CoA cross membrane?
it cant, uses citrate shuttle
What is tetracyclic sterane and how is it formed?
tetracyclic Sterane is the backbone of most steroids and is formed from six units of IPP
Describe the structure of cholesterol?
allicyclic compound made of 4 fused rings
molecular weight - 386 kDa
27 carbons
What is the most abundant sterol and what is it components of?
cholesterol
component of plasma membranes and precursor of biologically active compounds: bile acids/salts, vit D, steroid hormones
What is the daily production of cholesterol?
about 1g, mostly in liver
some in small intestine, adrenal cortex, ovaries, and skin
What is the biosynthesis of cholesterol regulated by?
dietary intake
Describe phase 1 of cholesterol synthesis
Acetyl CoA->acetoacetyl CoA
then HMG CoA synthase ->HMG CoA
HMG CoA reductase (rate limiting) ->Mevalonate
->isopentenyl pyrophosphate (IPP)
What is the rate limiting step of phase 1 cholesterol synthesis? what stimulates this step?
HMG->Mevalonate
HMG CoA reductase
+insulin, thyroxine
What inhibits the rate limiting step of cholesterol synthesis in phase 1?
glucagon, sterols, high AMP, vit E, Statins
What are some compounds derived from intermediates in cholesterol synthesis?
Quinol form of ubiquinone (CoQ10)
Heme A in cytochromes
Describe phase 2 of cholesterol synthesis
6 IPP->squalene ->lanosterol*->cholesterol
*inhibited by: azoles (antifungal agents like miconazole and keyoconazole), KCN, tamoxifen, morpholine, triparanol
What is needed to be taken with statins?
supplements of CoQ10 or it will have myotoxic effects
What is the fate of cholesterol in all tissues?
Cholesterol incorporated into cellular membranes
What is the fate of cholesterol in liver?
cholesterol used to synthesize bile acids
What is the fate of cholesterol in adrenal glands, ovaries, and testes?
cholesterol used to synthesize steroid hormones
What is the fate of cholesterol in skin?
cholesterol used to synthesize vit. D
What is cholesterol packaged in to be released into circulation?
In VLDL
What are lipid rafts?
cholesterol enriched microdomains on the PM
also enriched in sphingolipids and gangliosides
Detergent insoluble, low buoyant density
local centers for signal transduction processes
sites for abnormal processing of proteins in neurodegenerative disorders
What is the synthesis of cholesterol directly inhibited by?
Free fatty acids
bile acids
oxysterols
statins (competitive inhibitor of the enzyme)
In what covalent form is HMG CoA reductase active?
Active when dephosphorylated
What phosphorylates HMG CoA reductase and how is it activated?
Conditions of low energy, characterized by high AMP levels, stimulate AMP-activated kinase which phosphorylates and inactivates it
Is glucagon a stimulator or inhibitor of cholesterol synthesis?
Glucagon inhibits HMG CoA reductase by preventing dephosphorylation
What is the role of insulin in cholesterol synthesis?
insulin activates HMG CoA reductase by promoting dephosphorylation
What does HMG CoA reductase gene have in its promotor? What does it bind to?
sterol regulatory element
TFs called SREBP that promotes transcription of HMG CoA Reductase and several other genes
What complex changes the inactive precursor form of SREBP to become mature?
SREBP-SCAP complex.
With low sterol, it is released from ER to Golgi where SREBP undergoes proteolysis
How is SREBP-SCAP complex retained in the ER?
when cholesterol or oxysterols are present, it is kept in ER due to binding to INSIG
What is translation of HMG CoA reductase reduced by?
Gamma-tocotrienol (Vit E) and oxylanosterols
When is HMG CoA reductase turnedover?
in the presence of cholesterol and/or oxysterols
degradation enhanced by sterols, methylated sterols, oxysterols, tocotrienols, mevalonate derivatives, and bisphosphonate SR-12813
How is HMG CoA reductase turnover?
HMG CoA interacts with INSIG which promotes polyubiquitination of HMG CoA Reductase
Leads to removal from ER and degradation by 26S proteasome
Where does cholesterol biosynthesis occur?
liver
Cholesterol is packaged into VLDL and metabolized to what in peripheral tissues?
LDL
How is dietary cholesterol delivered to the liver?
via chylomicron remnants
What is the major source of nascent HDLs?
Liver
What organ helps to clear the bulk of lipoproteins from blood and synthesizes bile acids and eliminates cholesterol into bile?
liver
What is the role of cytochrome P450 enzymes?
convert linear isoprenoid squalene into cholesterol and detoxify xenobiotics and pharmacological agents - including statins
What effects does itraconozole, clarithromycin, and cyclosporine, citrus juices, and grapefruit have on CYP?
they are agents that inhibit CYP and will cause an increase in statin levels leading to toxic side effects (myopathy and rhabdomyolysis)
What are the agents that induce CYP?
rifampicin, carbamazepine, and st john’s wort - decrease levels of statin in plasma
How is cholesterol eliminated?
converted to bile acids and stored in bile
some cholesterol and bile excreted in feces
What is the precursor of bile acids and bile salts?
hepatic cholesterol
Bile acids and bile salts are strong _______
detergents - amphipathic, with polar and non-polar regions
What is the function of bile acids and bile salts?
lipid emulsifying mixture
aids in lipid digestion by forming micelles which increase surface area of lipids exposed to lipases
What is bile made of?
bile acids (7-alpha-hydroxycholesterol), cholesterol, phospholipids, fatty acids, proteins, bile pigments, and inorganic salts
What are bile salts deconjugated by?
bacteria - then reabsorbed at 95% efficiency
What are gallstones?
crystals made up of bile supersaturated with cholesterol
What is cholelithiasis?
insufficient secretion of bile salts or phospholipids or excess cholesterol secretion
What does chronic disturbance in bile salt metabolism lead to?
mal-absorption syndromes (steatorrhea), and deficiency in fat soluble vitamins
What can reduce cholesterol secretion into bile?
oral administration of ursodeoxycholic acid (a secondary bile acid)
Used to dissolve small-medium sized stones
What can be used to assess liver function?
albumin levels - hypo: liver disease
Transaminases: AST and ALT - if ALT present then liver disease and 2:1 - alcoholic liver disease
ALPL - high levels is bile duct obstruction
