Liver Biochemistry Flashcards
What is the makeup of the blood supply to the liver?
75% of the blood supply to the liver comes from the portal vein; 25% of the blood supply to the liver comes from the hepatic artery
what is the biliary component made of?
bile ducts and the gallbladder
what is the one way blood gets out of the liver?
blood flows out of the liver through 3 hepatic veins into a big vein called the inferior vena cava
what is the main cell type found in the liver?
hepatocytes
what is the main function of the hepatocytes?
they carry out most of the metabolic functions of the liver
where are the endothelial cells of the liver found?
in the lining of the sinusoids
how can the endothelial cells of the liver be characterized?
they present loosely, they have pores and fenestrations in the plasma membrane to allow exchange of material from the liver to the blood
where are Kupffer cells found?
they are present in the lining of the sinusoids
what are kupffer cells?
they are macrophages that protect the liver from gut-derived microbes, removed damageed/dead RBCs, and orchestrate an immune response by secreting cytokines
what do the kupffer cells have?
a well-developed endocytic and phagocytic function and lots of lysosomes
What are the hepatic stellate cells?
they are lipid-filled cells and they serve as the primary storage site for vitamin A
what do the hepatic stellate cells control?
the turnover of hepatic connective tissue and extracellular matrix and regulate the contractility of the sinusoids
what are pit cells?
liver associated lymphocytes or natural killer cells
what is the function of pit cells?
they serve as a defense mechanism against the invasion of the liver by potentially toxic agents
what are cholangiocytes and where are they found?
they line the bile ducts and they control bile flow rate and bile pH
what blood proteins does the liver synthesize?
albumin, IgGs (antibodies), apoproteins, fibrinogen, prothrombin, blood clotting proteins and acute phase response proteins
what are acute phase response proteins?
acute phase response encompasses all systemic changes in response to infection or inflammation
what are two examples of acute phase response proteins?
C-reactive protein and protease inhibitors (alpha-1 Antitrypsin and alpha-1 antichymotrypsin)
where does the arterial and venous blood mix in the liver?
in the sinusoids
what features of the liver allow for greater access and increased contact between liver and blood?
lack of basement membrane and absence of tight junctions between hepatocytes and endothelial cells and fenestrations (pores) in the endothelial cell membrane
what is bile made of?
bile acids, bile salts, and cholesterol
what is the main function of bile acids and bile salts?
they emulsify fats so that they can be broken down and absorbed
what are bile acids and salts known to be?
strong detergents; amphipathic- with polar and non-polar regions
what are bile acids and salts synthesized from?
hepatic cholesterol
where is bile made?
in hepatocytes
where is bile released?
into bile canaliculi
when is bile released into the duodenum?
in response to food
what form is a bile acid in?
the protonated form (COOH)
what form is bile salt in?
the de-protonated form (COO-)
what surface of the bile salt molecule associates with the TAG?
the hydrophobic surface
what surface of the bile salts faces outward, allowing the micelle to associate with pancreatic lipase/colipase?
the hydrophilic surface
what is the rate limiting enzyme of the synthesis of bile acids?
7 alpha- hydroxylase
what does 7 alpha-hydroxylase transform cholesterol into?
7 alpha-hydroxycholesterol (adds a hydroxyl group on the 7th position- so now there are 2 hydroxyl groups)
where is the hydroxyl group positioned on cholesterol?
3rd position
what happens when 7 alpha-hydroxycholesterol gets 1 COOH group added?
it becomes chenodeoxycholic acid
what happens when 7 alpha hydroxycholesterol gets 1 COOH group and another OH group added?
it becomes cholic acid
why do we need to conjugate?
by conjugating, you have increased the efficiency of the bile acid to emulsify
what is pKa’s association to efficiency of the bile acid to emulsify?
the lower the pKa, the more ionized the molecule, the better the detergent effect
what happens to bile acids before secretion?
they are conjugated
what are the primary bile acids?
cholic acid and chenodeoxycholic acid
how many primary conjugated bile acids are there?
4
how do you get the primary conjugated bile acid Glycocholic acid?
you add glycine to cholic acid
how do you get the primary conjugated bile acid taurocholic acid?
you add taurine to cholic acid
how do you get the primary conjugated bile acid Taurochenodeoxycholic acid?
you add taurine to chenodeoxycholic acid
how do you get the primary conjugated bile acid glycochenodeoxycholic acid?
you add glycine to chenodeoxycholic acid
how do you get secondary bile acids?
bacteria in the gut deconjugate and dehydroxylate primary bile salts
what are the secondary bile acids?
deoxycholic acids and lithocholic acid
what is an example of a medication used to treat hypercholesterolemia?
bile acid-binding resins
what is an example of a bile acid-binding resin?
cholestyramine
what effect does cholestyramine have?
they cause a large increase in secretion of bile acids, which in turn causes the rate of bile acid synthesis to be increased
once the bile salts have done their jobs, what happens to them?
they are recycled back to the liver
what happens when the rate of bile acid synthesis is increased?
there is depletion of the liver cholesterol pool, so there will be an increase in hepatic uptake of LDL from circulation–> lower plasma cholesterol levels
what are gallstones?
crystals made up of bile supersaturated with cholesterol
what is cholelithiasis?
insufficient secretion of bile salts into the gallbladder or excess cholesterol secretion into bile
what does chronic disturbance in bile salt metabolism lead to?
malabsorption syndrome (steatorrhea) and deficiency in fat soluble vitamins
the liver is the primary site for conversion and or degradation of what two things?
xenobiotics and/or metabolites
what are xenobiotics?
compounds ingested from outside with no nutritional value/ potentially toxic
what are metabolites?
compounds that are made in the body (intermediates and/or end products of metabolism)
There are two phases to waste management. What do they entail?
first phase- polarity is increased. second phase- functional groups are conjugated to further increase polarity
when the polarity of a compound is increased what happens?
it is easier to get rid of it (makes it more soluble)
what are the phase I reactions catalyzed by?
cytochrome P450 (CYP) enzymes
what happens in the phase one reactions and what do you get after them?
an oxygen is added to a xenobiotic or a waste metabolite- you get R-OH
where are most drugs metabolized?
in the liver
what does hepatic metabolism increase?
increases the hydrophilicity and hence their ability to be excreted
hepatic metabolizing enzymes deal with infinite range of molecules that can be administered. How is this achieved?
by the responsible enzymes having low substrate specificity
what is a characteristic of CYP?
they are a heme-containing protein present in the ER
what do CYPs work with?
cytochrome P450 reductase (CYPR)
Which CYP enzyme accounts for 30-40% of the CYP450 enzymes?
the CYP3A4 isoform
how do CYPs operate?
via an electron transfer system
the CYP protein is a heme containing protein that has iron in what form?
the ferric form
what does the cytochrome P450 reductase provide as a releasing power?
NADPH
Are CYPs present in high amounts in the liver?
no but they are induced by their substrates
Agents that inhibit CYP will cause what?
increase in drug levels in the plasma
agents that stimulate CYP will cause what?
decrease in drug levels in the plasma
what is an example of a CYP inhibitor?
citrus juice
what happens if a patient regularly takes their statins with a glass of grapefruit juice?
there will be an increase in statin levels in the plasma
what is an example of a CYP inducer?
St. John’s Wort
what happens if a patient takes a statin and St. John’s Wort?
there will be a decrease in statin levels in the plasma
how is tylenol/acetaminophen eliminated?
it occurs via conjugation with glucuronic acid or sulfate
what happens in acetaminophen overdose?
the capacity for normal conjugation is overwhelmed and it is oxidized by the liver CYP3A4 to NABQ1
what is the NABQ1 detoxified by?
glutathione, but in acetaminophen overdose, the glutathione stores become depleted and the liver cells become damaged
what can be given as an antidote to acetaminophen poisoning?
a sulphydryl compound called N-acetyl cysteine- it replenishes the glutathione
what is the major change in all of the diseases of the liver?
the normally leaky basement membrane between endothelial cells and hepatocytes is replaced by high-density membrane containing fibrillar collagen
what does increased stiffness of hepatic vascular channels offer?
resistance to free flow of blood through the liver, elevated intra-sinusoidal fluid pressure; portal hypertension
what is the primary effect of all diseases of the liver?
impairment of free exchange of material between hepatocytes and blood
