14. Liver Biochemistry COPY Flashcards
What is the structure of the liver
2 lobes subdivided into multiple lobules and sinusoirs
covered by CT
What is the blood supply for the liver
2 ways in:
75% Portal V - nutrient rich from bowel (enteric circulation)
25% Hepatic A - O2 rich (periphery)
How does blood leave the liver
through 3 hepatic Vs that come together and make the IVC
What cells carry out most of the metabolic function of the liver
hepatocytes
what is the function of the endothelial cells in the liver
allow exchange of material from liver to blood & vice versa via pores & fenestrations in plasma mem
What are Kupffer cells & what all its functions
lining sinusoids
= macrophages -protect from gut derived microbes, remove damaged/dead RBC, cause immune response, secrete cytokines
=endocytic & phagocytic fxn
& lots of lysozomes
what are storage sites for Vit A and other lipids in the liver
hepatic stellate cells
What are Pit Cells
=lymphocytes
-NKCs- protect liver against viruses & tumor cells
What are Cholangiocytes
line bile ducts
control bile flow rate & bile pH
what are the functions of the liver
MAJOR: monitoring, synthesizing, modifying, receiving, distribution & recycling center
-carb, lipid, NT, AA/protein, bilirubin metabolism
synthesis of blood proteins
waste management
how does carb metabolism occur in the liver
= glucostasis - maintain glucose levels in diff fed states
- glycogen synthesis, glygocenolysis, gluconeogensis
- use G6P to release free glucose to blood
- under starvation - make ketone bodies
how does lipid metabolism occur in the liver
biosynthesis of TAG, phospholipids, steroids (chol & bile acids & salts) & lipoproteins (VLDL, LDL, HDL)
degrade TAG & plasma lipoproteins
regulate FFA metabolism
breakdown FFA (beta-ox)
what happens if you are unable to clear ammonia
brain damage
liver has protein/AA metabolism –> & remove N via urea cycle
what are structural features of liver
- lack of basement mem & absence of tight jxn btn heptaocyte & endothelial cell
- gap jxns btn endothelial cells
- fenestrations in endothelial cells
- allow greater access & increased contact btn liver & blood
what is bile made of
bile acids
bile salts
cholesterol
phospholipid
FA
proteins
bile pigment
inorganic salt
what are the functions of the bile acids & salts
- emulsifcation of fat
- abs of fat soluble vitamin
- digestion & abs of fat
- prevention of cholesterol precipitation
- elimination of cholesterol
how and where are bile acids & salts made
made in hepatocytes - released into bile canaliculi
stored & concentrated in gallbladder
how do the bile acids & salts act as strong detergents
amphipathic - w/ polar & nonpolar
help to form micelles –> increase SA of lipids & expose them to lipase
what is the difference btn bile acids & salts
acids = protonated form (COOH)
salt = de-protonated form (COO-)
How does emulsification occur by bile salts
- cholic acids (typical bile acid) - ionize to cognate bile salt
- hydrophobic surface of bile salt associate w/ TAG & aggregate to form a micelle
- hydrophobic surface face outward –> allow micelle to associate w/ pancreatic lipase/colipase
- hydrolytic action of lipase/colipase free FA & associate in smaller micelle
- these then abs-ed through intestinal mucosa
How are bile acids synthesized
- cholesterol + 7a-hydrolase (committed step)
- 7a-hydroxycholesterol –> reduction, hydroxylation & conversion of hydroxyls to alpha –> 3a,7a diol
- oxidation of side chain –> 3a,7a,12a-triol –> cholic acid
- or 3a,7a-diol –> chenodeoxycholic acid
how are bile acids conjugated
how is pKa related to detergent effect
lower pKa –> more ionized = better detergent effect
how is bile metabolized
taurochenodeoxycholic, glycochenogeoxycholic, taurocholic & glycocholic acid –> into gallbladder as bile
what happens when gallbladder release primary bile salt
- used in duodenum to emulisify dietary lipids to help digest & abs
- bacteria deconjugate & dehydroylate primary salt into primary & secondary bile acids –> absed by ileum & then excreted in feces or recycled to liver via enterohepatic circulation
how do bile acid-binding resins work
non-absorbable bile-acid bind resin like cholestyramine –> cause increase in excretion of bile acids
rate of bile synthesis increased by 7a hydroxylase
deplete liver cholesterol pool
increase in hepatic uptake LDL cheolesterol by receptor mediated & receptor-independent mechanism
-lower plasma cholesterol levels
what is cholelithiasis
insufficient secretion of bile salts or phospholipids into gallbladder or excess cholesterol secretion into bile
form gallstones - made of bile supersaturated w/ cholesterol
what happens with chronic disturbance in bile salt metabolism
malabsorption syndrome (steatorrhea)
deficiency in fat soluble vitamina
liver is the primary site for converion &/or degradation
metabolites: compounds made in body (intermediates &/or end products of metabolism)
xenobiotics: compounds ingested from outside (w/ no nutritional value, potentially toxic) -ie pharmacological agents, recreational drugs, components of food
what are the steps of xenobiotic detoxification
phase 1: increase polarity (catalyzed by Cytochrome P450 enzymes)
phase 2: fxnal groups are conjugated for safe excretion (make it more soluble)
how does drug metabolism occur
metabolized in liver
hepatic metabolism - increases hydrophilicity –> increase ability to excrete
enzymes have low substrate specificity - deal w/ infinite range of molecules
-usually drug metabolites less pharmacologically active than parent drugs but some are also some inactive –> convert to active form after metabolism
what are cytochrome P450 enzymes (CYP)
superfam of proteins = 18 fams (3 responsible for phase I drug metabolism; CYP1,2,3) & 43 subfam w/ 57 genes
CYPs are contain heme, present in ER & operate via electron transfer system
co-localize w/ NADPH: cytochrome P450 reductase (CYPR - rate limiting)
= key role in metabolism of multiple hydrophobic compounds
what is the reaction sequence of cytochrome P450
what do CYPs do to phamacological agents
detoxify
agents that inhibit CYP –> increase drug levels in plasma (vice versa)
what are examples of CYP inhibitors
citrus juice, grapefruit juice, itraconozole, clarithromycin & cyclosporine
-increase drug levels
what are examples of CYP inducers
St. John’s Wort, rifampicin, carbamazepine
-decrease drug levels in plasma
what is personalized medicine
allelic variation & polymorphisms of CYPs exist in individuals - influence catalytic activity of CYPS & influence drug metabolism
genotyping CYPs identify gene-relevant polymorphisms may become more common in order to personalize an ind’s response to particular drug
What is drug hepatotoxicity
drug in excess = toxic (may be due to genetic or immunologic causes)
how is NABQ1 detoxified
detoxify via glutathion
-in overdose - stores are depleted
What happens with overdosed acetaminophen
tylenol - eliminate via conjugation w/ glucouronic acid/sulfate & excrete via kidney
if overdose - normal conjugation capacity is overwhelmed
- oxized by liver CYP3A4 to NABQ1 –> cause free radical mediated peroxidation of membrane lipids –> damage hepatocytes ==> heptaic faillure/death
what occurs w/ diseases of liver
normally leak basement mem btn endothelial cells & hepatocytes - replaced by high density mem containing fibrillar collagen
spaces btn endothelial cells & fenestrations in plasma mem lost
- increased stiffness of hepatic vascular channels offers resistance to free flow of blood thru liver
- elevated intra-sinusoidal fluid pressure - portal HTN
=impairment of free exchange of material btn hepatocytes & blood
what is ALT and AST
involved in interconversion of AA & ketoacids & are required for proteins & carb metabolism
-both located in mito & ALT also in cytosol (so its more sensitive)
serum ALT & AST increase in liver damage as enzymes released from damaged hepatocytes
