Liver function Flashcards
why is cholesterol important
synthesis of cell membranes and contributes to fluidity
lipid rafts- patches of fluidity
precursor for synthesis of several molecules eg vit D
cholesterol synthesis
80% production in the liver
from Acetyl CoA
Multi step pathway
cholesterol synthesis step 2/3
squalene synthesised from isopentenyl pyrophosphate
cyclization of squalene to form lanosterol
lanosterol goes through several steps to form cholesterol
statins
inhibit HMG CoA-reductase in cholesterol synthesis pathway
how is cholesterol transported in the body and why
lipophilic so does not dissolve well in water.
Packaged with phospholipids and apolipoproteins to form a series of different lipoproteins (have a lipid core and hydrophlic outer surface with phospholipids, free cholesterol and apolipoproteins.
include LDLs and HDLs
How to treat atherosclerosis
Inhibit cholesterol synthesis, because high LDL levels associated with atherosclerosis
HDL vs LDL
Ldl risk factor of CVD and athersclerosis, HDL protective
Bile salt production recap
Primary bile salts formed in the liver, go into GI tract, where modified by gut bacteria to form secondary bile salts
dehydroxylation
bile contains
bile salts lecithin HCO3- cholesterol bile pigments trace metals
Bile production
Hepatocytes secrete hepatic bile into canaliculi
hepatic bile
bile salts, bile pigments, cholesterol and lecithin
what do epithelial cells that line the bile ducts secrete
a bicarbonate rich fluid that increases the volume of the bile
what are precursors of bile salts
bile acids synthesized from cholesterol
Primary bile acids
cholic acid and chenodeoxycholic acid
synthesised in the hepatocytes
secondary bile acids
deoxycholic and lithocholic- are formed inthe intestine by the dehydroxylating action of bacteria flora
conjugation
in the liver, primary or secondary bile acids are conjugated to amino acids to generate water soluble bile salts
bile salts have
hydrophobic and hydrophilic regions that aggregate to form micelles at a critical concentration
Important for the emulsification of fats
where are the majority of bile salts reabsorbed
by a sodium dependent pathway in the ileum (last segment of the small intestine)
how do bile salts get recycled back to the liver from the intestine
portal vein
how does uptake of bile salts from portal blood into hepatocytes occur
active transport
enterohepatic circulation
recycling from the GI tract to the liver
sphincter of oddi
ring of smooth muscle where common bile enters small intestine
Cholecystokinin (CCK)
peptide hormone
produced by small intestine
stimulus for release- AAs, fatty acids in the intestine
What does increased CCK lead to
gallbadder contraction, increased bile flow into common bile duct
relax sphincter of oddi, incr bile flow into duodenum
what happens when the sphincter of oddi is closed
bile diverted to gall bladder
what does the gall bladder do with bile stored for digestion
concentrates it by removal of salts and water
bile pigments
breakdown product of heme portion of haemoglobin from erythrocytes broken down in the liver and spleen
major pigment is bilirubin found in bile and secreted into duodenum
pigments responsible for characteristic bile colour
what else does the liver secrete
plasma proteins
albumin
plasma protein, transport lipids and steroid hormones
Globulins
approx 40% total plasma proteins
a-globulins and B-globulins also transport lipids and steroid hormones
clotting factors
most produced by the liver
IGF- insulin like growth factors
Important mediator of growth hormone action
Liver synthesises IGF 1 and 2 in response to growth hormone
structurally similar to pro-insulin
IGF-1
levels low in infancy, peak in puberty during growth and declines in adult
IGF 2
more important in fetal and neonatal growth
Phase 1 reactions drug metabolism
Cytochrome p450 enzymes important
Population variation in these is important in terms of therapeutics
Naturally occurring dietary substances can inhibit or induce p450 enzymes with impact on drug metabolism
clopidogrel
anti-thrombotic agent that inhibits platelet activation
pro drug that requires oxidation
what is a pro drug
a biologically inactive compound which can be metabolized in the body to produce a drug.
metabolism of clopidogrel
2 step, using hepatic P450 enzymes to generate the active thiol metabolite that reacts with platelets
Binds selectively and irreversibly to P2Y12 receptor on platelet membranes
What happens to majority of clopidogrel
inactivated by blood esterases so only 15 % metabolised by hepatic P450 enzymes
What are mutations in P450 enzymes associated with
reduced response to clopidogrel treatment
Phase 2 reactions
conjugation step that leads to pharmacologically inactive or less soluble lipid product that is eliminated in urine or bile
groups often associated with conjugation
glucuronyl, sulphate, methyl, acetyl etc
what is paracetamol
non-narcotic analgesic-antipyretic agent
paracetamol peak plasma conc
30-60 mins
paracetamol inactivated in liver by
conjugation to glucuronide or sulphate
Toxic dose causes
hepatotoxicity and renal toxicity
what happens with paracetamol toxic dose
normal conjugation pathways saturated and drug metabolised by mixed function oxidases to form N-acetyl-p-benzoquinone imine (NAPBQI)- toxic to cells
kupffer cells function
phagocytize pathogens from entering blood circulation
first line of defence against particulates and immunoreactive material from GI tract via portal circulation
cholesterol synthesis 1st step
Acetyl CoA is joined to acetoacyl CoA to form HMG CoA. This product is converted to melvalonate by HMG-CoA reductase.
Mevalonate is phosphorylated by three kinases sequentially utilizing three ATPs and is then decarboxylated to form isopentenyl diphosphate.
cholic forms
deoxycholic
chenodeoxycholic forms
lithocholic
phase 1 reaction processes
Oxidation Hydroxylation Dealkylation Deamination hydrolysis
involve the creation of a functional group or the modification of an existing one by oxidation, reduction, or hydrolysis.
