liver: lipoproteins, fatty acid oxidation, detoxification, bile Flashcards
what is the structure of a lipoprotein?
outside - protein layer
inside - fat (protected)
what determines the density of a lipoprotein?
the protein to lipid ratio
ie. HIGH density = HIGH ratio (lots of protein, less fat)
HDL’s
- good or bad?
good
high protein:lipid
ie. not many lipids
HDL’s
- function
essentially empty inside as no fats
so removes excess cholesterol from blood and tissue
deliver to liver (excreted as bile)
HDLs
- where are they synthesised?
in liver
LDLs
- good or bad?
bad
low protein:lipid
ie. lots of fat inside (TCAs)
deposits can cause build up of cholesterol eg. in arterial walls
LDL’s
- function
deliver their cholesterol to different cells in body via endocytosis
cholesterol is used to synthesis cell membrane components and steroid hormones
bad if too much
VLDLs
- good or bad
very low protein:lipid
aka.chylomicrons
highest amount or TAGs
where are lipoproteins synthesised?
HDLs - liver
LDLs - plasma
VLDs - liver
VDLS
- function
carries TGs from glucose in liver to adipocytes
IDLs
- what are they?
intermediate
covert to LDLs
what is the purpose of fatty acid catabolism?
provides long-lasting energy for when body is in FASTED state
describe the levels of insulin and glucagon when body is in FASTED state?
high glucagon
low insulin
what is the main type of fatty acid beta oxidation?
mitochondrial
what is the functional group of a fatty acid?
C double bond O
carboxyl
what is the functional group of a glycerol molecule?
-OH
what is phase 1 of fatty acid catabolism?
free fatty acids transported from adipocyte to target cell
what is phase 2 of fatty acid catabolism?
fatty acid enters the mitochondria
- via the carinine mechanism
what are the 3 regulators of the carinine mechanism,?
CPT: carinine palmitosyl transferase
the carinine concentration
malonyl-coA : inhibits CPT
what is phase 3 of fatty acid catabolism?
beta oxidation
during beta oxidation of FAs, what enzyme links to the FA to activate it?
what is the product?
Coenzyme A
replaces -OH
makes an acetyl CoA subunit
why do beta oxidation reactions repeat?
each oxidation reaction shortens the R chain on the acetyl coA subunit by 2 C atoms
the shorter the chain, the easier it is to condense it into a ketone body, and then it can be fed into the TCA cycle and provide energy
what are xenobiotics?
foreign substances (eg. drugs, alcohol) that are not metabolised by body (because no nutritional value) and so need to be excreted
why is it difficult to excrete xenobiotics?
they are often lipophilic, non-polar, insoluble, non-ionised
not very suitable to be excreted in urine or bile
the liver, during detoxification, modifies xenobiotics to make them more suitable for excretion. how does it make them ‘more soluble’ ?
makes metabolites that are soluble and hydrophilic
what is phase 1 of detoxification of xenobiotics?
biotransformation reactions
- reactions that dd a functional group to create a small increase in hydrophilicity
give 3 types of biotransformation reaction
oxidation
reduction
hydrolysis
which is the most common biotransformation reaction ?
what enzyme catalyses it?
oxidation: add -OH
uses the microsomal enzyme CYP 450
what are microsomal enzymes?
microsome = small particle consisting of a piece of endoplasmic reticulum to which ribosomes are attached
microsomal enzymes are found within these
what factors can induce/inhibit a biotransformation reaction ?
drugs, food, age, bacterial, alcohol
give 2 differences between microsomal and non-microsomal enzymes?
microsomal
- specific (mainly used in phase I biotransformation reactions)
- within Endoplasmic reticulum
non-micromsal
- non specific but mainly II
- within mitochondria/cytoplasm
what are CYPs?
= cytochrome P450 enzymes
used for biotransformation reactions
generate a free radical
are microsomal
give 2 factors that induce CYPs?
smoking and grapefruit
what is phase 2 of detoxification of xenobiotics?
conjugation
-bind the xenobiotic to a very hydrophilic molecule (covalently)
explain the most common conjugation reaction
glucuronidation
- conjugates to glucuronic acid molecule
- makes the xenobiotic much more hydrophilic
what enzyme catalyses glucuronidation? is it microsomal or non-microsomal?
microsomal enzyme
- only microsomal for conjugation reactions (all the rest are NON)
glucuronosyltransferase (UGT)
give an example of a non-microsomal enzyme?
non-microsomal are involved in all conjugation reactions except glucuronidation
eg. alcohol dehydrogenase
alcohol detoxification:
- what does alcohol dehydrogenase convert alcohol to? (1)
acetaldehyde
alcohol detoxification:
- what does acetaldehyde dehydrogenase convert acetaldehyde to? (2)
what is the product used for?
acetate
- intermediate for krebs (why alcohol can be an energy source)
- converted into CO2 and H2O
what can happen during alcohol detoxification if too much alcohol is consumed to quickly?
the 2nd metabolism reaction is overwhelmed
build up of toxic acetaldehyde intermediate
liver damage
what can go wrong during paracetamol detoxification ?
- overwhelmed
- build up of harmful NAPQI intermediate
what is bile made up of?
2/3 bile salts
1/3 phospholipids
+ bilirubin, electrolytes, xenobiotics etc.
what are bile salts made of?
conjugated bile acids
w/ glycine or taurine
what is bilirubin?
yellow pigment made from breakdown
ARE BILE ACIDS HYDROPHOBIC OR hydrophilic?
both
amphipathic
bile acid function
induces bile flow
cholesterol hoemostasis
protein absorbtio
digests dietary fats
removes xenobiotics
induces secretion of biliary lipids
prevents calcium gallstones and oxalate renal stones
what is in the portal triad?
hepatic portal venuole
hepatic arteriole
common bile duct
what is the first step of bile acid formation ?
cholesterol in hepatocytes
converted to 2 primary bile acids that are water soluble
when do the primary bile acids become the secondary bile acids?
in the small intestine due to presence of bacteria
what is enterohepatic circulation?
movement of bile acid from liver into small intestine and back to liver
how do the bile salts get transported into the duodenum? (8)
- canaliculus
- ductules
- R&L hepatic ducts
- common hepatic duct
- common bile duct (also receives gall bladder contents via cystic duct)
- pancreatic duct feeds in
- ampulla of vater (through sphincter of oddi)
- duodenum
what % of bile salts are reabsorbed from terminal ilium (enterohepatic circulation) ?
95%
what is the transporter that allows bile salt reabsorption at terminal ileum?
what type of transport is it?
apical sodium bile acid transporter
by active transport
through what vein do the bile salts travel back to liver in the enterohepatic circulation?
the portal vein
what does FXR do in the enterohepatic circulation?
involved in negative feedback - slows circulation down
synthesis FGF-19 hormone which inhibits formation of primary bile acids
where do bile acids go in fasted state?
no food being digested
stored in gallbladder
concentrated by 10x
in FED state, what does CCK hormone do?
Cholecystokinin
- relaxes sphincter of oddi, allowing common bile duct and pancreatic duct to empty into duodenum
- stimules gall bladdder contraction, which squeezes bile into duodenum
in what form is cholesterol secreted from body?
as bile
how do statins affect cholesterol homeostasis?
statins inhibit HMG coA reductase
this stops cholesterol from forming
what does ezetimibe do in cholesterol homeostasis?
stops transport of cholesterol into enterocyte membrane (into SI) causing it to be excreted
what breaks fat down slightly into emulsion droplets?
how are these droplets prevented from reclumping?
motility
bile salts and phospholipids coat surface to stop it from reforming
forms a hydrophobic outside
what doe lipase break a fat globule into?
1 monoglyeride (glycerol + 1 FA)
2 FAs
these are called micelles, and they are continuously broken down and reformed
where do micelles transport to after breakdown/reformation process
diffuse into enterocytes in SI
here they reform TAGs
what is glycogenolysis?
hydrolysis of glycogen to monomers of glucose-6-phosphate
within liver and skeletal muscles
what is the functional unit of the liver?
hepatic lobule
explain where the blood drains from the hepatic venuole and arteriole
portal triad - central vein of the lobular - joins with other central veins to form interlobular vein - joins with others to make hepatic vein - IVC
what blood is in the hepatic sinusoid?
- O2 rich from hetpric arteriole
- nutrient rich from portal vein
mixed as it flows from sinusoids into centra vein
what is the life span of a RBC?
120 days
where are RBC broken down in the liver?
kuppfer cells (macrophages)
what is haemoglobin broken down into during catabolism?
where does this happen?
phagocytosis in macrophage
haem and globin (globin is broken down into AAs, used )
what is haem broken don into during catabolism (catalysed by haaemoxygenase)
biliverdin
Fe2+ & CO
what is biliverdin converted into?
bilirubin (unconjugated)
what enzyme allows bilirubin to become conjugated?
UGT
where does conjugated bilirubin travel?
through bile duct and into duodenum
from here can go to fences, enterohepatic circulation or kidney as urobilin
what colour is bilirubin?
yellow
what causes jaundice?
yellow discolouration of skin caused by high serum bilirubin levels
what are the 3 types of jaundice?
pre hepatic
hepatic
post hepatic/obstructive
