Metabolic functions of the liver Flashcards
What metabolism occurs in the liver?
- Regulation of carbohydrate metabolism
- Regulation of fat metabolism
- Regulation of protein metabolism
- Cholesterol synthesis and excretion
- Synthesis of specialized molecules
What does the regulation of carboydrate metabolism do?
To maintain blood glucose
What is involved in fat metabolism?
-Synthesis
-Beta oxidation
What is involved in the regulation of protein metabolism?
– Plasma protein synthesis
– Detoxification of ammonia - Urea formation
What is involved in the synthesis of specialised molecules?
-Bile acids
-Haemin
Where does the liver receive blood from and via what vein?
receives blood from the
gastrointestinal tract via the portal
vein
Where does the liver empty its blood into and what does this ensure?
-Empties directly into major vessel
entering the heart.
-Ensure rapid circulation of its
products
Where does the bile duct empty directly into and why?
Bile ducts empty directly into gut.
-Can rapidly influence the digestive
process
What are the 2 routes of the metabolism of ethanol?
– Oxidation through the activity of alcohol
dehydrogenase
– Microsomal oxidation using cytochrome P450
What is involved in the metabolism of ethanol, including enzymes and where it occurs?
-Cytosolic process
-Enzyme involved alcohol dehydrogenase
-Ethanol converted into acetaldehyde and NAD+ –> NADH + H+
What is the rate at which body metabolises alcohol?
Body metabolises approximately 10g of alcohol/hour
What is methanol metabolised to?
Methanol is metabolised to formaldehyde
What is formaldehyde associated with?
Formaldehyde is very toxic and is associated
with blindness, paralysis and loss of consciousness
What is involved in the metabolism of acetaldehyde including where it occurs and what enzymes are involved?
-Mitochondrial process
-Enzyme involved is aldehyde dehydrogenase
-Acetaldehyde converted into acetate and NAD+ +H20–> NADH + 2H+
What happens to the acetate formed in the metabolism of acetaldehyde and what enzyme is invovled?
Acetate–>Acetyl CoA
-Assisted by enzyme acetyl CoA synthase
What isoform of enzymes do caucasians have aldehyde dehydrogenase?
ALDH-1 and ALDH-2
Km value comparison between ALDH-1 and ALDH-2
ALDH-2 has a lower Km than ALDH-1
-Therefore higher affinity
What enzyme do certain ethnic minorities only express and therefore what do they suffer from when consuming alcohol?
- Some only express less effective ALDH-1
- Suffer from with symptoms of vasodilatation,
facial flush, tachycardia and nausea
What does microsomal ethanol-oxidising system(MESO) involve?
Involves the oxidation of ethanol by members of the cytochrome P450 family of enzymes
What does the MESO pathway generate?
The pathway generates acetaldehyde?
What does this system consume and hence what can this result in?
As this system consumes NADPH required for the
synthesis of the antioxidant glutathione it results in
increased oxidative stress
What is the reactivity of acetaldehyde like and what can it inhibit?
Acetaldehyde is very reactive and can inhibit enzyme
function.
What can acetaldehyde lead to in the liver?
In the liver this can lead to a reduction in the secretion of
both serum protein and VLDL
What can acetaldehyde enhance production of and what can this lead to?
Can also enhance free-radical production – leading to
tissue damage such as inflammation and necrosis
What is stage 1 of liver damage?
Fatty liver
What is stage 2 of liver damage?
alcoholic hepatitis, groups of cells
die resulting in inflammation
What is stage 3 of liver damage?
Cirrhosis which includes fibrosis,
scaring and cell death
What cannot function as a cirrhotic liver and what can this result in?
As the cirrhotic liver cannot function
properly ammonia will accumulate resulting
in neurotoxicity, coma and death
What does high NADH do to gluconeogenesis and what does this stimulate and cause?
High NADH inhibits gluconeogenesis and stimulates the
conversion of pyruvate to lactate leading to hypoglycaemia
and lactic acidosis
What does high NADH do to fatty acid oxidation and what does this stimulate?
High NADH inhibits fatty acid oxidation and stimulates fatty
acid synthesis and the formation of triglycerides
What does Acetyl CoA, NADH and ATP formed in ethanol metabolism inhibit and by inhibiting what?
Acetyl-CoA, NADH and ATP formed inhibit glucose
metabolism by inhibiting PFK and pyruvate dehydrogenase
What cycle does NADH inhibit and what does this inhibit?
-TCA cycle and acetyl CoA
-This increases inhibition of glucose metabolism
What does Acetyl-CoA result in the formation of?
Acetyl-CoA results in ketone body formation
What are the 3 common phases involved in the metabolism of xenobiotics?
- Phase 1 oxidation
- Phase 2 conjugation
- Phase 3 elimiation
What happens in Phase 1 in the metabolism of xenobiotics?
-Oxidation is the most common modification but also get hydroxylation and reduction
-Modification increases solubility
-These reactions are facilitated by cytochrome P450 enzymes
Where is cytochrome P450 found organ and where exactly in cells?
Found mainly in liver and cells of the intestine
-In Endoplasmic reticulum
What are P450 enzymes inducible by?
P450 enzymes are inducible both by their own
substrates (5-10 fold) but also related substrates (2-4 fold)
What happens in phase 2 conjugation in the metabolism of xenobiotics?
Xenobiotic are modified by addition of groups
such as
* Glutathione
* Glucuronic acid
* Sulphate
What does modification in phase 2 conjugation increase and do?
Modification with these groups increase
solubility and targets them for excretion
What is aflatoxin B1 produced by?
Produced by the fungus
Aspergillus flavus
What is aflatoxin activated by and what does this lead to?
Aflatoxin activated by
P450 isoenzymes leading
to epoxide formation and
hepato-carcinogenesis
What do statins inhibit?
Statins inhibit HMG-CoA
reductase
What are statins degraded by?
Are degraded by CYP3A4
What activity does CYP3A4 activity inhibit and what does this do to Statin levels?
- CYP3A4 activity inhibited by
grapefruit juice - statin levels can rise by 15 fold
What happens to modified compounds by the liver?
- Actively transported into bile and then into the intestines
- Fate of these molecules is the following:
-Digestion
-Excretion
-Reabsorption via the enterohepatic circulation
