Metabolic Functions of Liver Flashcards
1
Q
Features of liver?
A
- 1st major organ in line from the gut.
- Handles large amounts of newly absorbed nutrients.
- Between gut + heart.
- “Protects” major vessels from direct contact with dietary nutrients etc.
- Empties directly into major vessel entering heart.
- Ensure rapid circulation of its products.
- Bile ducts empty directly into gut.
- Rapidly influence the digestive process
- Involved in metabolism of other sugars eg fructose + galactose
2
Q
Removal of glucose from blood after meal?
A
- Regulating flux into pathways that remove free glucose –> lowering blood glucose levels.
- Adipose tissue + muscle switch on their biosynthetic pathways –> remove glucose from blood
3
Q
How does liver maintain constant blood glucose levels?
A
- Removal of glucose from blood after meal,
- Storing glucose as glycogen,
- Restoring blood glucose levels via glycogenolysis + gluconeogenesis,
- Regulating fluxes via glycolysis, gluconeogenesis, PPP
4
Q
Importance of liver for protein + AA metabolism?
A
- Synthesises serum proteins eg albumin + blood clotting factors
- Body doesn’t store protein - utilises it for building tissue + excess broken down, C skeleton used for energy (gluconeogenesis) but N is toxic so removed :
- glucogenic AA -> sugars
- ketogenic AA -> ketone bodies
- Transamination, deamination of AA, detoxification of ammonia via urea
5
Q
Interaction between liver + muscle?
A
- excess lactate -> glucose
- degradation of proteins -> alanine
- transported in blood to liver where converted -> glucose -used for further muscle activity or brain
6
Q
Describe liver in fat transport
A
-chylomicrons synthesised in gut + transport TAG to
peripheral tissues
-chylomicron remnants go to liver for repackaging of lipids into lipoproteins (VLDLs)
-cholesterol cannot be used for energy so body cannot
degrade cholesterol so :
disposed by biliary system as cholesterol or conversion to bile acids
7
Q
Features of synthesis of cholesterol?
A
- 50% made by liver, rest made by intestine, adrenal cortex, reproductive tissue
- Made from ACoA + key enzyme is HMG-CoA reductase
- Transported from liver as VLDL
8
Q
Features of excretion of cholesterol?
A
-Secretion oof VLDL
cholesterol cannot be used for energy so body cannot
degrade cholesterol so :
-Disposed by biliary system as free cholesterol or
-Conversion to bile acids + secreted in to intestines
9
Q
What’s cholesterol pool in liver from?
A
dietary, de novo by extra-hepatic tissue, makes its own
10
Q
Why metabolise ethanol?
A
gut synthesises ethanol by microorganisms present in gut
11
Q
Ethanol for energy?
A
ethanol 7.1 kcal/g so empty calorie only has calorific value, it lies above pure carb + little below fat as a source of energy.
12
Q
2 ways to metabolise ethanol?
A
- Oxidation via activity of alcohol dehydrogenase 90%
- Microsomal ethanol oxidising system (MEOS)using cytochrome P450 10-20%
13
Q
Describe common metabolism of ethanol
A
- alcohol dehydrogenase in liver has high affinity for alcohol so has a low Km + readily saturated
- saturated (alcohol dehydrogenase) after 1st drink
- quickly exceed capacity of enzyme
- metabolises 10g of alcohol/hr
- methanol metabolised to formaldehyde – toxic, associated with paralysis, loss of consciousness, blindness
14
Q
Rate limiting step of ethanol metabolism?
A
- ADH but need NAD+.
- Alcoholics prone to vitamin and mineral deficiencies as they can survive on the calories alone
- Km of ADH 46mg/liter so saturated after 1st drink
- Genetic variation in ADH –> diff in tolerance for alcohol
15
Q
Describe metabolism of acetaldehyde
A
- product of alcohol dehydrogenase is acetaldehyde -toxic (very reactive)
- builds up –> vasodilation, facial flush, tachycardia, nausea
- acetaldehyde broken down by aldehyde dehydrogenase -> acetate
- acetate is substrate for enzymes that produce ACoA.
- 2 isoforms of enzyme : ALDH-1 + ALDH-2
- ALDH-2 is mitochondrial with low Km
16
Q
Dominant negative mutation of alcohol?
A
- Only ADLH-1 40% of Asians + Native Americans have low aldehyde dehydrogenase so intolerance to alcohol - flush
- Aldehyde dehydrogenase rate limiting due to single AA sub Glu -> Lys
17
Q
Why are alcoholics treated with drugs that inhibit ALDH?
A
inducing symptoms experienced
18
Q
Why does NADH accumulate in cytosol?
A
- NADH bad negative inhibitor of ADH + ALDH
- so NADH in cytosol accumulates
19
Q
What happens to acetate produced in liver vs othe rtissue?
A
- acetate produced enters blood
- taken up by skeletal muscle + other tissues
- activated ACoA + oxidised in TCA cycle
- in liver ACoA synthase is cytosolic
- so ACoA produced used to synthesis FA + cholesterol
- non-hepatic tissue have high levels of mitochondrial form ALDH-2
- so ACoA formed enter TCA cycle
20
Q
Features of ethanol metabolism?
A
- Oxidation of alcohol > other nutrients
- Metabolism of alcohol not regulated by negative feedback –> lots of ACoA, NADH, ATP formed
21
Q
Pathways inhibited by metabolism of ethanol?
A
- ACoA, NADH, ATP formed inhibit glucose metabolism by inhibiting PFK + pyruvate dehydrogenase
- NADH inhibits TCA cycle + ACoA increases further
- ACoA –> ketone body formation + stimulation of FA synthesis
- FA esterified to TG for export as VLDL
22
Q
Describe pathways inhibited by ethanol metabolism
A
- increased NADH inhibits FA oxidation
- FA accumulate in liver
- increase G3P production together–> increased TG formation
- TG incorporated into VLDL
- released into blood –> hyperlipidaemia.
- high NADH/NAD ration shifts oxaloacetic acid in TCA cycle to malate
- ACoA formed from ethanol diverted to ketone body formation –> alcohol induced ketoacidosis
- high NADH/NAD ration pushes lactate dehydrogenase towards lactate –> lactic acidosis
- high NADH/NAD ration inhibits gluconeogenesis –> hypoglycaemia
23
Q
Features of microsomal ethanol-oxidising system MESO?
A
- 2nd route of metabolism
- Involves oxidation of ethanol by members of cytochrome P450 enzymes
- Uses NADPH which is required for synthesis of antioxidant glutathione
24
Q
Features of acetaldehyde?
A
- Highly reactive + accumulates with excessive ethanol intake
- Inhibit enzyme function
- Causes reduction in secretion of both serum protein + VLDL in liver
- Enhance free-radical production –> tissue damage eg inflammation + necrosis
25
Describe stages of liver damage
1. Fatty liver
2. Alcoholic hepatitis, groups of cells die --> inflammation
3. Cirrhosis which includes fibrosis, scaring, cell death
26
Effect of cirrhotic liver?
- Cannot function properly ammonia accumulate --> neurotoxicity, coma, death
- Cirrhosis arises in 25% of alcoholics + 75% all cirrhosis is due to alcohol
27
Features of xenobiotics?
- Strange..
- No nutritional value eg: plant metabolites, synthetic compounds. food additives, agrochemicals, cosmetics, by-products of cooking, drugs
- Water soluble compounds excreted easily in urine but lipophilic compounds difficult
28
Role of liver in xenobiotic metabolism?
- Make xenobiotic harmless + readily disposed of by kidney in urine or gut in faeces
- Intestines + lungs also involved
29
Phases of xenobiotic metabolism?
Three common phases
Phase I oxidation
Phase II conjugation
Phase III elimination
30
Describe metabolism of xenobiotics : oxidation (phase I)
- oxidation common modification but also hydroxylation + reduction
- modification increases solubility
- introduces functional groups enabling participation in further reactions
- reactions promoted by family of enzymes = cytochrome P450
31
Features of cytochrome P450?
- In liver + cells of intestine
- Make up family of 50 diff enzymes
- Haem proteins + related to mitochondrial enzymes
- Found in endoplasmic reticulum
- Hydroxylation of ibuprofen
- Inducible both by their own substrates (5-10 fold) but also related substrates (2-4 fold)
32
Describe metabolism of xenobiotics : conjugation (phase II)
- xenobiotic modified by addition of:
* Glutathione
* Glucuronic acid
* Sulphate
- modification with these groups increase solubility + targets them for excretion
- compounds sequentially modified
33
Features of drug metabolism?
- Xenobiotics metabolism is bodies natural defences
- Body cannot distinguish between harmful vs beneficial compounds eg therapeutic drugs
- Metabolism of drugs by liver play role in their effectiveness
- Drug taken orally pass via liver first
- Modifications made by liver can reduce effectiveness of drug or be advantageous
34
What do statins inhibit?
HMG-CoA reductase
35
How are statins degraded?
CYP3A4
36
How to reduce statin degration?
CYP3A4 activity inhibited by grapefruit juice --> statin levels rise by 15 fold
37
What's Aflatoxin B1?
- Produced by fungus Aspergillus flavus
| - Aflatoxin activated by P450 isoenzymes --> epoxide formation + hepatocarcinogenesis
38
Effect of metabolism of paracetamol (acetaminophen)?
-paracetamol conjugated with glucoronate or sulphate + excreted by kidney
-10% of hepatic metabolism of paracetamol --> production of reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI)
-NAPQI cleared when conjugation with glutathione (GSH)
-if not cleared then NAPQI -> NAPQI-protein adducts
-oxidative stress, mitochondrial dysfunction, necrotic cell death
-when GSH insufficient
-excessive ethanol activates microsomal ethanol-oxidising system which uses NADPH
-NADPH required for GSH synthesis
Ethanol metabolism --> reduction in NADPH, a reduction in GSH required to clear NAPQI --> builds up -->liver damage
39
What happens to modified compounds?
- Small water soluble molecules <60,000kDa removed by kidney
- Actively transported to bile then into intestines
- Fate of molecules are 3 fold :
* Digestion
* Excretion
* Reabsorption via enterohepatic circulation
- t½ for 50% of substance to be lost
40
Summary
- Regulation of carbohydrate metabolism to maintain blood glucose
- Regulation of fat metabolism :
* synthesis
* β-oxidation
- Regulation of protein metabolism
* plasma protein synthesis
* detoxification of ammonia - urea formation
- Cholesterol synthesis + excretion
- Synthesis of specialized molecules
* bile acids
* haemin
- Central role in metabolism of xenobiotics
