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GI > Metabolic Functions of Liver > Flashcards

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
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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
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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
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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
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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
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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

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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
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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

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9
Q

What’s cholesterol pool in liver from?

A

dietary, de novo by extra-hepatic tissue, makes its own

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10
Q

Why metabolise ethanol?

A

gut synthesises ethanol by microorganisms present in gut

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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.

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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%

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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
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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
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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
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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
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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
Q

Describe stages of liver damage

A
  1. Fatty liver
  2. Alcoholic hepatitis, groups of cells die –> inflammation
  3. Cirrhosis which includes fibrosis, scaring, cell death
26
Q

Effect of cirrhotic liver?

A
  • Cannot function properly ammonia accumulate –> neurotoxicity, coma, death
  • Cirrhosis arises in 25% of alcoholics + 75% all cirrhosis is due to alcohol
27
Q

Features of xenobiotics?

A
  • 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
Q

Role of liver in xenobiotic metabolism?

A
  • Make xenobiotic harmless + readily disposed of by kidney in urine or gut in faeces
  • Intestines + lungs also involved
29
Q

Phases of xenobiotic metabolism?

A

Three common phases
Phase I oxidation
Phase II conjugation
Phase III elimination

30
Q

Describe metabolism of xenobiotics : oxidation (phase I)

A
  • 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
Q

Features of cytochrome P450?

A
  • 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
Q

Describe metabolism of xenobiotics : conjugation (phase II)

A
  • xenobiotic modified by addition of:
  • Glutathione
  • Glucuronic acid
  • Sulphate
  • modification with these groups increase solubility + targets them for excretion
  • compounds sequentially modified
33
Q

Features of drug metabolism?

A
  • 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
Q

What do statins inhibit?

A

HMG-CoA reductase

35
Q

How are statins degraded?

A

CYP3A4

36
Q

How to reduce statin degration?

A

CYP3A4 activity inhibited by grapefruit juice –> statin levels rise by 15 fold

37
Q

What’s Aflatoxin B1?

A
  • Produced by fungus Aspergillus flavus

- Aflatoxin activated by P450 isoenzymes –> epoxide formation + hepatocarcinogenesis

38
Q

Effect of metabolism of paracetamol (acetaminophen)?

A

-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
Q

What happens to modified compounds?

A
  • 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
Q

Summary

A
  • 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

GI (15 decks)

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