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sem 2 Liver and GI > Metabolic functions of the Liver > Flashcards

Metabolic functions of the Liver Flashcards

1
Q

the liver is the first major organ in line from the gut, what does this mean?

A

it can handle large amounts of newly absorbed nutrients

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2
Q

the liver is between the gut and the heart, what is the relevance of this?

A

“protects” major vessels from direct contact with dietary nutrients etc.

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3
Q

the liver empties directly into the major vessel entering the heart, what is the importance of this?

A

ensures a rapid circulation of its products

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4
Q

the bile ducts empty directly into the gut, why is this good?

A

can rapidly influence the digestive process

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5
Q

what is the liver responsible for? (give an example)

A

Responsible for packaging and synthesising a lot of the molecules that we require
-eg. FA’s packaged up as TG’s and transported via LDL’s

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6
Q

the liver is important for maintaining what? give examples

A

The liver is extremely important for maintaining constant blood glucose levels

  • By removal of glucose from the blood after a meal
  • By storing glucose in the form of glycogen
  • By restoring blood glucose levels through glycogenolysis and gluconeogenesis
  • By regulating the fluxes through glycolysis, gluconeogenesis and pentose phosphate cycle
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7
Q

how do other organs like adipose tissue and muscle help remove glucose from the blood?

A

they switch on their biosynthetic pathways

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8
Q

the liver is involved in the metabolism of what?

A

other sugars

-fructose, galactose

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9
Q

explain the importance of the liver in protein and amino acid metabolism:

A
  1. The liver is the major site for the synthesis of many serum proteins, such as albumin and the blood clotting factors.
  2. The liver degrades excess amino acids, particularly during gluconeogenesis

glucogenic a.a –> sugars

ketogenic a.a –> ketone bodies

  1. The liver is the major site for transamination and deamination of amino acids, and for detoxification of ammonia
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10
Q

what is the interaction between the liver and muscle?

A

actively contracting muscle will produce lactate, and breakdown of protein will produce alanine-glucose is synthesised from both of these products through the:

  • glucose-alanine cycle
  • cori cycle
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11
Q

role of liver in fats?

A

plays a central role in the synthesis, transport and metabolism of lipids and fats

  • Transport
  • Fatty acid synthesis
  • Beta oxidation
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12
Q

explain where the synthesis of cholesterol occurs in the body?

A
  • 50% of cholesterol made in the body is made by the liver

- rest is made by intestines, adrenal cortex and reproductive tissue

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13
Q

what is cholesterol made from, and what is the key enzyme involved?

A
  • made from ACoA

- the key enzyme is HMG-CoA reductase

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14
Q

cholesterol is transported from the liver in what?

A

transported from the liver in VLDL

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15
Q

can the body degrade cholesterol?

A

body cannot degrade cholesterol

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16
Q

how is cholesterol excreted?

A

Cholesterol is eliminated from the liver as:

1) unmodified cholesterol in bile
2) OR, converted into bile salts and secreted into the intestines

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17
Q

is cholesterol an energy source?

A

No, it’s not a molecule that can be broken down and used to synthesise energy

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18
Q

in humans, is the flux of cholesterol tightly regulated?

A

the flux of cholesterol is not tightly regulated

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19
Q

over time what happens to cholesterol in the body?

A

With time there is an accumulation of cholesterol in the tissues, particularly in the endothelial cells

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20
Q

why do we need to metabolise ethanol?

A

it’s only there as a consequence of either diet or lifestyle

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21
Q

even if you don’t drink, you will still have ethanol in your body- how?

A

your body will still produce ethanol directly or indirectly:

– Indirectly is through the gut flora, as gut bacteria produces alcohol which will be absorbed

– Also, ripe fruit contains an element of ethanol.

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22
Q

name the 2 routes of metabolising ethanol:

A
  1. Oxidation through the activity of alcohol dehydrogenase (90%)
  2. Microsomal oxidation using cytochrome P450 (10-20%)
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23
Q

Most of the alcohol we ingest is metabolised through the 1st route, when does this change?

A

changes when the consumption of alcohol increases

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24
Q

explain why is meant by ethanol representing “empty calories”

A

doesn’t contain many vitamin, fats etc.

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25
Q

explain the process of oxidation through the activity of alcohol dehydrogenase:

A
  1. ethanol –> acetaldehyde
    via alcohol dehydrogenase
  2. acetaldehyde –> acetate
    via aldehyde dehydrogenase
26
Q

name another compound alcohol dehydrogenase metabolises

A

methanol, which is metabolised to formaldehyde

27
Q

consequences of producing formaldehyde?

A
  • very toxic

- associated with paralysis, loss of consciousness and blindness

28
Q

caucasians have 2 isoforms of which enzyme?

A

ALDH

ALDH 1 and ALDH 2

29
Q

what is ALDH 2?

A

ALDH 2 is a mitochondrial enzyme with a low Km (ie. a high affinity for alcohol)

30
Q

a lot of ethnic groups have a reduced capacity of which ALDH type? what does reduced capacity mean (+ symptoms)?

A
  • their ALDH-2 enzyme is either absent or present in a form that is not active
  • this means they are intolerant/less tolerant to alcohol (40% of Chinese, Japanese, Mongolians, Koreans, Vietnamese, Indonesians and Native Americans)
  • symptoms of vasodilatation, facial flush, tachycardia and nausea
31
Q

what type of mutation causes the production of a faulty ALDH protein?

A

a single amino acid substitution, Glu to Lys

  • produces what is a dominant negative mutation. This is where an enzyme is generated which has no activity but acts as if it does
  • prevents metabolism of acetaldehyde even though there is a lot present.
32
Q

alcoholics can be treated with drugs that do what?

A
  • drugs that inhibit ALDH, inducing the symptoms experienced

- so, if a drinker starts to drink again they start to feel sick, so the aim is to remove the will to drink further

33
Q

NADH is not a good negative inhibitor of either ADH or ALDH which means what?

A

NADH generated in the cytosol will accumulate

34
Q

the metabolism of alcohol is not regulated by negative feedback, what does this mean?

A

large quantities of acetyl-CoA, NADH, and ATP are formed

35
Q

name pathways that are inhibited by the metabolism of ethanol:

A

AcoA, NADH and ATP inhibit glucose metabolism (glycolysis) by PFK and pyruvate dehydrogenase

NADH inhibits the TCA cycle and ACoA increases further

AcoA results in:

  • ketone body formation, which has an effect on circulating pH
  • stimulation of FA synthesis
36
Q

how do high levels of ethanol cause hyperlipidaemia?

A
  1. High levels of NADH inhibits fatty acid oxidation therefore FA accumulate in the liver
  2. Increase G-3-P production together with the above leads to increased TG formation
  3. TG are incorporated into VLDL and released into the blood causing hyperlipidaemia.
37
Q

what is the consequence of the high NADH/NAD ratio caused by metabolism of ethanol?

A
  • shifts the OAA in the TCA cycle to malate and the acetyl-CoA formed from ethanol is diverted to ketone body formation leading to alcohol induced ketoacidosis
  • pushes the activity of lactate dehydrogenase towards lactate resulting in lactic acidosis
  • inhibits gluconeogenesis, and in a fasting individual this would lead to hypoglycaemia
38
Q

why do these problems occur because of ethanol?

A
  • Oxidation of alcohol takes precedence over other nutrients
  • The metabolism of alcohol is not regulated by negative feedback
  • As a result, large quantities of acetyl-CoA, NADH, and ATP are formed
39
Q

what Microsomal Ethanol-Oxidising System (MESO) and what does it involve?

A
  • second route of metabolism
  • involves the oxidation by members of the cytochrome P450 family of enzymes.
  • uses NADPH which is required for the synthesis of the antioxidant glutathione
40
Q

what is the role of glutathione?

A

antioxidant
glutathione protects the body from oxidative stress. XS alcohol will lead to a situation where the body is less able to protect itself from oxidative stress

41
Q

what is acetaldehyde?

A
  • highly reactive and can accumulate with excessive ethanol intake
  • can inhibit enzyme function
  • in the liver this can lead to a reduction in the secretion of both serum protein and VLDL
  • can enhance free-radical production – leading to tissue damage such as inflammation and necrosis
42
Q

list the 3 stages of alcohol liver damage:

A

Stage 1: Fatty liver
-deposition of XS fat within the tissues of the liver-has a big effect on the function of the liver

Stage 2: alcoholic hepatitis
-groups of cells die resulting in inflammation

Stage 3: Cirrhosis
-includes fibrosis, scaring and cell death

43
Q

what is the consequence of the cirrhotic liver not functioning properly?

A
  • it can no longer act to detoxify the ammonia that is produced from the breakdown of proteins
  • so, ammonia will accumulate resulting in neurotoxicity, coma and death
44
Q

what are xenobiotics?

name some:

A

compounds with no nutritional value (body can’t deal with them as a food source)

  • plant metabolites
  • synthetic compounds
  • food additives
  • agrochemicals
  • cosmetics
  • by-products of cooking etc (when you BBQ you can produce chemicals which have 0 nutritional value)
  • drugs
45
Q

what type of compounds can be excreted easily in the urine, which compounds are more difficult?

A

water soluble compounds can be excreted easily in the urine, lipophilic compounds are more difficult

46
Q

what is the livers role in xenobiotic metabolism?

A

-the aim is to make the xenobiotics harmless and more readily disposed of by the kidney in urine or the gut in faeces

47
Q

what are the 3 common phases to xenobiotic metabolism?

A

Phase I
• Oxidation

Phase II
• Conjugation

Phase III
• Elimination

48
Q

describe Phase 1

A

Oxidation

  • the most common modification but also get hydroxylation and reduction
  • increases solubility of the molecule
  • introduces functional groups which enables participation in further reactions (which aid elimination)
  • these reactions are promoted by a family of enzymes called cytochrome P450
49
Q

describe cytochrome P450 enzymes? give an example of their action

A
  • Found mainly in liver and cells of the intestine
  • Make up a family of about 50 different enzymes, they are haem proteins and are related to the mitochondrial enzymes
  • Found in the ER
  • An example of their action would be the hydroxylation of ibuprofen
  • P450 enzymes are inducible by both by their own substrates (5-10 fold) but also related substrates (2-4 fold)
50
Q

describe Phase 2

A

conjugation

Xenobiotics are modified by addition of groups such as
• Glutathione
• Glucuronic acid
• Sulphate
• Modification with these groups increase solubility and targets them for excretion

51
Q

is the modification of xenobiotic compounds a single process?

A

NOT a single process- often multiple processes

compounds are often sequentially modified

52
Q

xenobiotic metabolism is a part of what?

A

part of the body’s natural defences

53
Q

why is liver and drug metabolism important?

A
  • Metabolism of drugs by the liver can play a significant role in their effectiveness
  • A drug taken orally will pass through liver first- you have to consider what the liver will do to the drug
  • Modifications made by the liver can significantly reduce the effectiveness of a drug, e.g. the liver may view it as something that has to be removed
  • Although this could also be advantageous eg. the liver may produce something that is therapeutically advantageous like a drug given as a prodrug as the basis that the liver will activate and circulate it.
54
Q

what does the body not distinguish between?

A

harmful compounds and beneficial compounds such as therapeutic drugs

55
Q

statins- what are they used for, how do they work and how are they degraded

A
  • Statins are used to regulate cholesterol metabolism
  • Work by inhibiting HMG-CoA reductase

-They are degraded by CYP3A4
o CYP3A4 activity is inhibited by grapefruit juice, statin levels can rise by 15 fold

56
Q

what is Aflatoxin B1 produced by?

A

The fungus Aspergillus flavus and found in peanuts (fungal contaminant of peanuts)

57
Q

what is Aflatoxin B1 activated by?

A

Aflatoxin is activated by P450 isoenzymes and leads to epoxide formation and hepatocarcinogenesis

58
Q

mechanism of paracetamol

A

look at ADME notes from sem 1

59
Q

What happens to the modified compounds?

A

Small water-soluble molecules <60,000kDa can be removed by the kidney

Actively transported in to bile and then into the intestines

The fate of these molecules are 3 fold
– Digestion
– Excretion
– Re-absorption via the enterohepatic circulation (this occurs with a fraction of molecules)

60
Q

so, is everything made by the liver excreted?

A

not everything made by the liver is excreted-some is ultimately reabsorbed

61
Q

what is t1/2?

A
  • the time required for 50% of a substance to be lost

- impacts how long you wait before you re-administer a drug

62
Q

summary- roles of the liver in the regulation of metabolism:

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 and excretion

• Synthesis of specialized molecules
– bile acids
– haemin

• Central role in the metabolism of xenobiotics

sem 2 Liver and GI (11 decks)

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