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GI > Metabolic functions of the liver > Flashcards

Metabolic functions of the liver Flashcards

1
Q

What is the liver extremely important in maintaining?

A

extremely important for maintaining constant blood glucose levels

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2
Q

How does the liver maintain constant blood glucose level?

A
  • 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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3
Q

What is the liver involved in the metabolism of?

A

involved in the metabolism of other sugars, such as fructose and galactose

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4
Q

What is the liver the major site of synthesis of?

A

liver is the major site for the synthesis of many serum proteins, such as albumin and the blood clotting factors.

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5
Q

What does the liver degrade, and particularly when?

A

liver degrades excess amino acids, particularly during gluconeogenesis

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6
Q

What is the liver the major site involving amino acids for?

A

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

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7
Q

What interaction is there between muscles and liver?

A

Gluconeogenesis in the liver allows the synthesis of glucose which can be transported to muscles when the muscle requires it

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8
Q

How much cholesterol is made by the liver?

A
  • 50% of cholesterol made in the body is made by the liver
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9
Q

Where is the rest of cholesterol made by?

A

rest made by intestine, adrenal cortex and reproductive tissue

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10
Q

How is cholesterol synthesized in the liver and what enzymes are involved?

A
  • Made from acetyl CoA and the key enzyme is HMG-CoA reductase
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11
Q

What is cholesterol transported as in the liver?

A
  • Transported from the liver as VLDL
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12
Q

How is cholesterol excreted from the body?

A
  • disposed of by the biliary system either as cholesterol or following conversion to bile acids/salts
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13
Q

How does cholesterol enter the livers cholesterol pool?

A
  • Cholesterol enters the livers cholesterol pool from a number of sources
    o dietary
    o de novo by extra-hepatic tissue
    o makes its own
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14
Q

What flux is not tightly regulated in humans?

A
  • In humans the flux of cholesterol is not tightly regulated. With time there is an accumulation of cholesterol in the tissues particularly in the endothelial cells
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15
Q

What are the 2 routes of the metabolism of ethanol?

A

– Oxidation through the activity of alcohol dehydrogenase

– Microsomal oxidation using cytochrome P450

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16
Q

How much ethanol does the body approximately metabolize per hour?

A
  • The body metabolises approximately 10g of alcohol/hour
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17
Q

What is methanol metabolised into?

A
  • Methanol is metabolised to formaldehyde
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18
Q

Side effect of formaldehyde and why?

A

associated with paralysis, loss of consciousness and blindness because its toxic

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19
Q

What drugs can alcoholics be treated with?

A
  • Alcoholics can be treated with drugs that inhibit ALDH thereby inducing the symptoms experienced
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20
Q

What is not a good negative inhibitor and therefore what will accumulate?

A
  • NADH is not a good negative inhibitor of either ADH or ALDH therefore NADH generated in the cytosol will accumulate
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21
Q

What are 3 problems with the metabolism 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
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22
Q

What pathways are inhibited by the metabolism of ethanol?

A
  • acetyl-CoA, NADH and ATP are formed and they inhibit glucose metabolism by inhibiting PFK and pyruvate dehydrogenase
  • NADH inhibits the TCA cycle and acetyl-CoA increases further
  • acetyl-CoA results in ketone body formation and the stimulation of fatty acid synthesis
  • Fatty acids are esterified to TG for export as VLDL
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23
Q

The steps and consequences due to high levels of NADH

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 leading to increased TG formation
  3. TG are incorporated into VLDL and released into the blood causing hyperlipidaemia.
  4. The high NADH/NAD ration 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
  5. The high NADH/NAD ration pushes the activity of lactate dehydrogenase towards lactate resulting in lactic acidosis
  6. The high NADH/NAD ration inhibits gluconeogenesis in a fasting individual this would lead to hypoglycaemia
24
Q

What is the second route of metabolism of ethanol?

A

Microsomal Ethanol-Oxidising System (MESO)

25
Q

What does MESO involve?

A

• Involves the oxidation by members of the cytochrome P450 family of enzymes

26
Q

What does MESO use and what is it required for?

A

• This system uses NADPH which is required for the synthesis of the antioxidant glutathione

27
Q

What is the reactivity of acetaldehyde like and with what can it accumulate with?

A

• Is highly reactive and can accumulate with excessive ethanol intake

28
Q

What can acetaldehyde inhibit?

A

can inhibit enzyme function

29
Q

What can acetaldehyde lead to i the liver?

A

ead to a reduction in the secretion of both serum protein and VLDL in the liver

30
Q

What can acetaldehyde enhance and what can this lead to?

A

Can also enhance free-radical production – leading to tissue damage such as inflammation and necrosis

31
Q

What are the 3 stages of alcohol liver damage?

A

Stage 1: Fatty liver
Stage 2: alcoholic hepatitis, groups of cells die resulting in inflammation
Stage 3: Cirrhosis which includes fibrosis, scaring and cell death

32
Q

What are xenobiotics?

A

compounds with no nutritional value

33
Q

What compounds are excreted more easily in the urine?

A

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

34
Q

What type of metabolism does the liver play a major role in?

A

Liver plays a major role in xenobiotic metabolism

35
Q

What is the aim in xenobiotic metabolism?

A
  • The aim is to make the xenobiotic harmless and more readily disposed of by the kidney in urine or the gut in faeces
36
Q

What are the 3 common phases in xenobiotic metabolsim?

A 
	Phase I
•	Oxidation
	Phase II
•	Conjugation 
	Phase III
•	Elimination
37
Q

What is the most common modification in phase 1?

A
  • Oxidation is the most common modification but also get hydroxylation and reduction
38
Q

What does modification in phase 1 increase?

A
  • Modification increases solubility
39
Q

What does phase 1(oxidation) introduce?

A
  • Introduces functional groups which enables participation in further reactions
40
Q

What promotes the reactions in phase 1?

A
  • These reactions are promoted by a family of enzymes called cytochrome P450
41
Q

Where is Cytochrome P450 mainly found?

A

• Found mainly in liver and cells of the intestine

42
Q

Where in the cells is cytochrome P450 found?

A

• They are found in the endoplasmic reticulum

43
Q

What are P450 induced by?

A

• P450 enzymes are inducible by both by their own substrates (5-10 fold) but also related substrates (2-4 fold)

44
Q

What happens to xenobiotics in phase 2(Conjugation)?

A
  • Xenobiotic are modified by addition of groups such as
  • Glutathione
  • Glucuronic acid
  • Sulphate
  • Modification with these groups increase solubility and targets them for excretion
45
Q

In phase 2, how are the compounds modified?

A

• Compounds are often sequentially modified

46
Q

What do statins regulate?

A
  • Regulate cholesterol metabolism
47
Q

What do statins inhibit?

A
  • Statins inhibit HMG-CoA reductase
48
Q

What are statins degraded by?

A
  • They are degraded by CYP3A4
49
Q

What can inhibit CYP3A4 activity?

A

o CYP3A4 activity is inhibited by grapefruit juice

50
Q

What is aflatoxin beta 1 produced by?

A

• Produced by the fungus Aspergillus flavus and found in peanuts

51
Q

What is aflatoxin activated by and what does it lead to the formation of what?

A

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

52
Q

What happens to modified small water soluble compounds?

A

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

53
Q

Where are modified compounds actively transported to?

A

• Actively transported in to bile and then into the intestines

54
Q

What is the fate of these modified compounds?

A

– Digestion
– Excretion
– Re-absorption via the enterohepatic circulation

55
Q

What is the Central Role of the Liver in the regulation of metabolism?

A
  • Regulation of carbohydrate metabolism
  • Regulation of fat metabolism
  • Regulation of protein metabolism
  • Cholesterol synthesis and excretion
  • Synthesis of specialized molecules
  • Central role in the metabolism of xenobiotics

GI (7 decks)

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