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GI > Liver Physiology > Flashcards

Liver Physiology Flashcards

1
Q

Structure of ferritin

A

Large spherical protein consisting of 24 noncovalently linked subunits
Subunits form a shell surrounding a central core
Core contains up to 5000 atoms of iron

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2
Q

Functions of the liver

A

Carbohydrate metabolism
Fat metabolism
Protein metabolism
Hormone metabolism
Toxin/drug metabolism and excretion
Storage
Bilirubin metabolism and excretion

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3
Q

Where is ferrritin found

A

In cytoplasm of cells and can also be found in the serum

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4
Q

What is the concentration of ferritin directly proportional to

A

Total iron stores in the body

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5
Q

Excess iron storage disorders

A

Hereditary haemochromatosis
Haemolytic anaemia
Sideroblastic anaemia
Multiple blood transfusions
Iron replacement therapy

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6
Q

Non-iron overload

A

Liver disease
Some malignancies
Significant tissue destruction
Acute phase response:
-Inflammation
-Infection
-Autoimmune disorders

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7
Q

Ferritin deficiency (iron deficiency)

A

Can result in anaemia

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8
Q

Ferritin less than 20ug/L

A

Depletion

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9
Q

Ferritin less than 12ug/L

A

Complete absence of stored iron

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10
Q

Average amount of iron absorbed each day

A

1-2 mg/day

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11
Q

Where is iron absorbed in the body

A

Duodenum

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12
Q

Where is iron stored

A

Liver parenchyma
Reticuloendothelial macrophages

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13
Q

Iron utilisation

A

Myoglobin in muscle
Haemoglobin

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14
Q

Which molecule stores iron

A

Ferritin

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15
Q

How many atoms of iron can a molecule of ferritin store

A

Up to 5000

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16
Q

Number of subunits in ferritin

A

24

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17
Q

Function of vitamins

A

Gene activators
Free-radical scavengers
Coenzymes or cofactors in metabolic reactions

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18
Q

Water soluble vitamin examples

A

Vitamin B and C

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19
Q

Fat soluble vitamin examples

A

Vitamins A, D, E and K

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20
Q

Vitamin A

A

Retinoids
Vertebrates ingest retinal directly from meat or produce retinal from carotenes

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21
Q

Sources of vitamin A

A

Retinols
Carotenoids

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22
Q

Sources of carotenoids

A

Tomatoes
Spinach
Carrots
Sweet potato

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23
Q

Sources of retinols

A

Dairy
Eggs
Cereal
Meat

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24
Q

Male daily requirement of vitamin A

A

0.6 mg/day

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25
Q

Female daily requirement of vitamin A

A

0.7 mg/day

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26
Q

Vitamin A functions

A

Vision
Reproduction
Growth
Stabilisation of cellular membranes

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27
Q

Vitamin A and vision

A

Used to form rhodopsin in the rod cells of the retina

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28
Q

Vitamin A and reproduction

A

Spermatogenesis in male
Prevention of fetal resorption of female

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29
Q

Vitamin A deficiency

A

Rare in affluent countries as vitamin A levels drop only when liver stores are severely depleted.
Deficiency may occur due to fat malabsorption
Clinical Features:
-Night blindness
-Xeropthalmia
-Blindness

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30
Q

Clinical features of vitamin A deficiency

A

Night blindness
Xerophthalmia- inability to produce tears
Blindness

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31
Q

What molecules does the liver store

A

Ferritin
Vitamins
Clotting factors

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32
Q

Acute vitamin A excess

A

Abdominal pain, nausea and vomiting
Severe headaches, dizziness, sluggishness and irritability
Desquamation of the skin

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33
Q

Chronic vitamin A deficiency

A

Joint and bone pain
Hair loss, dryness of the lips
Anorexia
Weight loss and hepatomegaly

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34
Q

Storage of water soluble vs fat soluble vitamins

A

Water soluble vitamins pass more readily through the body so require more regular intake than fat soluble vitamins
Fat soluble vitamins more readily stored

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35
Q

Carotenemia and vitamin A excess

A

Reversible yellowing of the skin
Does not cause toxicity

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36
Q

Vitamin D functions

A

Increased intestinal absorption of calcium
Resorption and formation of bone
Reduced renal excretion of calcium

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37
Q

Sources of vitamin D

A

Sunlight
Vitamin D3 = fish, meat
Vitamin D2= supplements

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38
Q

Vitamin D deficiency

A

Demineralisation of bone:
- rickets in children
- osteomalacia in adults

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39
Q

Where is vitamin E stored

A

Non-adipose cells such as liver and plasma - labile and fixed pool
Adipose cells- fixed pool

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40
Q

Function of vitamin E

A

Important antioxidant

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41
Q

Male daily vitamin E requirements

A

4 mg/day

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42
Q

Female vitamin E daily requirements

A

3 mg/day

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43
Q

Sources of vitamin E

A

Nuts
Oils
Avocado
Carrots
Spinach

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44
Q

Causes of vitamin E deficiency

A

Fat malabsorption eg cystic fibrosis
Premature infants
Rare congenital defects in fat metabolism eg abetalipoproteinaemia

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45
Q

Vitamin D3

A

Cholecalciferol

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46
Q

What does liver convert vitamin D3 to

A

25-hydroxyvitamin D3

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47
Q

Which molecule maintains calcium balance in the body

A

1,25-dihydroxyvitamin D3

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48
Q

Which organ converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D

A

Kidney

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49
Q

Clinical manifestations of vitamin E deficiency

A

Haemolytic anaemia
Myopathy
Retinopathy
Ataxia
Neuropathy

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50
Q

Vitamin E excess

A

Relatively safe

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51
Q

Fixed pool of vitamin E

A

Adipose cells

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52
Q

Labile and fixed pool of vitamin E

A

Non-adipose cells such as liver and plasma

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53
Q

Types of vitamin K

A

K1
K2
K3
K4

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54
Q

Vitamin K1

A

Phylloquinone
Synthesised by plants and present in food

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55
Q

Vitamin K2

A

Menaquinone
Synthesised in humans by intestinal bacteria

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56
Q

Synthetic vitamin Ks

A

K3
K4

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57
Q

Vitamin K3

A

Menadione
Synthetic

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58
Q

Vitamin K4

A

Menadiol
Synthetic

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59
Q

Vitamin K and the liver

A

Rapidly taken up by the liver
Transferred to very low density lipoproteins (VLDL) and low density lipoproteins (LDL) which carry it into the plasma

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60
Q

Functions of vitamin K

A

Activation of some blood clotting factors
Necessary for liver synthesis of plasma clotting factors II, VII, IX , X

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61
Q

How to measure vitamin K levels

A

Prothrombin time

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62
Q

Sources of vitamin K

A

Green leafy vegetables
Sunflower pil

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63
Q

Vitamin K deficiency

A

Haemorrhagic disease of the newborn: vitamin K injection given to newborn babies
Rare in adults unless on warfarin

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64
Q

Vitamin K excess

A

K1 is relatively safe
Synthetic forms are more toxic
Can result in oxidative damage, red cell fragility and formation of methaemoglobin.

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65
Q

Functions of vitamin C

A

Collagen synthesis
Antioxidant
Iron absorption

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66
Q

Adult daily requirement of vitamin C

A

40 mg/day

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67
Q

Sources of vitamin C

A

Fresh fruit
Vegetables

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68
Q

Vitamin C deficiency

A

Scurvy:
Easy bruising and bleeding
Teeth and gum disease
Hair loss

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69
Q

Treatment of vitamin C deficiency

A

Treated with vitamin C
Improves symptoms quickly
Joint pain gone within 48 hours
Full recovery within 2 weeks

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70
Q

Vitamin C excess

A

Doses > 1g/day can cause GI side effects
No evidence that increased vitamin C reduces the incidence or duration of colds.

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71
Q

Vitamin B12

A

Cobalamins

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72
Q

2 active forms of vitamin B12

A

Methylcobalamin
5-deoxyadenosylcobalamin

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73
Q

Where is vitamin B12 released from

A

Food by acid and enzymes in stomach

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74
Q

Transportation of vitamin B12

A

Binds to R protein to protect it from stomach acid
Released from R proteins by pancreatic polypeptide
Intrinsic factor produced by the stomach needed for absorption
IF-B12 complex absorbed in terminal ileum

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75
Q

Where is vitamin B12 stored

A

Liver

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76
Q

Where is intrinsic factor produced

A

Stomach

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77
Q

Which protein protects vitamin B12 from stomach acid

A

R protein

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78
Q

What molecule is needed for absorption of Vitamin B12

A

Intrinsic factor

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79
Q

Where is IF-B12 complex absorbed

A

Terminal ileum

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80
Q

Sources of Vitamin B12

A

Meat
Fish
Eggs
Milk

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81
Q

Which enzyme releases vitamin B12 from R protein

A

Pancreatic polypeptide

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82
Q

Causes of vitamin B12 deficiency

A

Pernicious anaemia – autoimmune destruction of IF-producing cells in stomach.
Malabsorption – lack of stomach acid, pancreatic disease, small bowel disease.
Veganism

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83
Q

Symptoms of vitamin B12 deficiency

A

Macrocytic anaemia
Peripheral neuropathy in prolonged deficiency

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84
Q

Folate

A

found in may foods fortified with folic acid.
Individuals have higher requirements in pregnancy.

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85
Q

Functions of folate

A

Coenzyme in methylation reactions
DNA synthesis
Synthesis of methionine from homocysteine

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86
Q

Causes of folate deficiency

A

Malabsorption
Drugs that interfere with folic acid metabolism (anticonvulsants, methotrexate)
Disease states that increase cell turnover (e.g. leukaemia, haemolytic anaemia, psoriasis)

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87
Q

Symptoms of folate deficiency

A

High homocysteine levels
Macrocytic anaemia
Foetal development abnormalities (neural tube defects)

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88
Q

Clotting factors

A

Intrinsic pathway activated by contact
Extrinsic pathway activated by FVII coming in contact with tissue factor
Initiates a cascade which ultimately results in fibrin clot formation

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89
Q

What is intrinsic clotting pathway activated by

A

Contact

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90
Q

What is extrinsic clotting pathway activated by

A

FVII coming in contact with tissue factor

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91
Q

Clotting factors produced by the liver

A

I (fibrinogen)
II (prothrombin)
IV
V
VI
VII

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92
Q

Performance of clotting pathways measured using

A

Prothrombin time (extrinsic pathway)
International normalised ratio
Activated partial thromboplastin time (aPTT) (intrinsic pathway)

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93
Q

What measures extrinsic clotting factor

A

Prothrombin time

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94
Q

What measures intrinsic clotting pathway

A

Activated partial thromboplastin time

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95
Q

Prolonged PT

A

May indicate a deficiency in the synthetic capacity of the liver

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96
Q

Causes of prolonged prothrombin time

A

Liver disease
DIC
severe GI bleeding
Some drugs
Vitamin K deficiency

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97
Q

Unwanted dietary components

A

Xenobiotics

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98
Q

How many phases are there of biotransformation reactions

A

2

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99
Q

Phase I biotransformation reactions

A

Functionalisation - non synthetic
Add or expose functional groups -OH, -SH, -NH2, -COOH

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100
Q

Phase II biotransformation reactions

A

Conjugation- biosynthetic
Conjugation with endogenous molecules: glucuronic acid, sulphate, glutathione
Covalent bonds formed

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101
Q

Purpose of xenobiotic biotransformation reactions

A

Make compounds non-toxic and water soluble

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102
Q

Xenobiotics

A

foreign substances that don’t have nutritional value. Xenobiotic compounds are mostly in the diet, but we also breathe in potential toxins, and importantly the body treats medications as xenobiotics.

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103
Q

Phase I and hydrophilicity

A

Small increase

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104
Q

Phase II and hydrophilicity

A

Large increase

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105
Q

Glucuronides

A

Polar and hydrophilic
Eg paracetamol

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106
Q

glucuronyl group

A

has a number of hydroxyl groups which make the molecule polar and facilitate excretion in the urine.

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107
Q

Where does detoxification take place

A

Most in liver
some takes place in the lungs & small intestine before compounds are absorbed into the bloodstream.

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108
Q

Detoxification in liver

A
  • inactivation and facilitated elimination of drugs and other xenobiotics
  • active metabolites formed, with similar or occasionally enhanced activity
  • activation of pro-drugs
  • toxification of less toxic xenobiotics
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109
Q

Where does biotransformation occur in liver cells

A

Smooth endoplasmic reticulum

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110
Q

Coding for cytochrome P450 enzymes

A

Encoded by a superfamily of more than 50 different genes in humans

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111
Q

Common features of cytochrome P450 enzymes

A

All present in sER- microsomal enzymes
All oxidise the substrate and reduce oxygen
All have a cytochrome reductase subunit which uses NADPH
Are inducible- enzyme activity may be increased by certain drugs, some dietary components and some environmental toxins eg smoking
Generate a reactive free radical compound

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112
Q

What can cytochrome P450 enzymes be induced by

A

Certain drugs, some dietary components, some environmental toxins eg smoking

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113
Q

What does the cytochrome reductase subunit use

A

NADPH

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114
Q

Phase I reactions- oxidation

A

Hydroxylation (addition of -OH groups)
N- and O- dealkylation (removal of -CH side chains)
Deamination (removal of -NH side chain)
Epoxidation (formation of epoxides)

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115
Q

Phase I reactions - reduction

A

Hydrogen addition (unsaturated—>saturated)
Donor molecules include GSH, FAD, NAD(P)H

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116
Q

Phase I reactions - hydrolysis

A

Splitting of C-N-C (amide) and C-O-C (ester) bonds

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117
Q

Reason for biotransformation reactions

A

To be filtered and excreted in the urine a molecule needs to be polar (thus more hydrophilic) increasing its solubility
Can occur via 2 methods

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118
Q

Phase II reactions

A

Glycoside conjugation - glucuronidation (most common)
Sulphate - sulphation
Glutathione (GSH)

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119
Q

Example of molecule that can go straight to phase II biotransformation reactions

A

Morphine

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120
Q

Pharmacokinetics

A

A = absorption
D - distribution
M = metabolism
E = elimination/excretion

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121
Q

Effect of xenobiotics

A

Damage proteins, lipids and can bind to DNA (carcinogens)

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122
Q

Mechanism of Xenobiotics

A

React with O2 and release free radicals

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123
Q

Why do most medications require 2 phase biotransformation

A

Tend to be lipophilic, non-polar and non-ionised at physiological pH to allow pharmaceutical action

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124
Q

Location of microsomal enzymes

A

Smooth ER of liver, kidneys and intestinal mucosa

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125
Q

Microsomal enzymes

A

Mono-oxygenases (CYPs, FMOs)

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126
Q

Reaction of microsomal enzymes

A

Majority of drug biotransformation

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127
Q

Are microsomal enzymes inducible

A

Yes by diet and drugs

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128
Q

Location of non-microsomal enzymes

A

Cytoplasm and mitochondria of hepatocytes

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129
Q

Non-microsomal enzymes

A

Protein oxidases, esterases etc

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130
Q

Reaction of non-microsomal enzymes

A

Non-specific enzymes for conjugation

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131
Q

Are non-microsomal enzymes inducible

A

No but have polymorphisms

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132
Q

Which organ excretes drugs and metabolites

A

Kidney

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133
Q

When are cytochrome-P450 enzymes required

A

Phase I biotransformation

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134
Q

Which cytochrome-P450 enzyme is in highest concentration

A

CYP3A4
Responsible for 2/3 all known drugs

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135
Q

How many main groups of cytochrome-P450 are there

A

At least 10

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136
Q

Enzyme induction of cytochrome-P450

A

Molecule binds to an intracellular receptor within the cytoplasm
This molecule-receptor complex migrates to the nucleus
Increases transcription of mRNA for cytochrome-P450s
Increases the effect of the CYP
One substance can induce a number of enzymes

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137
Q

cytochrome-P450 mechanism of action

A

Contain a haem component which is capable of oxidising molecules (-OH addition) by becoming reduced themselves
The reductase use NADPH to become active
It reduces CYPs allowing the oxidation of the foreign molecule
Reaction forms water and has an intermediate of a haem free radical
Overall the addition of the -OH group increases the solubility of the molecule

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138
Q

What 3 things can metabolism of compounds results in

A

Complete inactivation and elimination
Formation of another active compound
Activation of pro-drugs
Toxification of less toxic Xenobiotics
Active drug to reactive intermediates

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139
Q

Phase III

A

Removal of drugs/ metabolites by transporter-mediated elimination via the liver gut kidney and lung

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140
Q

Where does phase III occur

A

Liver
Gut
Kidney
Lung

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141
Q

Complete inactivation and elimination

A

Eg phenobarbital (barbiturate derivative)
Metabolised using phase I and II
distributed into fat and bound to plasma proteins so metabolism is slow

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142
Q

Formation of another active component

A

Can have similar or new activity
Eg codeine breaking down into morphine
Eg diazepam into oxazepam

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143
Q

Activation of pro-drugs

A

Eg hetacillin converted into ampicillin
Eg into-glycerine into nitric oxide

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144
Q

Active drug to reactive intermediates

A

Eg benzopyrene in cigarette smoke
Bind to DNA and induce CYPs which increase epoxide levels

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145
Q

CYP and smoking

A

CYP1A2 can be induced by smoking
This increased activity has effects on metabolism of other molecules
Eg clozapine- dose has to be tightly controlled depending on how much the patient smokes

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146
Q

CYP and grapefruit

A

Grapefruit juice has effects on medications eg statins
Contains products that inhibit CYPs
Statins become more potent
Grapefruit is contraindicated

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147
Q

CYP2E1 and paracetamol

A

Usually disposed of safely by glucuronidation (50%) as glucuronide has a lot of -OH groups, also by sulfation (40%)
Harmful intermediate NAPQI is created from CYP2E1 (10%)
If normal pathways are overwhelmed, CYP2E1 becomes more significant and more NAPQI created- normally metabolised by glutathione-S-transferase but this is overwhelmed by high levels
Hepatocytes then become damaged

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148
Q

CYP2E1 and ethanol

A

Uses the same enzyme as paracetamol so has a dual effect when taken together
Enzymes are induced by 2 factors
More likely to go done the harmful route- enzymes overwhelmed

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149
Q

Treatment for paracetamol overdose

A

Acetylcysteine

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150
Q

Acetaminophen——> conjungation ——> elimination

A

Glucuronidation
Sulfation

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151
Q

Acetaminophen——> NAPQI

A

CYP450

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152
Q

NAPQI ——> conjugation ——> elimination

A

GSH

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153
Q

NAPQI ——> adducts NO-, O2 nitration peroxidation ——> cell death

A

GSH-depletion

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154
Q

Ethanol and alcohol dehydrogenase

A

Alcohol is polar but also slightly lipid soluble
Can be excreted (2-10%) but is more commonly used as fuel
Metabolised in acetaldehyde (tocis)
Further metabolism to acetate by ALDH which can be used in Kreb’s cycle
This second metabolism becomes overwhelmed and acetaldehyde builds up

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155
Q

What percentage of ethanol is excreted

A

2-10%

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156
Q

First metabolism reaction of ethanol

A

Acetaldehyde

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157
Q

Acetaldehyde—> acetate

A

ALDH

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158
Q

What is acetaldehyde converted to

A

Acetate

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159
Q

Ethanol and microsomal system- uses CYP2E1

A

Microsomal ethanol oxidising system (MEOS) also produces acetaldehyde
Chronic alcohol use increases CYP2E1 levels 5-10 fold therefore alcohol is metabolised quicker
Acetaldehyde is produced quicker and in larger quantities- more toxic
Results in liver damage from the production of free radicals

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160
Q

2 processes that produce acetaldehyde from ethanol

A

Microsomal ethanol oxidising system
Alcohol dehydrogenase

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161
Q

Inhibition cytochrome P450 enzymes

A

can result in increased blood concentrations of certain medications (less breakdown).

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162
Q

Suitable molecule that can bind to nuclear hormone receptor

A

phenobarbital

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163
Q

Vitamin D produced in the body

A

Cholecalciferol

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164
Q

Vitamin D found in food

A

Ergocalcaiferol

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165
Q

Which vitamin protects vitamin A

A

Vitamin E

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166
Q

How much vitamin B12 is stored in the body

A

2-5 mg

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167
Q

What percentage of vitamin B12 is stored in the liver

A

50%

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168
Q

Vitamin metabolism

A

Liver is important in metabolic activation of vitamin D

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169
Q

3 types of jaundice

A

pre-hepatic, hepatic or post-hepatic

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170
Q

Pre-hepatic jaundice

A

caused by increased haemolysis- results in increased presence of unconjugated bilirubin in the blood as the liver is unable to conjugate it all at the same rate
• Any bilirubin that manages to become conjugated will be excreted normally, yet it is the unconjugated bilirubin that remains in the blood stream to cause the jaundice.

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171
Q

Causes of pre-hepatic jaundice

A

• Tropical disease eg malaria, yellow fever
• Genetic disorders eg sickle-cell anaemia, Gilbert’s syndrome
• Haemolytic anaemias

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172
Q

Hepatic jaundice

A

caused by liver impairment- causes the decreased ability of the liver to conjugate bilirubin, resulting in the presence of conjugated and unconjugated bilirubin in the blood
• The liver loses the ability to conjugate bilirubin, but in cases where it also may become cirrhotic, it compresses the intra-hepatic portions of the biliary tree to cause a degree of obstruction. This leads to both unconjugated and conjugated bilirubin in the blood

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173
Q

Causes of hepatic jaundice

A

• Viral hepatitis
• Hepatotoxic drugs eg paracetamol overdose, alcohol abuse

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174
Q

Post-hepatic jaundice

A

caused by the blockage of bile ducts- results in back-flow of conjugated bilirubin into the blood as it cannot move past the obstruction
• bilirubin that is not excreted will have been conjugated by the liver, hence the result is a conjugated hyperbilirubinaemia.

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175
Q

Causes of post-hepatic jaundice

A

Gallstones
• Hepatic tumours
• Pancreatic tumours

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176
Q

Gilbert’s syndrome

A

• inherited disorder where there is hyperbilirubinaemia (excess bilirubin in bloodstream) due to a fault in the UGT1A1 gene leading to a deficiency in UPD-gluconoryltransferase.
• Results in slower conjugation of bilirubin in the liver so it builds up in the bloodstream
• When well, patients are usually asymptomatic and have normal bilirubin levels
• Under physiological stressors such as illness, alcohol abuse and extreme exercise, patients can become markedly jaundiced

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177
Q

Why does jaundice give you dark urine

A

excessive conjugated bilirubin excreted through the kidneys

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178
Q

Why does jaundice give you pale stool

A

reduced levels of stercobilin entering the GI tract. Obstructive or post-hepatic liver cause as normal faeces get their colour from bile pigments

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179
Q

Hepatobiliary system

A

Between adjacent hepatocytes, grooves in the cell membranes provide room for bile canaliculi: these are small ducts that accumulate the bile produced by hepatocytes. Bile flows first into bile ductules and then into bile ducts which unite to form the larger left and right hepatic ducts. These merge and exit the liver as the common hepatic duct. The common hepatic duct then joins with the cystic duct (from the gallbladder), forming the common bile duct which flows into the duodenum.

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180
Q

Bilirubin

A

yellow bile pigment produced through the breakdown of red blood cells (haemolysis). It is metabolised prior to excretion through the faeces and urine.
Bilirubin exists in 2 forms: conjugated and unconjugated. Unconjugated bilirubin is insoluble in water so can only travel in the bloodstream if bound to albumin and cannot be directly excreted from the body. Whereas, conjugated bilirubin is water soluble so it can travel in the bloodstream and excreted out of the body.

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181
Q

2 forms of bilirubin

A

Conjugated and unconjugated

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182
Q

Unconjugated bilirubin

A

insoluble in water so can only travel in the bloodstream if bound to albumin and cannot be directly excreted from the body

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183
Q

Conjugated bilirubin

A

water soluble so it can travel in the bloodstream and excreted out of the body.

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184
Q

Creation of bilirubin

A

reticuloendothelial cells are macrophages which are responsible for the maintenance of blood through destruction of old or abnormal cells. They take up red blood cells and metabolise the haemoglobin present into its individual components: haem and globin. Globin is further broken down into amino acids which are recycled. Haem is broken down into iron and biliverdin, catalysed by haem oxygenase. The iron is recycled and the biliverdin is reduced to form unconjugated bilirubin.

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185
Q

Bilirubin conjugation

A

In the bloodstream, unconjugated bilirubin binds to albumin to facilitate its transport to the liver. In the liver, glucuronic acid is added to unconjugated bilirubin by the enzyme glucuronyl transferase. This forms conjugated bilirubin, which is soluble, allowing it to be excreted into the duodenum in bile.

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186
Q

Bilirubin excretion

A

Once in the colon, colonic bacteria deconjugate bilirubin and convert it into urobilinogen. Around 80% is further oxidised by intestinal bacteria and converted to stercobilin and then excreted through faeces (giving it its colour). Around 20% of the urobilinogen is reabsorbed into the bloodstream as part of enterohepatic circulation. It is carried to the liver where some is recycled for bile production, and a small percentage reaches the kidneys. In the kidneys, it is further oxidised to urobilin and then excreted into the urine.

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187
Q

Which cells destroy old or damaged red blood cells (haemolysis)

A

reticuloendothelial cells

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188
Q

What is haemoglobin metabolised into

A

Haem and globin

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189
Q

What is globin broken into

A

Amino acids which are recycled

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190
Q

What is haem broken down into

A

Iron and biliverdin

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191
Q

Which enzyme breaks down haem

A

Haem oxygenase

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192
Q

What happens to the iron produced by haemolysis

A

It is recyled

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193
Q

What happens to biliverdin

A

It is reduced to form unconjugated bilirubin

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194
Q

What must unconjugated bilirubin bind to in order to be transported in blood

A

Albumin

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195
Q

Where is unconjugated bilirubin conjugated

A

Liver

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196
Q

Which enzyme conjugates bilirubin

A

glucuronyl transferase

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197
Q

What is added to unconjugated bilirubin to form conjugated bilirubin

A

Glucuronic acid

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198
Q

How is conjugate bilirubin excreted from the liver

A

In the bile into the duodenum

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199
Q

What happens to conjugated bilirubin in the colon

A

Colonic bacteria deconjugates it forming urobilinogen

200
Q

What is formed in the colon from conjugated bilirubin

A

Urobilinogen

201
Q

What happens to 80% of the urobilinogen

A

further oxidised by intestinal bacteria and converted to stercobilin and then excreted through faeces (giving it its colour)

202
Q

What gives faeces its colour

A

Stercobilin

203
Q

What happens to 20% of the urobilinogen formed

A

reabsorbed into the bloodstream as part of enterohepatic circulation. It is carried to the liver where some is recycled for bile production, and a small percentage reaches the kidneys. In the kidneys, it is further oxidised to urobilin and then excreted into the urine.

204
Q

Where is urobilinogen metabolised before excretion in the urine

A

Kidneys

205
Q

What is urobilinogen oxidised to in the kidneys

A

Urobilin

206
Q

What is urobilinogen oxidised to by intestinal bacteria

A

Stercobilin

207
Q

Scheme of principal blood flow through the liver

A

Heart —> abdominal aorta —> hepatic artery proper —> liver —> hepatic veins —> inferior vena cava —> heart

208
Q

Microanatomy of liver

A

Organised in lobules with a central hepatic wein
Hexagon- portal triads in the corners

209
Q

Number of functions of the liver

A

Approximately 500

210
Q

Main functions of liver

A

Detoxification - filters and cleans blood of waste products (drugs, hormones)
Immune functions - fights infections and diseases (RE system)
Involved in synthesis of clotting factors, proteins, enzymes, glycogen and fats
Production of bile and breakdown of bilirubin
Energy storage- glycogen and fats
Regulation of fat metabolism
Ability to regenerate

211
Q

Metabolic role of the liver

A

Maintains a continuous supply of energy for the body by controlling the metabolism of CHO and fats

212
Q

What is the liver regulated by

A

Endocrine glands eg pancreas, adrenal, thyroid
Nerves

213
Q

Lipid definition

A

Esters of fatty acids and glycerol or other compounds (cholesterol)
Large and diverse group of naturally occurring organic compounds that are insoluble in water
Variety of structure and functions

214
Q

Tri(acyl)glycerides TG, TAG

A

1 glycerol molecule esterified to 3 fatty acids bonded at carboxylate head

215
Q

Function of triglyceride

A

Storage form of fat in our body
-adipocytes
-hepatocytes
-elsewhere

216
Q

Saturated fatty acid

A

Lining up close together
Esters are solid at room temperature
Solid ‘fats’

217
Q

Unsaturated fatty acids

A

Needs more space due to kink in chain
Less tightly packed
MUFA, PUFA
Esters are liquid at room temperature
‘Oils’

218
Q

Lipid functions

A

Energy reserve
Structural and other functions
Hormone metabolism

219
Q

Lipid functions: structural and other functions

A

Part of cell membranes
Integral to form and functions of cells
Inflammatory cascade (LC-PUFAs precursors to eicosanoids, eg prostaglandins)

220
Q

Lipid functions: inflammatory cascade

A

LC-PUFAs precursors to eicosanoids e.g. prostaglandins

221
Q

Lipid functions: hormone metabolism

A

Cholesterol is backbone of adrenocorticoid and sex hormones
Vitamin D

222
Q

Lipids yield how much energy per gram

A

9-10 kcal

223
Q

Lipid reserve 100000 kcal can last how long

A

30-40 days

224
Q

Lipid transport

A

Often transported as TGs or FAs bound to albumin or within lipoproteins
Triglycerides cannot diffuse through cell membrane
Fatty acids are released through lipases to facilitate transport into cells- in the cell re-esterified to triglycerides

225
Q

Fatty acid uptake

A

Diffusion through the lipid bilayer of the cell membrane
Facilitated transport

226
Q

Facilitated transport of fatty acids

A

Increases if increased substrate or increase in receptor molecules
Several transporter systems

227
Q

Transporter systems for facilitated diffusion of fatty acids

A

FA binding protein = mitochondrial AST - induction to increased expression may result in increased uptake of fatty acid in hepatocytes
FAT -fatty acid translocase
FATP- fatty acid transport polypeptide

228
Q

Trans fats

A

Hardly kinked
Hard to metabolise

229
Q

What percentage of dietary fats of triglycerides

A

90%

230
Q

Proportion of western diet that are dietary fats

A

1/3

231
Q

What inhibits absorption of cholesterol in small intestine

A

Ezetimibe

232
Q

Bile acids

A

polar derivates of of cholesterol - aid diestestion of fats and fat soluble vitamins
Ba are amphipathic and emulsify fat globules into smaller miclelles -= hence higher surface area for lipid hydrolysing emzymes – they act as detergents (washing up liquid)

233
Q

Secretion of bile acids and cholesterol

A

Secretion of BA and cholesterol through bile is the only excretion mechansim of cholesterol

234
Q

Enterohepatic circulation

A

Reabsorption of bile acids and cholesterol in the ileum

235
Q

What can disrupt reabsorption of cholesterol in ileum

A

Resins- like cholestyramine
Diet- oat, bran fibre and fruit pectins

236
Q

Chylomicrons

A

From the gut are transported through the lymphatic system to be delivered to muscle and adipose tissue, bypassing the liver- protects the liver from a large fatty acid influx

237
Q

5 ways lipids accumulate in the liver

A

Excess intake - triglycerides in Chylomicrons remnants reach liver
Increased de novo synthesis
Increased fatty acid influx from lipolysis in adipocytes
Reduced export
Reduced oxidation in liver

238
Q

Action of insulin

A

Fat storage in adipocytes
Stimulates LPL (lipoprotein lipase)—> breakdown of triglycerides, releases free fatty acids to store )in form of TG) in adipocytes
Reduced activity of hormone sensitive lipase (HSL) leading to reduced fatty acid export from adipocytes

239
Q

Insulin resistance

A

Increased lipolysis in adipocytes leading to increased triglyceride in circulation
Increased ‘offer’ of fatty acids to hepatocytes leading to increased uptake
Increased glucose level leads to less demand for lipids to be used as energy source

240
Q

Normal fatty acid uptake into hepatocytes

A

Lipoprotein lipase —> free fatty acids —> facilitated diffusion into adipocytes—> triglycerides—> hormone sensitive lipase —> free fatty acid -> hepatic lipase —> facilitated diffusion into hepatocytes

241
Q

Enzymes involved in uptake of fatty acids

A

Lipoprotein lipase
Hormone sensitive lipase
Hepatic lipase

242
Q

What is De novo lipogenesis in the liver dependent on

A

Insulin concentration and sensitivity

243
Q

Purpose of hepatic de novo lipogenesis

A

Export in lipoproteins as energy source and structural components for membranes

244
Q

De novo lipogenesis in the liver

A

Sequential extension of alkanoic chain staring from Acetyl-CoA via serial decarboxylative condensation reactions

245
Q

Control of de novo lipogenesis in the liver

A

Nutrition and hormones
High KH diet increases hepatic lipogenesis- KH are burnt to generate ATP, surplus glucose fills glycogen stored and further surplus is converted to fatty acids
Fasting and fat feeding inhibit it

246
Q

De novo lipogenesis in adipocytes

A

Long term energy storage

247
Q

SREBP-1c

A

Activated fatty acid synthase

248
Q

ChREBP

A

Carbohydrate response element binding protein

249
Q

Dietary protein intake

A

0.75g/kg/day

250
Q

Loss of nitrogen

A

Faecal loss- 10g/day
Renal excretion- 70g/day in form of urea
Skin/hair/sweat loss

251
Q

Positive nitrogen balance examples

A

Pregnancy
Lactation
Bodybuilder and anabolic steroids
Recovery ohase

252
Q

Negative nitrogen balance examples

A

Protein malnutrition
Severe illness/sepsis/trauma/burns
Corticosteroids
Cahexia: malignancy/heart failure/uraemia
Essential amino acid deficiency

253
Q

Nitrogen balance

A

concept that compares the amount of nitrogen (overwhelmingly in the form of dietary proteins) that enters the body compared to that which is excreted from the body. Nitrogen is said to be in balance when the two are roughly equal (+/- 4g/day)

254
Q

Positive nitrogen balance

A

Intake of nitrogen greater than excretion
Anabolic- gain of protein

255
Q

Negative nitrogen balance

A

Excretion is greater than intake
Catanolism- loss of protein

256
Q

3 main fates of amino acids

A

they can be incorporated ‘as is’ with other amino acids to form peptides and proteins
they can be modified to form other biomolecules such as nucleotide bases and neurotransmitters
they can have their nitrogenous amino group removed (to be excreted as urea) and have their ‘carbon backbone’ reutilised for energy, either via the Citric acid cycle or through the formation of glucose via gluconeogenesis.

No amino acid is stored.

257
Q

Kwashiorkor

A

Adequate calories but inadequate proteins
Protein-energy metabolism
Features: oedema , fatty liver, dermatoses

258
Q

Marasmus

A

Both protein and calories insufficient

259
Q

Amino acid metabolism: fed state

A

Amino acids are absorbed from the gut and enter the portal circulation where they travel to the liver, which is the centre for the majority of metabolic processes. Accordingly, it is also the site where most of the humoral, that is to say, blood-bourne proteins are formed.
They may be utilised here in protein formation, or be used to form other nitrogen-containing compounds.
Some enter the systemic circulation to supply the builiding blocks of protein to different bodily tissues.

Those which cannot be used in such a fashion have their amino groups removed and their carbon backbones used as metabolic substrates, helping to form carbohydrates like glucose from gluconeogenesis or fatty acids to form triacylglycerols.

260
Q

GI proteolysis

A

Dietary protein —> denatured protein —> oligopeptides and AAS —> amino acids in blood stream (active transport)

261
Q

What converts dietary protein to denatured protein

A

HCl and pepsin in stomach

262
Q

What converts denatured protein to oligopeptides and AAs

A

Chymotrypsin
Trypsin
Aminopeptidase
In small intestine

263
Q

What converts oligopeptides and AAs to amino acids in bloodstream

A

Enterocyte peptidases
In enterocytes

264
Q

Transportation of free amino acid into enterocyte

A

first stage is via a cell surface channel where it is cotransported with a sodium ion.
Then via the basal membrane is is actively transported into the portal veinous circulation by an ATP consuming process.
From there it travels into the liver.

265
Q

Glucogenic amino acids

A

Carbon backbone produces gluconeogenic/TCA cycle intermediates

266
Q

Ketogenic amino acids

A

Carbon backbone produces Acetyl-CoA/ Acetoacetyl-CoA

267
Q

Which amino acids are solely ketogenic

A

Leucine
Lysine

268
Q

Essential amino acids

A

Phenylalanine
Valine
Leucine
Isoleucine
Tryptophan
Methionine
Threonine
Histidine

269
Q

What are essential amino acids

A

Cannot be synthesised de novo in vivo

270
Q

Important hepatic proteins

A

Albumin
Coagulation factors
IGF-1
C-reactive protein
Carrier proteins eg caeruloplasmin
Apolipoproteins

271
Q

Importance of albumin

A

Maintains oncotic blood pressure
Important carrier protein eg for sex hormones, magnesium, calcium and drugs

272
Q

Glycine derivatives

A

Heme
Creatinine
Purine bases

273
Q

Biosynthetic pathways for nitrogen from amino acids

A

Can produce non-peptide molecules eg neurotransmitters, nitric oxide and nucleotides

274
Q

Aspartate derivatives

A

Purine and pyrimidine bases

275
Q

Arginine derivatives

A

Nitric oxide

276
Q

Tryptophan derivatives

A

Serotonin
Melotonin

277
Q

Tyrosine derivatives

A

Dopamine
Catecholamines (enable fight or flight response)
Thyroid hormones
Melanin

278
Q

Alpha-ketoacid

A

Carbon backbone after R group of amino acid cleaved
Used in kreb’s cycle eg alanine —>pyruvate

279
Q

Transamination enzyme

A

Aminotransferase (with PLP group)

280
Q

Transamination of alanine

A

Alanine + Alpha-ketoglutatate <—> pyruvate + glutamate
Alanine aminotransferase (ALT)

281
Q

Transamination

A

In most transamination reactions, a-ketoglutarate and glutamate form one of the a-ketoacid/amino acid pairs.

This means a-ketoglutarate is a receiver of nitrogen (the amino group), which is transferred to glutamate.

282
Q

Fate of nitrogen after degradation of amino acids

A

Forms ammonia (NH4+) which is combined with bicarbonate to form carbamyl phosphate
Enters urea cycle to produce urea which is excreted

283
Q

What enzyme converts glutamate to alpha-ketoglutarate

A

Glutamate dehydrogenase

284
Q

Other products when glutamate converted to alpha-ketoglutarate

A

NADP + H20 ——> NADPH + NH4+ (ammonium)

285
Q

What two molecules form carbamyl phosphate

A

Ammonium and bicarbonate

286
Q

Causes of Protein degradation

A

Faulty/aging/obsolete proteins
Signal transduction
Flexible system to meet protein/energy requirements of environment

287
Q

Main means of protein degradation

A

Proteasome (ubiquitin-dependent)
Lysosome

288
Q

Ubiquitin

A

Mark of death
Small protein
Carboxyl group forms isopeptide bond with multiple lysine residues
Formation of ubiquitin chains (stronger signal, especially >4)

289
Q

3 Enzymes involved with ubiquitin

A

Ubiquitin-activating enzyme
Ubiquitin-conjugating enzyme
Ubiquitin-protein ligase

290
Q

Proteasome

A

The executioner

291
Q

N-terminal rule

A

N-terminal residues determine protein half-life
PEST sequences (proline, glutamate, serine, threonine)
Cyclin destruction box

292
Q

Lysosomes

A

Proteolytic enzymes within lysosome separated from cytosolic components

293
Q

4 types of lysosomal mechanisms

A

Macroautography
Microautography
Chaperone-mediated autographs
Endocytosis/phagocytosis

294
Q

Macroautography

A

Non-selective
ER derived autophagisomes engulf cytosolic proteins/aggregates organelles
Lysosome fuses with this to initiate proteolysis

295
Q

Microautophagy

A

Non-selective
Invaginations of lysosomal membrane engulf proteins/organelles

296
Q

Chaperone-mediated autographs

A

Selective
Chaperone protein hsc70 in cytosolic and intralysomal accompany specific cytosolic proteins in response to stressors (fasting/oxidative stress etc)

297
Q

Endocytosis/phagocytosis

A

Extracellular substances

298
Q

Cystinosis

A

Autosomal recessive condition
1 in 200000
Defect in transporter leads to cystine accumulation in tissue lysosomes
Eye and kidney problems

299
Q

Cortisol activates

A

Proteolysis
Gluconeogenesis

300
Q

Cortisol inhibits

A

Protein synthesis

301
Q

Alanine - amino acid catabolism

A

Glucose-alanine cycle transports nitrogen from amino acid breakdown from the tissues to the liver, whilst recycling a carbon backbone that can be converted to glucose for energy

302
Q

Glutamine - amino acid catabolism

A

Formed from BCAA degradation in the tissues
In the fasting state, it is an important metabolic fuel for the kidney and gut and provides ammonia to buffer proton diuretics in metabolic acidosis states

303
Q

Branched chain amino acids - amino acid catabolism

A

Isoleucine/valine/leucine
Major amino acids that can be oxidised in tissues other than the liver, especially skeletal muscle

304
Q

Glucagon - amino acid catabolism

A

Stimulates:
Glycogenolysis
Gluconeogenesis
Amino acid degradation
Ureagenesis
Entry of amino acids to liver

305
Q

What percentage of cholesterol is endogenous

A

90%

306
Q

What percentage of cholesterol is dietary

A

10%

307
Q

Excretion of cholesterol

A

Through bile
Enterohepatic circulation

308
Q

Cholesterol is esterified intracellularly in lipoprotein by

A

Acyl-CoA or by lecithin by cholesterol acyltransferase

309
Q

Which enzymes esterifies cholesterol

A

Cholesterol acyltransferase

310
Q

What do lipoproteins consist of

A

A core containing triglycerides and cholesterol-esters
A surface monolayer of phospholipids cholesterol and specific proteins (eg apoproteins)

311
Q

What determine the density of lipoproteins

A

Protein to lipid ratio

312
Q

Types of lipoprotein

A

Chylomicrons
VLDL
LDL
HDL

313
Q

Chylomicrons lipoproteins

A

Largest lowest density
High lipid to protein ratio
Highest triglyceride content

314
Q

VLDL

A

Very low density lipoprotein
2nd highest in triglycerides as percentage of weight

315
Q

LDL

A

Low density lipoprotein
High cholesterol ester as percentage of weight
Raised by saturated fats and trans fatty acids

316
Q

HDL

A

High density lipoprotein
Low lipid to protein ratio

317
Q

Chylomicrons remnant

A

Taken up by the liver via receptor-mediated Endocytosis
Recognition of ApoE by hepatocyte surface receptors

318
Q

Where is Apoprotein B synthesised

A

Rough ER

319
Q

Fatty acid export

A

Microsomal TAG transfer protein adds the lipid components to ApoB
Transported in vesicle to Golgi apparatus where ApoB is glycosylates
This buds off the Golgi and migrate the sinusoidal membrane of the hepatocytes
Vesicle fuse with the membranes and VLDL is released

320
Q

What is fatty acid export rate limiting for

A

VLDL production

321
Q

What combines the lipid components to ApoB

A

Microsomal TAG transfer protein

322
Q

Where is ApoB glycosylated

A

Golgi apparatus

323
Q

Rate limiting steps of lipogenesis

A

Acetyl-CoA —> Malonyl-CoA
Catalysed by Acetyl-CoA carboxylase
Rate is also related to FAS-FA synthetase

324
Q

What converts acetyl-CoA to malonyl-CoA

A

Acetyl-CoA carboxylase

325
Q

Lipogenesis and fasting

A

Reduced in fasting
Hepatic glycogen stores depleted
Triglycerides broken down in adipocytes and more free fatty acids released
Oxidised in the liver as an energy source

326
Q

Inflow into the liver of lipids from

A

Portal vein
Hepatic artery
Lymphatics

327
Q

Lipids enter liver in form of

A

Triglycerides
Lipoproteins
Chylomicron remnants
HDL
(Often transported as triglycerides of fatty acids bound to albumin or within lipoproteins)

328
Q

Lipids from adipocytes to hepatocytes

A

Hormone sensitive lipase release free fatty acids
Hepatic lipase enables the uptake into hepatocytes

329
Q

Release of lipids from liver

A

Release controlled by hormones
Released as VLDLs, energy substrates and detoxified substrates
Storage capacity of far higher than demand

330
Q

Lipids bypassing the liver

A

Chylomicrons can bypass the liver as transported by lymphatic system
Protects liver from large fatty acid influx

331
Q

3 locations of lipid oxidation in liver

A

Peroxysomal beta-oxidation
Mitochondrial beta-oxidation
ER Microsomal Ω -oxidation (CYP4a catalysed)

332
Q

Lipid oxidation in the liver

A

Fatty acid oxidation is proportional plasma levels of free fatty acids released from adipocytes
Peripheral fatty acid mobilisation when increased glucagon and decreased insukin

333
Q

What causes fatty acid mobilisation

A

Increased glucagon
Decreased insulin

334
Q

What is fatty acid synthetase activated by

A

Insulin
Substrate (citrate, isocitrate)

335
Q

What is FA synthetase inactivated by

A

Catecholamines
Glucagon

336
Q

FAS

A

FA synthetase
Negative feedback- high FAS in hepatocytes inhibit FAS
Related to de novo lipogenesis in the liver

337
Q

Mitochondrial beta-oxidation

A

Primarily involved in oxidation of fatty acids of various chain length
Multistep process
Progressive shortening into acetyl -CoA subunits
- condensed into ketone bodies providing oxidisable energy to cells
- enter tricarboxyl acid cycle- resulting in H20 and CO2

338
Q

What is mitochondrial beta-oxidation regulated by

A

CPT (carnitine palmitosyl transferase), carnitine concentration and malonyl-CoA (which inhibits CPT)

339
Q

What leads to hepatic steatosis

A

Genetic disorders inhibiting mitochondrial oxidation, certain drugs eg alcohol and toxins

340
Q

Number of carbons - short chain fatty acid

A

<8

341
Q

Number of carbons - medium chain fatty acid

A

8-12

342
Q

Number of carbons - long chain fatty acid

A

12-20

343
Q

Dicarbolic acids

A

Very toxic
Inhibits mitochondrial fatty acid oxidation

344
Q

Peroxisomal beta-oxidation

A

4 step process is repeatedly performed to shorten chain length
Each step can be carried out by at least 2 enzymes

345
Q

Disruption of Peroxisomal beta-oxidation

A

Leads to micro-vesicular steatosis

346
Q

What are enzymes of Peroxisomal beta-oxidation induced by

A

PPARά

347
Q

Main role of Peroxisomal beta-oxidation

A

detoxification of
-very long chain fatty acids (>C 20)
-2-methyl-branched FAs
-Dicarbolic acids – very toxic – inhibiting mitochondrial fatty acid oxidation
-Prostanoids
-C-27 bile acid intermediaries

348
Q

Microsomal Ω -oxidation

A

Normally a minor metabolic pathway but in fat overload increases
CYP4A enzymes oxidise saturated and unsaturated fatty acids
Ω-hydroxylation in the ER, followed by decarboxylation of the Ω-hydroxy fatty acid in the cytosol – in turn enter the β-oxidation pathway
Dicarboxyl FA act as ligands to PPARά – induction of the oxidation systems

349
Q

PPARά

A

Lipid sensor- gene transcription
Its activity determines whether fatty acids are stored as triglycerides in hepatocytes or oxidised for energy

350
Q

How do fatty acids regulate gene expression

A

Control activity of key transcription factors

351
Q

Function of transcription factors

A

Integration of signals from diverse pathways
Co-ordination of the metabolic machinery for fatty acid metabolism

352
Q

Transcription factors controlled by fatty acids

A

Peroxisome proliferator-activated receptors
(PPAR ά, β and γ)
Retinoid X receptor (RXR)
Sterol regulator element binding protein (SREBP)

353
Q

Peroxisome proliferator activated receptor (PPAR)

A

All PPARs (ά, γ,β/ δ) are involved in lipid homeostasis
PPAR ά and β/ δ facilitate energy combustion
PPAR γ facilitates energy storage
PPAR ά is a lipid sensor – gene transcription
Reduced PPAR ά sensing/activity leads to steatosis, possible by induction of CYP2E1, proinflammatory cytokines and TFN ά

354
Q

Role of PPAR ά and β/ δ

A

Facilitate energy combustion

355
Q

PPAR γ

A

Facilitates energy storage

356
Q

Reduced PPAR ά

A

sensing/activity leads to steatosis, possible by induction of CYP2E1, proinflammatory cytokines and TFN ά

357
Q

Adiposities

A

Increased energy storage

358
Q

Developing fatty liver

A

Increase plasma in fatty acids (mainly in TG)
Excess dietary fat intake
Excess dietary caloric intake overall
But also increased flux of FAs
Increased release of FAs from adipocytes
Increased FA uptake in hepatocytes
Decreased FA oxidation
Decreased demand for lipids for fuel leading to
increased storage
Resulting in bland steatosis

Insulin resistance augments the process

359
Q

Non-alcoholic fatty liver

A

Overstorage of unmetabolised energy exceeding the energy combustion capability of the PPAR a mediated system

360
Q

Hepatic steatosis

A

Fat content exceeding 5-10% of the weight of the liver

361
Q

Incidence of NAFL - diabetic patients

A

50%

362
Q

Incidence of NAFL - obese patients

A

75%

363
Q

Incidence of NAFL - morbidly obese patients

A

98%

364
Q

Steatohepatitis

A

Increased steatosis (bland)
Apoptosis of fat-laden hepatocyte releases TG and toxic FAs
FAs induce CYP2E1 & FA oxidation systems →generation of reactive oxygen species (ROS) resulting in oxidative stress
Oxidative stress induces release of proinflammatory cytokines from Kupffer cells (hepatitis) and ROS (and ethanol) activates stellate cells (fibrogenesis)
Lipidperoxidation products develop immunogenic properties causing inflammation
Gut derived products (e.g. endotoxins) also activate Kupffer cells

365
Q

causes of change from NAFLD—>NASH

A

Adipose tissue inflammation
Gut microbiota
Oxidative stress
Hepatocyte apoptosis
Hepatic inflammation

366
Q

Stages of NAFLD

A

1 simple fatty liver (steatosis)- a largely harmless build-up of fat in the liver cells that may only be diagnosed during tests carried out for another reason. Benign and no liver damage. Reversible
2 non-alcoholic steatohepatitis (NASH)- a more serious form of NAFLD, where the liver has become inflamed- estimated to affect up to 5% of the UK population
3 fibrosis - where persistent inflammationcauses scar tissue around the liver and nearbybloodvessels, but the liver is still able to function normally
4 cirrhosis- the most severe stage, occurring afteryears of inflammation, where the liver shrinks and becomes scarred and lumpy; this damage is permanent and canlead toliver failure andliver cancer

367
Q

Stage 1 of NAFLD

A

simple fatty liver (steatosis)- a largely harmless build-up of fat in the liver cells that may only be diagnosed during tests carried out for another reason. Benign and no liver damage
Reversible

368
Q

Stage 2 of NAFLD

A

non-alcoholic steatohepatitis (NASH)- a more serious form of NAFLD, where the liver has become inflamed- estimated to affect up to 5% of the UK population

369
Q

Stage 3 of NAFLD

A

fibrosis - where persistent inflammationcauses scar tissue around the liver and nearbybloodvessels, but the liver is still able to function normally

370
Q

Stage 4 of NAFLD

A

cirrhosis- the most severe stage, occurring afteryears of inflammation, where the liver shrinks and becomes scarred and lumpy; this damage is permanent and canlead toliver failure andliver cancer

371
Q

Management of fatty liver disease

A

Diet and exercise
↓ Supply - Reduced intake of calories
↑ Demand – increased consumption

The body will get energy from the “compartment” least in demand e.g.
Exercise – fat burning
Illness – muscle protein utilisation

372
Q

Alcohol and liver fat

A

High caloric load – energy load
Metabolised in the liver – increased load leads to:
Impairment and inhibition of PPARά and SREBP
PPARά ↓ - ↓ fat oxidation
SREBP ↓ - ↑ FAS - lipogenesis
Damage to cell organelles – mitochondria, ER – reduced fat oxidation
Apoptotic hepatocytes release TG and very-long chain FA – augment liver injury
Stellate cell activation –leading to increased fibrogenesis

373
Q

Conditionally essential amino acid

A

Under certain circumstances they may be needed to be consumed in the diet eg dependent on consumption of other amino acids

374
Q

Examples of conditionally essential amino acids

A

Arginine
Cysteine
Glycine
Glutamine
Proline
Tyrosine

375
Q

Universal acceptor of amine groups

A

Alpha-ketoglutarate

376
Q

Transamination

A

Turning an amino acid into an intermediate in the TCA cycle
Catalysed an amino transferase eg pyridoxal phosphate (PLP) dervived from vitamin B6
Taking an amine group from an amino acid to an alpha-ketoacid
Turns it into an amino acid and becomes and alpha-ketoacid itself

377
Q

What is pyridoxal phosphate derived from

A

Vitamin B6

378
Q

Deamination

A

Glutamate is converted back to alpha-ketoglutamate by glutamate dehydrogenase
Produces ammonia
Remove via the urea cycle

379
Q

Molecular weight of albumin

A

66 kDa

380
Q

g/day of albumin produced by the liver

A

9-12
Can increase to 36

381
Q

Transcapillary escape rate

A

Rate of movement of albumin between vessels

382
Q

How does albumin leave circulation

A

Interstitium

383
Q

How is albumin returned to circulation

A

Thoracic duct (lymphatics)

384
Q

Functions of albumin

A

Binding and transport
Maintenance of colloid osmotic pressure
Free radicals
Anticoagulant effects

385
Q

Fed (anabolic) state

A

Amino acid surplus to requirement for protein synthesis can be metabolised to non-nitrogenous substances
Eg glucose , glycogen or fatty acids
Can be oxidised to generate ATP

386
Q

Fasting (catabolic) state

A

Alanine transported to hepatocytes in large quantities
Alanine aminotransferase transaminates the amino group from glutamate- producing pyruvate
Pyruvate substrate in TCA cycle to form glucose
Glutamate recycled back and urea is formed
Glucose taken up by muscle cells and used in glycolysis
Pyruvate produced and lactate released as a by-product
Pyruvate then converted back to alanine

387
Q

Glucose-alanine cycle - removal

A

Moves carbon atoms of pyruvate
Moves excess ammonia from muscle to liver as alanine
In liver, alanine yields pyruvate- starting block for gluconeogenesis
Releases ammonia for conversion into urea]
Energetic burden of gluconeogenesis imposed on liver rather than muscle (muscle ATP devoted to muscle contraction)

388
Q

Pyruvate is the metabolic precursor for

A

Alanine

389
Q

Oxaloacetate is the metabolic precursor for

A

Aspartate
Asparagine

390
Q

Alpha-ketoglutarate is the metabolic precursor for

A

Glutamate
Glutamine
Proline
Arginine

391
Q

3-phosphoglycerate is the metabolic precursor for

A

Serine
Cysteine
Glycine

392
Q

Phosphoenolpyruvate and erythrose-4-P is the metabolic precursor for

A

Tyrosine

393
Q

Which hormone drives all metabolic pathways in fed state

A

Insulin

394
Q

Pathways of increased glucose in liver in fed state

A
  1. Glycogenesis
  2. Pentose phosphate pathway
  3. Formation of GA3P and DHAP to then form 2 pyruvate
  4. Fatty acid synthesis
395
Q

Pentose phosphate pathway

A

Forms ribose-5-phosphate from glucose
Generates NADPH

396
Q

If high levels of Acetyl-CoA in the liver

A

Kreb’s cycle inhibited
Citrate is broken down into oxaloacetate and acetyl-coa by citrate ligase
Acety-CoA is converted to malonyl-CoA—-> fatty acids

397
Q

Intermediate between acetyl-CoA and fatty acids

A

Malonyl-CoA

398
Q

Where does the urea cycle take place

A

Partly in the cytosol and partly in the mitochondria

399
Q

Control of the urea cycle

A

Via up/down regulation of the enzymes responsible
Long-term changes in level of dietary protein can result in 20-fold up regulation - could be seen in both high protein diets and starvation (protein breakdown)

400
Q

The urea cycle overview

A
  1. Ammonia enters cycle by a Transamination reaction to form glutamate (recycle by deamination)
  2. NH3 moves into the mitochondria and reacts with HCO3- (with ATP) to form carbamoyl phosphate catalysed by carbamoyl phosphate synthase
  3. Carbmoyl phosphate reacts with ornithine to form citrulline catalysed by ornithine transcarbamylase
  4. Moves out into cytoplasm through transporter
  5. Reacts with aspartate and ATP to form arginine succinate catalysed by argininosuccinate synthase
  6. This breaks down into arginine and releases demarcate catalysed by argininosuccinate lyase
  7. Arginine reacts with water to produce ornithine releasing urea catalysed by arginase/ornithine aminotransferase
  8. Ornithine then re-enters the mitochondria to continue the cycle
401
Q

Major proteins synthesised in the liver

A

Albumin
CRP
Hormone binding globulins
Apolipoproteins
Other transport proteins eg caeruloplasmin, ferritin
Factors in the complement cascade
Inhibitors of clotting
Fibrinolysis
Inhibitors of fibrinolysis
Complement

402
Q

Which proteins does the liver not synthesise

A

Immunoglobulins

403
Q

What charge does albumin have

A

Negative

404
Q

Causes of hypoalbuminaemia

A

Inflammation
Liver disease
Renal disease
Burns/trauma
Sepsis
Malnutrition

405
Q

Consequences of hypoalbuminaemia

A

Oedema
Effusions
Carrier proteins

406
Q

Albumin calculations

A

Exudates vs Transudates
Adjusting for electrolytes – esp Ca2+
Adjusting for hormone levels – eg free testosterone
Renal disease

407
Q

Chronic liver disease and bleeding

A

Reduced synthesis of clotting factors
-Hepatic dysfunction
-Vitamin K deficiency/malabsorption
Reduced synthesis of inhibitors
Production of abnormal/dysfunctional proteins
Enhanced fibrolytic activity
-Reduced clearance of activators of fibrinolysis
-Reduced production of inhibitors
Reduced hepatic clearance of clotting factors
Disseminated intravascular coagulation
-Multifactorial – includes endotoxaemia
Platelet abnormalities
-Number
-Function
Development of varices

408
Q

Which vitamin is required for the liver to produce clotting factors

A

Vitamin K

409
Q

How is NH4+ produced via catabolism

A

Amino acid split into alpha-keto acid and NH4+

410
Q

Hypoalbuminaemia

A

Low blood albumin

411
Q

Urea cycles treatment

A

Avoidance of catabolism, glucose polymers when unwell
Induction of anabolism – give dextrose 10% 2ml/kg/hr -> insulin!
Low dietary protein, arginine, benzoate, phenylbutyrate
Haemofiltration
Liver transplantation, umbilical vein hepatocyte transfusion
Gene therapy: NIH NGVL UPenn trial stopped after death (adenovirus E1 E4 del., fever, multi-organ failure)

412
Q

What is the only anabolic hormone

A

Insulin

413
Q

Energy requirements of 1 cycle of urea cycle

A

Consumes 3 ATP molecules
4 high energy nucleotide PO4-

414
Q

How is the energy consumed by urea production generated

A

Production of the cycle intermediates

415
Q

Products of urea cycle

A

Urea is only compound generated
Other components are all recycled

416
Q

How does ammonia enter urea cycle

A

Transamination reaction to form glutamate

417
Q

How is glutamate recycled

A

Deaminatiom

418
Q

What does NH3 react with to form carbamoyl phosphate in urea cycle

A

HCO3- with ATP

419
Q

NH3 and HCO3- forms

A

carbamoyl phosphate

420
Q

Which enzyme catalyses production of carbamoyl phosphate

A

carbamoyl phosphate synthase

421
Q

What does carbamoyl phosphate react with to form citrulline

A

Ornithine

422
Q

carbamoyl phosphate and ornithine forms

A

Citrulline

423
Q

Which enzymes catalyses formation of citrulline

A

Ornithine transcarbamylase

424
Q

At what stage does the urea cycle go from mitochondria to cytoplasm

A

Citrulline moves out of mitochondria via a transporter

425
Q

What does citrulline react with to form arginine succinate

A

Aspartate and ATP

426
Q

Fate of NH4+

A

Biosynthesis of amino acids, nucleotides and biological amines
Excretion

427
Q

Citrulline and aspartate forms

A

Arginine succinate

428
Q

Which enzyme catalyses production of arginine succinate

A

Argininosuccinate synthase

429
Q

What does arginine succinate break down into

A

Arginine and fumarate

430
Q

Which enzyme catalyses the break down of arginine succinate

A

Argininosuccinate lyase

431
Q

What does arginine react with to produce ornithine

A

Water

432
Q

Arginine and water form

A

Ornithine and releases urea

433
Q

Which enzyme catalyses production ornithine and urea

A

Arginase/ornithine aminotransferase

434
Q

How are the urea cycle and TCA cycle linked

A

Through the aspartate-argininosuccinate shunt of the TCA cycle

435
Q

Which molecule produced in the urea cycle enters the TCA cycle

A

Fumarate

436
Q

Urea and TCA cycle

A

Fumarate produced by argininosuccinate lyase enters the TCA cycle
Converted to oxaloacetate
Oxaloacetate accepts an amino group from glutamate (transamination)
Forms aspartate - leaves mitochondria
Donates its amino group to the urea cycle in the argininosuccinate synthetase reaction
Intermediates in the citric acid cycle are boxed

437
Q

What is added to oxaloacetate to form aspartate

A

Amino group from glutamate (transamination)

438
Q

Main problem with high ammonia

A

Neurotoxicity

Ammonia crosses the blood-brain barrier readily. Once inside it is converted to glutamate via glutamate dehydrogenase and so depletes the brain of α ketoglutarate. As ketoglutarate falls, so does oxaloacetate and ultimately citric acid cycle activity stops, leading to irreparable cell damage and neural cell death

439
Q

Early feature of hyperammonaemia

A

Respiratory alkalosis

440
Q

Bile acid function

A

Removal of lipid soluble xenobiotics/drug metabolites/heavy metals
Induce bile flow and secretion of biliary lipids
Digestion of dietary fat
Facilitates protein absorption
Cholesterol homeostasis
Anti microbial
Induce bile flow and solubilise cholesterol
Prevents calcium gallstones and oxalate renal stones

441
Q

Bile acid function- digestion of dietary fats

A

By solubilising lipids and lipid digestion products as mixed micelles facilitating aqueous diffusion across intestinal mucosa

442
Q

Bile acid function- facilitates protein absorption

A

Accelerating hydrolysis by pancreatic proteases

443
Q

Bile acid function- cholesterol homeostasis

A

Facilitates dietary absorption/elimination as bile acids are water soluble end products of cholesterol catabolism

444
Q

Bile acid function- induce bile flow and solubilise cholesterol

A

Enabling movement from hepatocyte to intestinal lumen

445
Q

Bile acid function- anti microbial

A

Physicochemical and inducing anti-microbial genes

446
Q

Bile acid composition

A

Water
Inorganic electrolytes
Organic solutes- bile acids, phospholipids, cholesterol, pigment

447
Q

Faecal bile acids (secondary)

A

2/3 deoxycholic
1/2 lithocholic

448
Q

Hepatic/gallbladder bile

A

2/3 bile acids (primary)
-cholic- 1/3
-chenodeoxycholic 1/3
Deoxycholic 1/3
-lithocholic and ursodeoxycholic
1/4 phospholipids
Small amounts of cholesterol, bilirubin, proteins

449
Q

Bile production per day

A

500-600 ml

450
Q

Primary Bile acid production

A

Synthesised from cholesterol in hepatocytes
Converted into cholic acid and chenodeoxycholic acid
Enzyme = CYP7A1
Conjugated with glycine/taurine before secretion into bile canaliculi

451
Q

Coagulation effects on bile salts

A

Increases hydrophilicity
Increases acidic strength of the side chain
Decreases passive diffusion of bile across cell membranes (keeps it intraluminal)

452
Q

Secondary bile acid production

A

Presence of intestinal bacteria converts primary to secondary
Enzyme = 7 alpha-dehydroxylase

453
Q

Which enzyme converts primary bile salts to secondary bile salts

A

7 alpha-dehydroxylase

454
Q

Formation of bile salts is dependent on

A

Hepatic synthesis and canalicular secretion of bile acids (major organic anion in bile)

455
Q

Which enzyme converts cholesterol into cholic acid and chenodeoxycholic acid

A

CYP7A1

456
Q

Two main acids cholesterol is converted into to form bile acids

A

Cholic acid
Chenodeoxycholic acid

457
Q

Number of enterohepatic circulation cycles per meal

A

2-3

458
Q

Regulation of bile acid secretion- fasted state

A

Bile acids travel down biliary tract to the gallbladder where it is concentrated 10-fold

459
Q

Regulation of bile acid secretion- fed state

A

CCK released from duodenal mucosa

460
Q

Effects of CCK on bile acid secretion

A

Relaxes sphincter of Oddi
Contracts gallbladder
Releasing concentrated solution of mixed micelles (bile acid, phospholipids, cholesterol)

461
Q

Reabsorption of bile acids

A

Conjugated bile acids remain intraluminal
Some reabsorbed passively in Jejunum-ileum
Actively transported via the apical sodium bile acid transporter in the ileum
Re-enters liver via portal circulation
Bile acids take up by hepatocytes and re-conjugated secreted into biliary canaliculi

462
Q

Negative feedback mechanism- bile acids

A

Too much bile acid
Ligand for farnisoid X receptor in ileum
Results in synthesis of FGF-19 (endocrine polypeptide molecule)
Inhibition of CYP7A1 (cholesterol 7 alpha hydroxylase) - first step in converting cholesterol into bile acids

463
Q

What are bile acids a ligand for

A

Farnisoid X receptor in ileum

464
Q

Activation of farnisoid X receptor synthesises

A

FGF-19

465
Q

What does FGF-19 inhibit

A

CYP7A1

466
Q

What inhibits formation of cholesterol

A

Statins- inhibit HMG CoA reductase

467
Q

What reduces absorption of cholesterol

A

Ezetimibe- stops protein mediated transport across enterocyte membrane

468
Q

Excess amino acids —> fatty acids

A

Amino acids —> Acetyl-CoA—> citrate—> acetyl-CoA —> malonyl CoA—> fatty acids

469
Q

3 fates of cholesterol in the liver

A
  1. Bile acids - CYP7A1
  2. Cholesterol esters for storage - ACAT
  3. Combine with triglycerides to form VLDLs
470
Q

What is produced in skeletal or adipose tissue from VLDL

A

IDL (intermediate density lipoprotein)
Cells use triglycerides and cholesterol

471
Q

IDL —> LDL

A

Loss of cholesterol

472
Q

Main hormones for fasting state metabolism

A

Glucagon
Cortisol
Growth hormone
Adrenaline
Noradrenaline
Thyroid hormone

473
Q

Bile acids are amphipathic

A

Reduce surface tension
Aid emulsification

474
Q

Ileal resection or disease

A

unabsorbed bile acids enter colon where inhibit water absorption / induce secretion resulting in ‘bile salt diarrhoea’

475
Q

Cholecystectomy

A

daily bile acid secretion is not altered much. Bile is ‘stored’ in proximal small intestine – likely big ‘shift’ to distal small intestine ‘overwhelms’ transport mechanism or feedback mechanism

476
Q

Biliary obstruction

A

CBD stone, pancreatic carcinoma – intestinal malabsorption of fat soluble vitamins and fat resulting in steatorrhoea and develop jaundice

477
Q

Disruption of enterohepatic circulation may be due to

A

bacterial overgrowth- deconjugation of bile acids
cholecystectomy
ileal resection may result in diarrhoea / steatorrhoea
malabsorption of fat soluble vitamins

478
Q

Small intestinal bacterial overgrowth

A

Alteration of number/composition of bacteria in small intestine
Bloating, diarrhoea, abdominal pain
Treat with antibiotics

479
Q

Which cells store vitamin C

A

None

480
Q

What clotting factors are vitamin K dependent

A

Factor II, VII, IX X

481
Q

Which hormone acts on the gallbladder to cause pain when suffering from gallstones

A

Cholecystokinin CCK- causes contraction of gallbladder but flow of bile is obstructed

482
Q

What is the relationship between bile acid synthesis in the liver and bile acid reabsorption in the small intestine

A

Inversely proportional
More bile acid reabsorbed— > bile acids recycled and re-secreted via enterohepatic cycle so less bile acids produced

483
Q

What stimulates bile secretion

A

Presence of partially digested fats and proteins in duodenum
Cholecystokinin and secretin released
CCK acts on gallbladder to secrete bile
Secretin stimulates biliary duct cells to secrete bicarbonate and water - expanding volume of bile

484
Q

How does glucose-6-dehydrogenase deficiency cause jaundice

A

Erythrocytes more susceptible to to oxidative stress
Increased haemolysis

485
Q

Where is iron stored in the body

A

Liver
Spleen
Bone marrow

486
Q

Gilbert’s syndrome

A

Non-functional glucuronyl transferase

487
Q

Why does jaundice cause itchy skin

A

Build up of bile salts

488
Q

Serum concentration of bilirubin to be able to see yellow skin cause of jaundice

A

50 mmol/L

489
Q

Serum concentration of bilirubin- jaundice

A

> 21 mmol/L

490
Q

Bilirubin is the by-product of Haemoglobin breakdown.

Microsomal enzyme uridine diphosphoglucoronosyl transferase (glucuronyl transferase) catalyses the formation of what?

A

Conjugated bilirubin

491
Q

A 53 year old patient is admitted with jaundice.

Which of the following causes an increased serum unconjugated (free) bilirubin and increased faecal urobilinogen?

A

Pre-hepatic

492
Q

Which coagulation factors does the liver produce

A

1972:
- 10
-9
-7
-2

493
Q

Which cells store iron in the form of ferritin

A

Kupffer cells

494
Q

Haemoglobin is the chemical responsible for carrying oxygen around the body, the products of its breakdown give urine and faeces their distinct colours. In one stage of the breakdown of haemoglobin, unconjugated bilirubin is converted to conjugated bilirubin. This process occurs in the liver. What enzyme is responsible for converting unconjugated bilirubin to conjugated bilirubin?

A

Glucuronyl transferase

495
Q

Carbamoyl phosphate synthetase deficiency I is an autosomal recessive disorder which causes toxic ammonia to accumulate in the body. Babies born with this disorder have a deficiency of the enzyme carbamoyl phosphate synthetase. In severe cases, this leads to respiratory distress, seizures and coma. What stage of the urea cycle is the enzyme carbamoyl phosphate synthetase important for?

A

Conversion of ornithine to citrulline

496
Q

Albumin, which is produced in the liver, is a vital plasma protein that has many functions in the body. Which of the following is NOT a function of albumin?

A

Bind to and transport iron

GI (12 decks)

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