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Semester 4 > case 5 - liver function > Flashcards

case 5 - liver function Flashcards

1
Q

where does the liver receive blood from

A

via the portal vein, receives blood from the spleen, and most of the GI tract

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2
Q

what does the liver respond to

A

insulin and glucagon

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3
Q

what does glycogenolysis do

A

makes glucose available in the fasting state

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4
Q

what is glycogenolysis promoted by

A

glucagon the hormone

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4
Q

what does gluconeogenesis produce

A

glucose from scraps and makes it available in the fasting state

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5
Q

what is gluconeogenesis promoted by

A

glucagon

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6
Q

what is ketogenesis

A

the use of acetyl-CoA to produce emergency fuel

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7
Q

what is this emergency fuel

A

ketone bodies

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8
Q

what is ketogenesis promoted by

A

the surplus of mobilised fatty acids in starvation or T1D

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9
Q

when does ketogenesis run

A

in the fasting state

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10
Q

what are the ketone bodies

A

acetoacetate and hydroxybutyrate

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11
Q

what does glycogenesis do

A

absorbs surplus of dietary glucose and stores as glycogen

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12
Q

what is glycogenesis driven by

A

high blood glucose

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13
Q

when does glycogenesis run

A

in the healthy state

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14
Q

what does fatty acid biosynthesis use

A

surplus carbon substrate to produce FA for delivery to adipose tisse

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15
Q

what is fatty acid biosynthesis promoted by

A

insulin and high cellular energy levels - ATP

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16
Q

what is fatty acid biosynthesis supressed by

A

glucagon

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17
Q

what does amino acid metabolism result in

A

the production of gluconeogenesis precursors

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18
Q

what are the precusors for gluconeogenesis

A

ketoglutaraten and oxaloacetate

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19
Q

when does the liver take up glucose

A

only at high glucose levels and uses some of it to produce glycogen

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20
Q

what happens to the rest of the glucose

A

degraded into acetyl-CoA first and then into fatty acids and triacylglycerols to deliver to adipose tossie

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21
Q

how does the liver produce and then release glucose into the blood stream in the fasting stat

A

It does this by breaking down glycogen and later by dementating amino acids to produce building blocks for gluconeogenesis

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22
Q

what does the hydrolysis of triacylcylcerols release

A

fatty acids that can be broken into acetyl-CoA

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23
Q

can acetyl-CoA ever be turned back into glucose

A

no

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24
Q

what is acetyl-CoA’s contiribution to fasting metabolism

A

via the production of ketone bodies

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25
Q

what is at the heart of carbohydrate metabolism

A

glycolysis

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26
Q

what does glycolysis do

A

catabolism (breaking down) of glucose (and most other carbohydrates via glucose) in all tissues
Generation of intermediates for other pathways
Generation of energy and (in aerobic conditions) by reducing equivalents

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27
Q

what is the end product dependent on

A

oxygen -produces pyruvate under aerobic conditions and lactate under anaerobic conditions

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28
Q

what facilitates the diffusion of glucose into cells

A

the family of glucose transporters - GLUT

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29
Q

where is GLUT4 specific for

A

adipose tissue

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30
Q

where is GLUT2 specific for

A

the liver

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31
Q

what can GLUT2 facilitate

A

both glucose entry into the liver cells and exit

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32
Q

what does phosphorylation do

A

traps glucose in the cell because the ionic phosphate cannot cross the membrane spontaneously

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33
Q

what is this phosphorylation catalysed by

A

enzym hexokinase

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34
Q

when are the enzyme variants in more tissues fully active

A

at low concetrations of glucose

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35
Q

what has a much higher capacity to trap glucose in the liver and when

A

Hexokinase-IV or glucokinase, in the liver has a much higher capacity to trap glucose in the liver, but only when glucose concentrations are high - especially after a meal

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36
Q

describe the steps in glycolysis

A

glucose 6-P is isomerised to fructose-6-P
F-6-P is phosphorylated again to yield F-1,6-BP in the most critical regulated step
this phosphorylation commits the molecule for further degradation
So this is something to be avoided in the fasting state when we want to preserve glucose
The next steps up to PEP are fully reversible
The energy from burning glucose as fuel depends on oxidation, but glycolysis is only the preparation for that
In the only oxidative step of glycolysis, GA-3P is converted into 1,3-BPG,
NADH + H+ generated in this oxidative step can be regenerated under anaerobic conditions by reducing pyruvate to lactate
The liver can re-oxidise lactate to pyruvate
Accounting for the investment of 2 ATP per molecule glucose early on, there is a net generation of 2 ATP per glucose in glycolysis

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37
Q

what is the Warburg effect

A

Compare 2 vs 28 ATP excessive glucose consumption of tumours. Aerobic glycolysis is inefficient but fast

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38
Q

what is glucose greatly preferred for

A

Glucose is greatly preferred as energy source by brain and nervous tissue, and essential for the adrenal medulla, testes and mature erythrocytes

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39
Q

the liver is the main tissue in performing what two maintenance mechanisms

A

gluconeogensis and glycogenesis

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40
Q

what is glycogen

A

is a highly branched, all glucose poly-saccharide with an alpha 1,4 linked backbone and alpha-1,6 linked branches
Is the storage form of glucose, mainly in skeletal muscle and liver

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41
Q

what is glycogen synthesised

A

after a meal and degradation during an over night fast as key mechanisms that maintain blood glucose levels

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42
Q

what is glycogen synthesis regulated by

A

glucagon

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43
Q

what is glycogen metabolism controlled by

A

glucagon and insulin

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44
Q

what does glucagon trigger

A

the production of cAMP in cells, which in turn activates protein kinase A -PKA

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45
Q

what does PKA do

A

phosphorylates glycogen synthase directly, and glycogen phosphorylase via phosphorylase kinase

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46
Q

what does glucagon do

A

promotes glycogenolysis and inhibits glycogenesis

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47
Q

what does phosphorylation have

A

Phosphorylation has opposite effects on the two enzymes: glycogen synthase becomes inactive, while glycogen phosphorylase is activated by phosphorylation

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48
Q

what is gluconeogenesis

A

a pathway active in the liver that regenerates glucose from non-carbohydrate precursors

this can happen in the kidney after prolonged fating

49
Q

describe lactate

A

from skeletal muscle is re-oxidised to pyruvate

this liver-muscle cycle is called the cori cycle

50
Q

what is glycerol released by

A

the hydrolysis of fats (TAGs) in adipocytes

51
Q

what are amino acids from tissue protein metabolised to

A

alpha-keto acids

52
Q

what is the main key regulator of gluconeogenesis

A

glucagon

53
Q

how does glucagon act

A

by repressing pyruvate kinase, thus increasing the availability of PEP for gluconeogensis

54
Q

what can glucagon also do

A

increase the expression of PEP carboxykinase

55
Q

what does glucagon also repress

A

finally, glucagon represses the formation of F-2,6 BP, which is a repressor of fructose-1,6-biphosphatase in gluconeogenesis (while it is an activator of PFK-1 in glycolysis)

56
Q

what does insulin increase the levels of

A

glucose uptake
Protein synthesis
Glycogen synthesis
Fat synthesi

57
Q

what does insulin decrease the levels of

A

ketogenesis
Lipolysis
Gluconeogenesis
Glycogenolysis

58
Q

what are the regulatory mechanisms

A

availability of substrates e.g glucokinase

Allosteric control (regulatory metabolites bind outside of the active site of enzymes and modulate activity) e.g PFK1 regulation by F2,6-BP

Regulatory phosphorylation e.g phosphorylation of glycogen synthase and phosphorylase kinase by PKA

Changes in transcription e.g increase in expression of glycolytic enzymes triggered by insulin; suppression of gluconeogenesis in the liver

59
Q

what is PFK1

A

phosphofructokinase

60
Q

when does PFK1 act

A

PFK1 acts after isomerisation of glucose-6-P to fructose-6-P and catalyses the most important regulated step of glycolysis

61
Q

what is the rate limiting slowest step in glycolysis

A

PFK1

62
Q

what is PFK1 allosterically activated by

A

AMP and repressed by ATP and citrate

63
Q

what else is PFK1 activated by

A

PFK-1 is activated by fructose-2,6-biphosphate whose biosynthesis in turn is regulated by insulin and glucagon

64
Q

what is the pyruvate dehydrogenase complex

A

The PDC complex is a gigantic multi-enzyme complex with dozens of copies each of three enzymes, E1,E2,E3 and end product is Acetyl-CoA - in the mitochondria

65
Q

what is the TCA cycle

A

the TCA cycle is a central ‘metabolic roundabout’ with multiple entry and exit points.
Several of the intermediates are involved in gluconeogenesis, amino acid and heme metabolism
The oxidative catabolism of carbohydrates, lipids and amino acids comes together here

66
Q

where do all TCA reactions happen and what do they require

A

All TCA cycle reactions happen in mitochondria and require oxygen to recycle the reduced co-enzymes NADH+H+ and FADH2

67
Q

what starts off these TCA reactions

A

Acetyl-CoA

68
Q

what does the TCA cycle produce

A

the TCA cycle produces a full oxidation of acetyl-CoA to 2 carbon dioxides

69
Q

what does the oxidation of NADH and FADH2 in the mitochondria generate

A

28 ATP per molecule of glucose and 2 GTP

70
Q

what are four intermediates of the TCA cylce

A

amino acid metabolites

71
Q

what does this allow

A

their conversion to glucose by gluconeogenesis

72
Q

where are TAGs stored

A

adipocytes

73
Q

what does fatty acid and TAG synthesis start with

A

cytoplasmic acteyl-CoA

74
Q

where is acetyl-CoA generated and what does this mean

A

Since most acetyl-CoA is generated in mitochondria and cannot cross the membrane, a shuttle is needed

75
Q

what is the regulation of hepatic lipogenesis by

A

Regulated by availability of substrate: carbohydrate rich meals provide carbon (pyruate/Acetyl-CoA) and NADPH via the pentose phosphate pathway

76
Q

what stimulates lipogenesis

A

Insulin stimulates lipogenesis via transcriptional activation of L-PK, ACC and other enzymes leading to TAG

77
Q

what is the next step and what is a feature of it

A

the next step, catalysed by acetyl-CoA carboxylase (ACC) is rate limiting and regulated:

78
Q

at is this step activated by

A

a citrate

79
Q

what is ACC inactivated directly by

A

ACC is inactivated directly by fatty acetyl-CoA and by phosphorylation by AMPK

80
Q

what happens via regulation of ACC phosphorylation

A

Via regulation of ACC phosphorylation, insulin indirectly activates ACC; glucagon and AMP inactive ACC

81
Q

the beta oxidation of fatty acids produces what

A

large amounts of energy:

Per 2-carbon unit, one FADH2, one NADH and one acetyl-CoA are produced. Ultimately, these produce 2,3 and 12 ATP, respectively.
Per 16-carbon (palmitoyl)-CoA, that’s 129 ATP!


82
Q

what are ketone bodies

A

ketone bodies are an ‘emergency fuel’ that the liver can produce to preserve glucose. The liver itself cannot use ketone bodies though

83
Q

what is a sign of ketoacidosis

A

Some will randomly become acetone and a sign of ketoacidosis

84
Q

what does lack of insulin do

A

lack of insulin lifts repression of hormone-sensitive lipase in adipocytes > TAG is hydrolysed and fatty acids are released

85
Q

what does the acidity of ketone bodies do

A

The acidity of ketone bodies lowers blood pH (ketoacidosis)

86
Q

what is spontaneous production of acetone from acetoacetate noticable as

A

fruity breath

87
Q

what happens early in untreated T1D

A

Early in untreated T1D, lack of insulin means that glucagon promotes gluconeogenesis in the liver > hyperglycaemia

88
Q

what does the catabolism of most amino acids begin with

A

the removal of the alpha amino group

89
Q

what happens to the amino group

A

The amino group is transferred to alpha-ketoglutarate in a transaminase reaction
when alanine is converted into pyruvate, alpha-ketoglutarate is converted into glutamate

90
Q

what do most transaminases transfer their amino group to

A

alpha-ketoglutarate

91
Q

why is ASP an exception that is not fully reversible and does not strongly favour one direction

A

ASP is an exception. The alpha amino group of glutamate that has come from many other amino acids is passed on to oxaloacetate to form aspartate , and from here is fed into the urea cycle

92
Q

what is the specific indicator for liver damage

A

ALT

93
Q

at is more sensitive and why

A

serum AST is more sensitive because the liver contains larger amounts of AST rather than ALT

94
Q

what is excess ammonia converted to in peripheral tissues

A

glutamine

95
Q

what can glutamine carry

A

2 nitrogen atoms

96
Q

what happens in the liver

A

In the liver, two molecules NH3 can be released from glutamine by glutaminase and then glutamate dehydrogenase

97
Q

what is the second route for delivering ammonia to the liver

A

a second route for delivering ammonia too the liver is via the alanine-glucose shuttle. Alanine from muscle delivers NH3 via ALT; resulting pyruvate goes into glyconeogenesis; glucose is returned to the muscle

98
Q

what else can ammonia also be transferred to

A

Ammonia can also be transferred to oxaloacetate by aspartate transaminase. The resulting aspartate feeds into the urea cycle

99
Q

what happens to the mitochondria, ammonia and CO2 in the liver

A

In liver mitochondria, ammonia and CO2 are joined by carbamoyl phosphate synthetase I. Two molecules of ATP are required to drive the process.

100
Q

what does glucokinase do

A

The low affinity, high-capacity glucokinase can channel glucose into glycolysis only when glucose is abundant

101
Q

what do high levels of glucose-6-phosphate promote

A

glycogenesis

promote NADPH production in the pentose phosphate pathway

102
Q

what happens to glucolysis and gluconeogenesis after this

A

Glycolysis is promoted and gluconeogenesis suppressed by a high insulin’glucagon ratio: PFK1 activation by F-2,6-BP, dephospho rylation (=activation) of pyruvate kinase and PDH

103
Q

what are surplus carbohydrates from a meal converted into

A

Surplus carbohydrates from a meal are converted to acetyl-CoA and then mainly channelled into fatty acid synthesis:

104
Q

what does high ATP do

A

high ATP inhibits isocitrate dehydrogenase, leading to an accumulation of citrate in mitochondria and export to the cytoplasm

105
Q

what does ATP-citrate lyase do

A

ATP-citrate lyase restores acetyl-CoA in the cytoplasm, and ACC is activated by dephosphorylation and by citrate

106
Q

what is TAG synthesis promoted by

A

TAG synthesis is promoted by the high availability of fatty actyl-CoA both from de novo fatty acid biosynthesis and from dietary Fats

107
Q

what happens to the surplus amino acids

A

Surplus amino acids are recycled, redistributed or degraded into pyruvate, TCA cycle intermediates or acetyl-CoA

108
Q

where are branched chain amino acids only used

A

by muscle

109
Q

what is the number one priority of the liver during fasting state

A

to maintain blood glucose levels for the glucose dependent tissues

110
Q

at does glucagon do

A

Glucagon stimulates the activation of glycogen phosphorylase via PKA mediated activation of phosphorylase kinase

111
Q

what does the liver specific enxyme glucose-6-phosphatase do

A

The liver specific enzyme glucose-6-phosphatase produces glucose from G-6-P. Glucose is released into the bloodstream

112
Q

what does glucagon also do

A

Glucagon also triggers a reduction in the concentration of fructose-2,6-biphosphate by shifting PFK-2 towards phosphatase activity

113
Q

what does the reduction in F2-6-BP mean

A

The reduction in F2,6-BP means that gluconeogenesis is favoured over glycolysis; the key enzyme fructose-1,6-biphosphatase is no longer inhibited by F-2,6-BP

114
Q

what are the main sources of carbon for gluconeogenesis

A

lactate from muscle and glycogenic amino acids

115
Q

what does the hydrolysis of TAGs do

A

the hydrolysis of TAGs in adipose tissue supplies the liver with fatty acids

116
Q

what is ACC directly inhibited by an indirectly

A

The key enzyme of fatty acid biosynthesis, ACC is inhibited directly by abundantly fatty acyl-CoA and indirectly by phosphorylation (mediated by AMPK and glucagon)

117
Q

what does ACC inhibition do

A

ACC inhibition lowers malonyl-CoA which in turn activates beta-oxidation

118
Q

what does the abundant acetyl-CoA do

A

The abundant acetyl-CoA activates pyruvate carboxylase (for gluconeogenesis) and inhibits degradation of pyruvate (inhibition of PDH)

119
Q

what does the liver produce during prolonged fasting

A

during prolonged fasting, the liver produces the ketone bodies aceto-acetate and 3-hydroxy-butyrate that can be used as emergency fuel by all tissues, even the brain

Semester 4 (80 decks)

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