Liver Functions - PowerPoint Presentation

Slide1

Liver Functions

Harry and JazSlide2

Protein synthesis and metabolismSlide3

Protein synthesis

Plasma proteins

Clotting factors

Complement factorsSlide4

Protein synthesis

Plasma proteins

Clotting factors

Complement factorsSlide5

Protein synthesis – plasma proteins

Main types:

Albumin

Globulin

FibrinogenSlide6

Protein synthesis – plasma proteins

Main types:

Albumin

Globulin

FibrinogenSlide7

Protein synthesis – albumin

Most common plasma protein

Functions

Maintenance of colloid osmotic pressure

Binding and transport of large, hydrophobic compounds

Bilirubin

, fatty acids, hormones,

drugs

Antioxidant (traps free radicals)

Anticoagulant and antithrombotic effectsSlide8

Protein synthesis – albumin

Most common plasma protein

Functions

Maintenance of colloid osmotic pressure

Binding and transport of large, hydrophobic compounds

B

ilirubin, fatty acids, hormones, drugs

Antioxidant (traps free radicals)

Anticoagulant and antithrombotic effectsSlide9

Starling forces

Capillary hydrostatic pressure

Capillary

Interstitial fluid

Capillary oncotic pressure

Interstitial hydrostatic pressure

Interstitial oncotic pressure

Opposing forces act to move fluid across the capillary wall

Net filtration pressure depends upon sum of four variables:Slide10

Capillary oncotic pressure

The pores of capillaries are impermeable to plasma proteins

 very low conc. of plasma proteins in interstitial fluid

Higher conc. of plasma proteins in plasma

 lower relative water conc. in plasma vs. that in interstitial fluid

 net movement of water out of interstitial fluid and into plasmaSlide11

Capillary oncotic pressure – when it goes wrong

…

The liver produces albumin

…

Liver failure

 dysfunction in albumin production

Decreased production  less albumin in blood (

hypoalbuminaemia

)

Albumin contributes to capillary oncotic pressure...

Hypoalbuminaemia  dec.

c

apillary oncotic pressure

 less of a difference in water conc.

between

plasma and interstitial fluid

 accumulation of water in interstitial fluid (

oedema

)

Hypoalbuminaemia  oedemaSlide12

Protein synthesis – plasma proteins

Main types:

Albumin

Globulin

FibrinogenSlide13

Protein synthesis - globulins

Functions

Antibody functions (most are gamma-globulins – not made by liver)

Blood transport of:

Lipids (by

lipoproteins

)

Iron (by

transferrin

)

Copper (by

caeruloplasmin

)Slide14

Protein synthesis

Plasma proteins

Clotting factors

Complement factorsSlide15

The liver and clotting

Production of clotting factors

All, except:

Calcium (IV)

von Willebrand factor (VIII)

Production of bile salts

Necessary for intestinal absorption of vitamin K

Vitamin K is required to produce numerous clotting factorsSlide16

Protein synthesis

Plasma proteins

Clotting factors

Complement factorsSlide17

Protein synthesis – complement factors

Function

Important part of the immune response to pathogensSlide18
Slide19

Protein metabolism – turnover

and degradation

Continuous degradation and re-synthesis of all cellular proteins

70-80% of liberated amino acids are re-

utilised

into proteins

Variable rate – reflecting usage and demand

Increase seen in:

Damaged tissue due to trauma

Skeletal tissue during starvation – gluconeogenesis

2 primary methods:

Lysosomal pathway

Ubiquitin-

proteosome

pathwaySlide20

Amino acid breakdown

Surplus of amino acids

Degradation

Amino acid catabolism

Requires removal of alpha-amino group

Produces:

Nitrogen

Incorporated into other compounds

Excreted

Carbon skeleton

Metabolised

Majority released as ammonia

2 processes:

Transamination

Oxidative deamination

R

CH

COO

-

+

H

3

NSlide21

Amino acid breakdown

Surplus of amino acids

Degradation

Amino acid catabolism

Requires removal of alpha-amino group

Produces:

Nitrogen

Incorporated into other compounds

Excreted

Carbon skeleton

Metabolised

Majority released as ammonia

2 processes:

Transamination

Oxidative deamination

R

CH

COO

-

+

H

3

NSlide22

Amino acid breakdown - transamination

Transfer of alpha-amino group from amino acid to alpha-ketoglutarate

Formation

An alpha-keto acid (e.g. pyruvate) – Krebs’

Glutamate

Oxidative deamination

Amino group donor (synthesis of non-essential amino acids)

Catalyst

Aminotransferase enzymes

Readily reversible process

Amino acid degradation (after protein-rich meal)

Amino acid synthesis (dietary supply



cellular demand)Slide23

Amino acid breakdown - transamination

-

OOC – C

O

– C – C – COO

-

+

R

CH

COO

-

+

H

3

N

-

OOC – C – C – C – COO

-

+

H

3

N

+

R

C

O

COO

-

Alpha-ketoglutarate

L-amino acid

L-glutamate

Alpha-keto acid

aminotransferaseSlide24

Amino acid breakdown

Surplus of amino acids

Degradation

Amino acid catabolism

Requires removal of alpha-amino group

Produces:

Nitrogen

Incorporated into other compounds

Excreted

Carbon skeleton

Metabolised

Majority released as ammonia

2 processes:

Transamination

Oxidative deamination

R

CH

COO

-

+

H

3

NSlide25

Amino acid breakdown –

oxidative deamination

Results in the liberation of amino group as free ammonia

Formation

An alpha-keto acid (e.g. pyruvate) Krebs’

Ammonia

Urea cycle

Catalyst

Glutamate dehydrogenase

Co-enzymes (NAD

+

/NADPH)

Readily reversible process

Dependent upon relative concentrations of:

Glutamate, alpha-ketoglutarate, ammonia

After protein rich-meal, glutamate concentration is high

Reaction degrades amino acid glutamate

 ammonia formationSlide26

Nitrogen balance

A measure of the equilibrium of protein turnover;

Anabolic

– positive balance

Catabolic

– negative balanceSlide27

Daily nitrogen intake

0.8g/Kg body weight 1.3g/Kg body weight 2.4g/Kg body weightSlide28

Glucose/Alanine CycleSlide29

Glucose/Alanine Cycle

Input of amine groups (NH2) comes from;

Dietary amino acids (9 cannot be synthesized by the human body)

A

lanine and glutamine from musclesSlide30

Glucose/Alanine Cycle

Excess amino acids are metabolised. They are not stored for use as potential energy as this can be done more efficiently by other sources.

α-keto acid

Fed into the Krebs cycle to

be incorporated into glucose

production

Ammonia

Mainly excreted, although some is used in the biosynthesis of amine containing substances e.g. amino acids, nucleotidesSlide31

Urea Cycle

Enzymes responsible are found in mitochondria and cytosol.Slide32

Urea Cycle

One turn of the cycle consumes;

3 ATP equivalents

4 high energy nucleotides

Deficiencies in any of the enzymes involved is associated with higher levels of ammonia in the blood.

- absence of the enzymes is not compatible with lifeSlide33

High levels of ammonia (neurotoxicity)

Increased ammonia crosses the BBB readily;

Converted to glutamate (

glutamate dehydrogenase

)

Decrease in

α

-ketoglutarate in brain

Decrease in oxaloacetate

Krebs cycle stops

This leads to irreparable cell damage and neural cell death

LEARN THE KREBS CYCLE…

AND GLYCOLYSISSlide34

Glucose regulationSlide35

Absorptive and post-absorptive state

Absorptive state

Ingested nutrients are absorbed from the GI tract into the blood

A proportion of nutrients are catabolised and used

The remainder are converted and stored for future use

Post-absorptive state

Nutrients are no longer absorbed from the GI tract

Nutrient stores must supply the energy requirements of the bodySlide36

Glucose regulation – post-absorptive state

Glucose is no longer being absorbed from the GI tract

Essential to maintain the plasma glucose concentration

Almost always fuels the CNS

(except in prolonged starvation)

Sources of blood glucose

Glycogenolysis

(hrs)

Hydrolysis of glycogen stores in liver (and skeletal muscle*)

Lipolysis

Glycerol released is enzymatically converted to glucose in the liver

Proteolysis

(>hrs)

Amino acids taken up by the liver and converted to glucose

Synthesis of glucose from above precursors (glycerol, amino acids) =

gluconeogenesis

*Note

Enzyme required to form glucose from glucose 6-phosphate formed in glycogenolysis is

not

present in skeletal muscle

Instead, glucose 6-phosphate formed in muscle undergoes glycolysis, yielding:

ATP

Pyruvate

Lactate

Lactate is taken up by the liver and converted to glucoseSlide37

Gluconeogenesis

The process of generating new molecules of glucose from non-carbohydrate precursors

Substrates

Pyruvate

= major substrate

Formed from lactate and other amino acids

Glycerol (formed through triglyceride hydrolysis)

6 ATP molecules are consumed per molecule of glucose formedSlide38

StorageSlide39

Liver storage

Iron

Fat soluble vitamins

Glycogen

MineralsSlide40

Liver storage

Iron

Fat soluble vitamins

Glycogen

MineralsSlide41

Iron

Distribution

Utilised by:

Haemoglobin

Myoglobin

Bone marrow

Stored in:

Liver

Reticulo-endothelial macrophages

Absorption

Transferrin

Transports iron in the plasma to the bone marrow – iron incorporated into new RBC

Ferritin

Storage form of iron

Main source is found in the liver

Duodenum

Primary location of iron absorptionSlide42

Liver storage

Iron

Fat soluble vitamins

Glycogen

MineralsSlide43

Fat soluble vitamins - ADEK

A

Stored in Ito cells (in space of

Disse

)

High levels stored in liver – prevent deficiency for 10 months

Function

Vision (retinal pigments)

Healthy skin

Growth and reproduction

D

Liver storage prevents deficiency for 3-4 months

Function

Increases calcium reabsorption from intestinal tract

Promotes intestinal phosphate reabsorptionSlide44

Fat soluble vitamins - ADEK

E

Function

Antioxidant

K

Function

Necessary for production of clotting factors

B

12

Liver stores prevent deficiency for >1yr

Function

Promotes growth and RBC formation + maturation

Intrinsic factor

Produced by parietal cells of stomach

Required for absorption of B

12

– deficiency

 pernicious anaemia

B

12

is absorbed in the terminal ileumSlide45

Liver storage

Iron

Fat soluble vitamins

Glycogen

MineralsSlide46

Glycogen

Sites of storage

Liver (~10% mass of liver)

Skeletal muscle (~2% mass of skeletal muscle)

Function

Readily mobilised storage form of glucose

Maintain blood glucose levels

Overall storage is larger in skeletal muscle as its mass is far greater

Glycogen is the secondary energy reservoir – with lipids being the primary sourceSlide47

Liver storage

Iron

Fat soluble vitamins

Glycogen

MineralsSlide48

Minerals

Iron

Stored as ferritin

CopperSlide49

Fat metabolism

Most

of the body’s fat is stored in adipocytes which form tissues

called

adipose

tissue. Some is stored in hepatocytes.

Body Energy

Reserve

Number of kcal

Length of effect

Blood glucose

40

A few minutes

Glycogen

600

Day

Muscle

25,000

7-10 days

Lipid reserve

100,000

30-40 daysSlide50

Triglycerides

Triglycerides (TGs, TAGs) consist of 3 fatty acids bound to a glycerol molecule.

It accounts for 78% of energy stored in body – proteins (21%) and carbohydrates (1%).Slide51

Lipoproteins

HDL

– formed in the liver

LDL

– formed in plasma

VLDL

– synthesized in hepatocytes

Also

IDL.

They are used to transport cholesterol through the blood.Slide52

Lipids

Lipids are esters of fatty acids and certain alcohol compounds.

They have several functions;

Energy reserves

Structural – part of cell membrane

Hormone metabolismSlide53

Digestion and absorption

Bile salts

and

phospholipids

emulsify dietary fats in the small intestine forming mixed

micelles

Intestinal lipases

degrade

TGs

Fatty acids

and other breakdown products are taken up into

intestinal mucosa

and converted into

triacyglycerols

Triacyglycerols

are incorporated with

cholesterol

and

apolipoproyeins

into

chylomicrons

Chylomicrons move through the lymphatic system and bloodstream into the tissuesLipoprotein

lipase converts triacyglycerols to fatty acids and glycerol

Fatty acids enter cellsFatty acids are oxidised as fuel or re-esterified for storageSlide54

Fat Catabolism

– breaking down into smaller units

Molecule of

coenzyme A

links to carboxyl at the end of a

fatty acid

Breakdown of

ATP > AMP + 2Pi

Coenzyme A derivative of fatty acid proceeds through

beta-oxidation

reactions

Molecule of

acetyl coenzyme A

is split off from fatty acid and

2H

+

transferred to coenzymes

Hydrogen atoms

from coenzymes enter the

oxidative phosphorylation

pathway to form

ATPAnother coenzyme A attaches to fatty acid and the cycle is repeated

Coenzyme – 2H molecules lead to the production of CO2 and ATP via the Krebs cycle

and oxidative phosphorylationSlide55

Hepatic metabolism of lipids

Lipoprotein lipase

- Hydrolyses TGs in lipoproteins (chylomicrons, VLDLs) into 2 free fatty acids and 1 glycerol molecule

Hepatic lipase

- Expressed in the liver and adrenal glands, it converts IDL into LDLSlide56

LIVER FUNCTIONS DONE!