Download Protein synthesis and metabolism

Liver Functions
Harry and Jaz
Protein synthesis and metabolism
Protein synthesis
• Plasma proteins
• Clotting factors
• Complement factors
Protein synthesis
• Plasma proteins
• Clotting factors
• Complement factors
Protein synthesis – plasma proteins
• Main types:
• Albumin
• Globulin
• Fibrinogen
Protein synthesis – plasma proteins
• Main types:
• Albumin
• Globulin
• Fibrinogen
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 effects
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 effects
Starling forces
• Opposing forces act to move fluid across the capillary wall
• Net filtration pressure depends upon sum of four variables:
Capillary
hydrostatic
pressure
Interstitial
hydrostatic
pressure
Capillary
oncotic
pressure
Interstitial
oncotic
pressure
Interstitial fluid
Capillary
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 plasma
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. capillary oncotic pressure
•  less of a difference in water conc. between plasma and interstitial fluid
•  accumulation of water in interstitial fluid (oedema)
Hypoalbuminaemia  oedema
Protein synthesis – plasma proteins
• Main types:
• Albumin
• Globulin
• Fibrinogen
Protein synthesis - globulins
• Functions
• Antibody functions (most are gamma-globulins – not made by liver)
• Blood transport of:
• Lipids
• Iron
• Copper
(by lipoproteins)
(by transferrin)
(by caeruloplasmin)
Protein synthesis
• Plasma proteins
• Clotting factors
• Complement factors
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 factors
Protein synthesis
• Plasma proteins
• Clotting factors
• Complement factors
Protein synthesis – complement factors
• Function
• Important part of the immune response to pathogens
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 pathway
Amino acid breakdown
• Surplus of amino acids
• Degradation
• Amino acid catabolism
R
• 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
+H N
3
CH
COO-
Amino acid breakdown
• Surplus of amino acids
• Degradation
• Amino acid catabolism
R
• 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
+H N
3
CH
COO-
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)
Amino acid breakdown - transamination
+H N
3
R
R
aminotransferase
-OOC
– CO – C – C – COO-
Alpha-ketoglutarate
+
+H N
3
CH
L-amino acid
COO-
-OOC
– C – C – C – COO-
L-glutamate
+
CO
COO-
Alpha-keto acid
Amino acid breakdown
• Surplus of amino acids
• Degradation
• Amino acid catabolism
R
• 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
+H N
3
CH
COO-
Amino acid breakdown – oxidative deamination
• Results in the liberation of amino group as free ammonia
• Formation
• An alpha-keto acid (e.g. pyruvate)
• Ammonia
Krebs’
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 formation
Nitrogen balance
A measure of the equilibrium of protein turnover;
• Anabolic – positive balance
• Catabolic – negative balance
Daily nitrogen intake
0.8g/Kg body weight
1.3g/Kg body weight
2.4g/Kg body weight
Glucose/Alanine Cycle
Glucose/Alanine Cycle
Input of amine groups (NH2) comes from;
• Dietary amino acids (9 cannot be synthesized by the human
body)
• Alanine and glutamine from muscles
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, nucleotides
Urea Cycle
Enzymes responsible are found in mitochondria and cytosol.
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 life
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
Glucose regulation
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 body
Glucose regulation – post-absorptive state
• Glucose is no longer being absorbed from the GI tract
*Note
• Essential to maintain the plasma glucose concentration
Enzyme required to form glucose from glucose 6phosphate formed in glycogenolysis is not
present in skeletal muscle
• 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)
Instead, glucose 6-phosphate formed in muscle
undergoes glycolysis, yielding:
•
•
•
ATP
Pyruvate
Lactate
Lactate is taken up by the liver and converted to
glucose
• Amino acids taken up by the liver and converted to glucose
• Synthesis of glucose from above precursors (glycerol, amino acids) = gluconeogenesis
Gluconeogenesis
• The process of generating new molecules of glucose from noncarbohydrate 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 formed
Storage
Liver storage
• Iron
• Fat soluble vitamins
• Glycogen
• Minerals
Liver storage
• Iron
• Fat soluble vitamins
• Glycogen
• Minerals
Iron
• Distribution
• Utilised by:
• Haemoglobin
• Myoglobin
• Bone marrow
• Stored in:
• Liver
• Reticulo-endothelial macrophages
Duodenum
Primary location of iron absorption
• 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
Liver storage
• Iron
• Fat soluble vitamins
• Glycogen
• Minerals
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 reabsorption
Fat soluble vitamins - ADEK
•E
• Function
• Antioxidant
•K
• Function
• Necessary for production of clotting factors
• B12
• 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 B12 – deficiency  pernicious anaemia
B12 is absorbed in
the terminal ileum
Liver storage
• Iron
• Fat soluble vitamins
• Glycogen
• Minerals
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 source
Liver storage
• Iron
• Fat soluble vitamins
• Glycogen
• Minerals
Minerals
• Iron
• Stored as ferritin
• Copper
Fat metabolism
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 days
Most of the body’s fat is stored in adipocytes which form tissues called
adipose tissue. Some is stored in hepatocytes.
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%).
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.
Lipids
Lipids are esters of fatty acids and certain alcohol compounds.
They have several functions;
• Energy reserves
• Structural – part of cell membrane
• Hormone metabolism
Digestion and absorption
1. Bile salts and phospholipids emulsify dietary fats in the small intestine
forming mixed micelles
2. Intestinal lipases degrade TGs
3. Fatty acids and other breakdown products are taken up into intestinal
mucosa and converted into triacyglycerols
4. Triacyglycerols are incorporated with cholesterol and apolipoproyeins
into chylomicrons
5. Chylomicrons move through the lymphatic system and bloodstream into
the tissues
6. Lipoprotein lipase converts triacyglycerols to fatty acids and glycerol
7. Fatty acids enter cells
8. Fatty acids are oxidised as fuel or re-esterified for storage
Fat Catabolism – breaking down into smaller units
1. Molecule of coenzyme A links to carboxyl at the end of a fatty acid
2. Breakdown of ATP > AMP + 2Pi
3. Coenzyme A derivative of fatty acid proceeds through beta-oxidation
reactions
4. Molecule of acetyl coenzyme A is split off from fatty acid and 2H+
transferred to coenzymes
5. Hydrogen atoms from coenzymes enter the oxidative phosphorylation
pathway to form ATP
6. Another coenzyme A attaches to fatty acid and the cycle is repeated
7. Coenzyme – 2H molecules lead to the production of CO2 and ATP via the
Krebs cycle and oxidative phosphorylation
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 LDL
LIVER FUNCTIONS DONE!