Metabollism (Including liver structure) Flashcards
What are the characteristics of the outer mitochondrial membrane?
Smooth and freely permeable to molecules under 5kDa
No ionic or electrical gradients
What are the characteristics of the inner mitochondrial membrane?
Permeable to only a small number of molecules via specific transporters
More protein than lipid
Folded into Cristal
Good insulator, maintains electrical and ionic gradients
What is the blood supply to the liver
INPUT = hepatic artery and portal vein. Receives 25% of cardiac output (75% of which comes from the portal vein and 25% of which comes from the hepatic artery) OUTPUT = hepatic venules drain into the hepatic vein which drains into the IVC
What is the structure of a liver lobule?
Liver divided into lobule separated by connective tissue, lobules are hexagonal with a portal triad at each vertice, the blood from the hepatic artery and portal vein flows through sinusoids in between plates of hepatocytes into a central venule which drains into the hepatic vein. Bile is secreted by cells and runs in bile canaliculi to hepatic duct (runs in opposite direction to blood)
In the liver what is the name of the space between endothelial cells and hepatocytes and what does it contain?
Space of Disse, contains collagen and stellate cells
What is special about the endothelial cells in the internal structure of the liver?
pores and fenestra ensure that endothelial cells do not form a barrier for most small molecules (though particles the size of chylomicrons are excluded).
What are the 5 cell types found in the liver?
1) Hepatocytes
2) Endothelial cells (lining sinusoids)
3) Kupffer cells (macrophages in sinusoidal lining, phagocytose old erythrocytes, gut derived bacteria etc.)
4) Hepatic stellate cells (fat filled cells, primary vitamin A storage, control turnover of connective tissue synthesising collagen and regulate contractility of sinusoids)
5) Pit cells (liver associated lymphocytes), natural killer cells that protect the liver from viruses/tumour cells
What are the basic functions of the liver?
Factory: protein, lipid and carbohydrate metabolism, bile formation
Waste management: detoxify xenobiotics, remove internal waste and degrade bilirubin
What are the components of bile?
Water, bicarbonate, bile salts, phospholipids, free cholesterol
What from and where are bile salts formed?
Formed from cholesterol in the liver
What are the steps in bile salt synthesis?
In liver:
1) Hydroxylation of cholesterol to from primary bile acids
2) Primary bile acids conjugated with either Glycine or taurine and excreted in bile
How are secondary bile acids formed?
In the gut, gut derived bacteria can deconjugate bile salts and can also dehydroxylate primary bile acids to form secondary bile acids (which can be taken back up by gut and circulate to the liver where they can be conjugated to bile salts and secreted in the bile)
Describe the recirculation of bile?
Either conjugated (bile salts) or deconjugated bile acids (primary or secondary) can be reabsorbed by the gut and circulate to the liver where they can be processed and excreted again in the bile
How is bile acid synthesis controlled?
Bile acids inhibit bile acid synthesis - feedback inhibition
What is cholestyramine and how does it work?
Cholesterol reducing drug which works by binding to bile salts and preventing them from being recirculated and thus increases bile salt synthesis from cholesterol
How does increasing dietary fibre reduce cholesterol?
Fibre binds to bile salts and prevents them being circulated so more bile acids are synthesised from cholesterol
Why do gall stones occur?
Bile contains free cholesterol as well as bile salts, if more cholesterol enters the bile than can be solubilised by the bile acids then cholesterol precipitates out
What percentage of bile salts are recirculated?
95%
What are xenobiotics?
They are potentially toxic substances with no nutritional value eg. Drugs/ food toxins or additives
What are the 3 main waste products from the body?
1) Hormones eg. Growth hormone, insulin
2) Bilirubin from the break down of Hb
3) Urea to remove ammonium ions mostly from the breakdown of proteins but some derived from gut bacteria
How are xenobiotics normally broken down?
Phase 1 reactions (oxidation, hydroxylation, reduction, hydrolysis:
Xenobiotic to primary metabolite
Phase 2 reactions (conjugation, sulphation, glucuronidation):
Primary metabolite to secondary metabolite
-Metabolites are normally pharmacologically inactive and more hydrophilic, they are excreted into he urine or bile
Where do phase 1 reactions of metabolism of Xenobiotic normally occur?
In hepatocytes
Which group of enzymes are mainly involved in phase 1 reactions of metabolism of Xenobiotic and where are they found?
Cytochrome P450 enzymes, large family of haem proteins (mono-oxygenases) found in the SER of hepatocytes
They are inducible by some drugs and alcohol
Individual variation in P450 enzymes could be of importance in therapeutics
Why can detoxification of Xenobiotic sometimes present a problem in therapeutics?
Can create problems when drugs delivered orally because of first pass metabolism
Where do phase 2 reactions of the metabolism of Xenobiotic occur and what do they involve?
Many enzymes involved, occur primarily in the liver but also in lung and kidney. Addition of glucuronyl, methyl, acetyl, sulphate and glycyl groups
When is alcohol metabolised by Cytochrome P450 enzymes?
Alcohol is only metabolised by these enzymes when alcohol levels are high, chronic alcohol use induces the synthesis of P450 enzymes
How is alcohol normally metabolised in the liver?
1) Ethanol to Acetaldehyde (by alcohol dehydrogenase in the cytosol of hepatocytes)
2) Acetaldehyde to acetate (be acetaldehyde dehydrogenase in the mitochondria of hepatocytes)
Both reactions produce NADH
How are red blood cells broken down and Bilirubin produced?
1)Old erythrocytes phagocytosed mainly by kupffer cells in the liver but also in the spleen or bone marrow
2) The Globin protein in Hb is degraded but the haem is converted to biliverdin (green) (iron part removed here) then to Bilirubin
HAEM - BILIVERDIN - BILIRUBIN
How is Bilirubin from the break down of erythrocytes transported to the liver?
Bound to albumin (as Bilirubin is very insoluble)
What processes does Bilirubin undergo in the liver?
1) Conjugation (mainly with glucuronic acid)
2) Secretion into bile canaliculi (an active process requiring ATP)
What happens to conjugated Bilirubin when it reaches the gut?
1) Conjugate Bilirubin is metabolised to urobilinogen by gut bacteria
2) Urobilinogen can then either be reabsorbed by the gut and circulate in the blood to the kidneys where is is converted to urobilin and excreted in the urine or…
3) Urobilinogen can be further metabolised in the gut to stercobillin which is excreted in the faeces
What happens to conjugated Bilirubin when it reaches the gut?
1) Conjugate Bilirubin is metabolised to urobilinogen by gut bacteria
2) Urobilinogen can then either be reabsorbed by the gut and circulate in the blood to the kidneys where is is converted to urobilin and excreted in the urine or…
3) Urobilinogen can be further metabolised in the gut to stercobillin which is excreted in the faeces
What is pre-hepatic jaundice?
Haemolytic anaemia eg. Sickle cell anaemia, no problem with liver function but simply too much Bilirubin is being produced to be processed by the liver
What is jaundice?
Can occur due to problems at various stages in the metabolism of Bilirubin, where unconjugated or conjugated Bilirubin cannot be excreted and builds up in the blood and gets deposited in the tissues
What is intrahepatic jaundice?
Can be caused by liver damage, cirrhosis, inflammation infection (or inherited - Gilbert’s syndrome) Liver fails to conjugate Bilirubin and excrete it in the bile
What is extrahepatic jaundice?
Due to a blockage in the bile duct eg. Gall stones, pancreatic carcinoma, bile cannot be excreted (so neither can Bilirubin which builds up and leaks into blood if alternative route is blocked)
What is pre-hepatic jaundice?
Haemolytic anaemia eg. Sickle cell anaemia, no problem with liver function but simply too much Bilirubin is being produced to be processed by the liver
What are the energy stores for a healthy 70kg man?
Fat 400MJ
Usable protein 100MJ
Liver glycogen 2.4MJ
Blood glucose 0.16MJ
In MJ what are the daily energy needs of a 70 kg man?
12MJ
In MJ what are the daily energy needs of a 70 kg man?
12MJ
How much ATP does the average human body contain and what is the rate of turnover of ATP?
Contains 75g but rate of turnover is about 75kg per day
How much energy in food is converted into ATP?
About half is converted into ATP and half is lost a ‘useful’ work
Under aerobic conditions how much cellular ATP is produced in the mitochondria?
About 95%
What are the 2 mitochondrial spaces called?
Matrix and intermembrane space
What are the characteristics of the mitochondrial matrix?
1) Contains a wide range of enzymes - fatty acid oxidation, krebs cycle, urea cycle (only in liver)
2) High concentration of co factors, substrates and ions
3) Contains mitochondrial DNA, RNA and ribosomes, though few mitochondrial proteins are coded on mitochondrial DNA
What are the characteristics of the intermembrane space in mitochondria?
1) Has metabolite and ion concentrations similar to cytosol
2) Contains cytochrome c
In respiration what is the link reaction?
The conversion of pyruvate to acetyl Co A
Which enzyme catalyses the link cycle of respiration?
Pyruvate dehydrogenase
Name an important co factor of the enzyme pyruvate dehydrogenase?
TPP (Thiamine Pyrophosphatase) Vitamin B1
What does deficiency in Vitamin B1 (Thiamine) cause and why?
Beri Beri (neurological/cardiovascular symptoms) - disrupts the function of Pyruvate dehydrogenase (from the link reaction)
What does deficiency in Vitamin B1 (Thiamine) cause and why?
Beri Beri (neurological/cardiovascular symptoms) - disrupts the function of Pyruvate dehydrogenase (from the link reaction)
What is Wernicke-Korsakoff syndrome?
Syndrome caused by lack of thiamine seen in alcohol addicts
How is action of the enzyme pyruvate dehydrogenase controlled?
PDH is inactivated (phosphorylated) when energy levels are high, activation is prompted by any sudden demands on the cell signalled by Ca2+
Why is the link reaction a ‘key decision point’ in metabolism?
Acetyl Co A cannot be converted back to glucose in humans, conversion commits the carbon atoms to energy production (lost as CO2) or lipid synthesis
What are the main outputs of the Krebs/citric acid cycle?
Reduced co enzymes NADH and FADH2, CO2 (waste product) and 1 GTP (=1 ATP)
What are the main outputs of the Krebs/citric acid cycle?
1) Reduced co enzymes NADH and FADH2
2) CO2 (waste product)
3) 1 GTP (=1 ATP)
How is action of the enzyme pyruvate dehydrogenase controlled?
PDH is inactivated (phosphorylated) when energy levels and levels of AcetylCoA from fat oxidation are high, activation is prompted by any sudden demands on the cell signalled by Ca2+
What are the main outputs of the Krebs/citric acid cycle?
1) Reduced co enzymes NADH and FADH2
2) CO2 (waste product)
3) 1 GTP (=1 ATP)
Where does the link reaction take place?
In the mitochondrial matrix. Pyruvate is transported across the inner mitochondrial membrane from the cytosol to the mitochondrial matrix
What are the 2 main stages of the Krebs cycle?
1) Synthesis of 6-C compound (citrate - by combining oxaloacetate and acetyl co A) which then loses 2 C as CO2 to become 4-C compound (succinyl CoA)
2) Oxidation of 4-C compound to regenerate oxaloacetate and initiate another round of the cycle
What is the TCA (tricarboxylic acid cycle)?
Another name for the Krebs cycle
Where does the Krebs/citric acid/TCA cycle take place?
Mitochondrial matrix
What are the key enzymes (control points) in Krebs cycle?
1) Citrate synthase (AcetylCoA + Oxaloacetate)
2) Isocitrate dehydrogenase (Isocitrate to a-ketoglutarate)
3) a-ketoglutarate dehydrogenase (a-ketoglutarate to succinyl co-A)
How are the key enzymes in the Krebs cycle controlled?
1) Inhibited by high levels of NADH and ATP (and succinyl CoA and citrate at points)
2) Stimulated by ADP and NAD+ (only isocitrate dehydrogenase)
How does the Krebs cycle act as an exchange for intermediates of other metabolic pathways?
1) Amino acid carbon chains can be fed into the Krebs cycle
2) Odd chain fatty acids can be fed in (succinyl CoA)
3) Citrate can be used in fatty acid and cholesterol synthesis
4) Malate (one step before oxaloacetate) can be used for glucose synthesis
5) a-ketoglutarate and oxaloacetate can be used in amino acid synthesis
6) SYNTHESIS OF OXALOACETATE FROM PYRUVATE (+CO2) IS IMPORTANT IN REPLENISHING OXALOACETATE FOR KREBS CYCLE TO CONTINUE - oxaloacetate can also come from amino acid carbon chains
Why can diabetic patients not effectively use blood glucose?
In the absence of insulin cells cannot detect blood glucose so start synthesising glucose (even when blood glucose levels are high)
Why do patients with Type 1 diabetes synthesise ketones?
1) Glycolysis is inhibited so conc. pyruvate is low
2) Gluconeogenesis is not inhibited so oxaloacetate and Malate being removed to synthesise glucose
3) In the absence of insulin fatty acids are mobilised from adipose tissue and oxidised to acetyl co A
4) Lack of oxaloacetate prevents this acetyl Co A from entering the Krebs cycle so it is used to synthesis ketones instead
Why do patients with type 1 diabetes develop ketoacidosis?
Even though ketones are being synthesised, brain doesn’t take up ketones as it simply uses the blood glucose that is present but cells can’t detect. Ketones then build up in the blood.
What are the 2 processes in oxidative phosphorylation?
1) Electron transport chain: OXIDATION
2) ATP Synthesis: PHOSPHORYLATION
Where do the processes of oxidative phosphorylation take place?
Across the inner mitochondrial membrane
What are the components of the electron transport chain?
Transmembrane proteins: Complexes 1-4 (also ubiquinone and Cytochrome c)
What process occurs in the electron transport chain of oxidative phosphorylation?
Electrons from NADH and FADH2 enter the ETC and Electrons are transferred from one electron carrier to the next - energy released is used
When the electrons reach Complex IV they are donated to oxygen, reducing it to water – this removes them from the chain.
What process occurs in the electron transport chain of oxidative phosphorylation?
Electrons from NADH and FADH2 enter the ETC and Electrons are transferred from one electron carrier to the next, each reduction step results in the release of energy - energy released is used to pump H+ across the inner mitochondrial membrane (4+4+2 = 10) creating a large proton gradient across the inner mitochondrial membrane
When the electrons reach Complex IV they are donated to oxygen, reducing it to water – this removes them from the chain.
Why is cyanide poisonous?
It blocks the accepting of electrons by oxygen to form water at the end of the ETC, electrons block up along the chain and stop you producing ATP - suffocate despite access to sufficient oxygen
Why are more H+ pumped across the inner mitochondrial membrane using electrons from NADH than FADH2?
FADH2 enters the ETC further along than NADH (at complex 2) so only pumps 8H+ across instead of 10
In oxidative phosphorylation how is ATP synthesised?
Protons flow across through the F0F1 ATPase enzyme down the concentration gradient, this provides the energy required to synthesise ATP
How many hydrogen ions are required to flow through F0F1 ATPase enzyme to produce 1 molecule ATP?
3
What transporters involved in ATP synthesis of oxidative phosphorylation are present in the inner mitochondrial membrane?
1) ADP/ATP antiporter - synthesised ATP flows out in exchange for APD to be used in ATP synthesis
2) Pi/H+ co transporter - Pi transport into matrix requires the removal of 1 H+ from intermembrane space (so synthesis of ATP actually requires 4 (3+1) H+ ions)
How does NADH produced in the cytosol reach the matrix?
NADH cannot directly cross the inner mitochondrial membrane so has to be oxidised in the cytosol, cross the inner mitochondrial membrane as NAD then be reduced in the matrix by electron transport
Why is ATP synthesis not possible if the ETC isn’t functioning?
No proton gradient to drive ATP syntheses enzyme
Why is ETC not possible if ATP synthesis is not occurring?
Protons flow across through the F0F1 ATPase enzyme down the concentration gradient
Energy cannot be released from the electron carriers, so they can’t accept any more electrons – electron transport stops
What are uncouplers into the context of oxidative phosphorylation?
Uncouplers are weak acids which are soluble in the membrane
When they penetrate the inner mitochondrial membrane they diffuse freely
At the inter-membrane space interface they associate with protons – driven by the relatively high [H+]
At the matrix surface they release protons – driven by relatively low [H+]
Overall effect is to dissipate the proton gradient and ETC can continue without ATP synthesis
How is uncoupling used in new born babies?
1) Babies possess brown adipose tissue – has more mitochondria/ different appearance to white adipose tissue
2) Mitochondria in brown adipose tissue contain thermogenin (uncoupling protein-1)
3) When core body temperature drops, sympathetic nervous system release of noradrenalin leads to increased concentrations of free fatty acids in the cytosol, which activate thermogenin
Babies use this mechanism to maintain core body temperature - they uses the ETC to generate heat rather than for ATP synthesis
What is the significance of brown adipose tissue in adults?
Recently identified in adults, decreases with obesity and age, may be a valuable therapeutic target to promote triglyceride clearance and weight loss
What is dinitrophenol?
Was available as a slimming pill, However side effects including hyperthermia, tachycardia, excess sweating, blindness (due to cataracts) & fatalities led to it being withdrawn in 1938
What are the 5 possible uses of amino acids in the body and what must be removed from them before they can be put to any of these uses?
Nitrogen must be removed
1) Protein synthesis
2) Glucose/ glycogen synthesis
3) Fatty acid, ketone body synthesis
4) Break down to form ATP
5) Synthesis of nitrogen containing metabollites
The nitrogen containing compounds dopamine, noradrenaline and adrenaline are synthesised from which amino acid?
Tyrosine
The nitrogen containing compound haem is synthesised from which amino acid?
Glycine
The nitrogen containing compound serotonin is synthesised from which amino acid?
Tryptophan
The nitrogen containing compound histamine is synthesised from which amino acid?
Histidine
The nitrogen containing compound creatine is synthesised from which amino acids?
Glycine and Arginine
The nitrogen containing compounds purine bases are synthesised from which amino acids?
glycine, aspartate and glutamine
Why would severe malnutrition lead to:
1) susceptibility to infection,
2) changes in hair/skin colour,
3) poor skin condition and poor nutrient absorption
4) Abdominal bloating
5) lower limb odema?
1) Ab made out of proteins
2) Not enough melanin
3) epithelial cells have fast turnover, tend to be the first hit by malnutrition
4) Cant make proteins to transfer lipids that are synthesised
5) Albumin is a key protein for maintaining oncotic pressure of the blood
What is kwashiorkor syndrome?
Lack of protein in severe malnutrition, predominantly a disease in children in developing countries
How is the nitrogen formed from amino acids excreted from the body?
As ammonia
What is hyperammonaemia, symptoms and causes?
High levels of ammonia in the blood
Symptoms - tremor, vomiting, cerebral oedema, coma and death
Causes - can occasionally result from a defect in urease enzymes but is more commonly caused by liver disease - hepatitis or cirrhosis
Where does disposal of ammonia occur?
Mainly in the liver, ammonia is converted to urea for excretion by the kidneys
What are the 3 steps in excretion of nitrogen and where do they principally occur?
1) Transamination - transfer of amino group from amino acid to a-ketoglutarate forming glutamate (IN MOST TISSUES)
2) Deamination - release of ammonia from glutamate (MAINLY IN LIVER)
3) Urea synthesis - urea cycle (IN THE LIVER)
How is ammonia transferred in the blood?
As glutamate (carrying 1 ammonia) or as glutamine (Extra ammonia added so carrying 2)
In the liver describe the process of deamination in the excretion of nitrogen?
Reverse of the transamination step that occurs in peripheral/muscle tissues
( 1) Ammonia removed from glutamine to make glutamate)
2) Ammonia released from glutamate to make a-ketoglutarate
Which enzyme (and co factor) is required in the transamination step of excretion of nitrogen
Transaminase, require pyridoxal phosphate (active form of vit B6)
Which enzyme is involved in the deamination step of excretion of nitrogen?
Glutamate dehydrogenase
As well as transamination of amino acids what is pyridoxal phosphate (active form of vit B6) required for?
1) Synthesis of amino acids
2) Decarboxylation reactions required for neurotransmitter synthesis
3) Haem synthesis
4) Some aspects of energy metabolism and lipid synthesis
What are the symptoms of Vit B6 (pyridoxal phosphate)?
1) Anaemia (lack of haem synthesis)
2) Neurological symptoms (lack of neurotransmitter and lipid synthesis)
3) Poor growth, skin lesions, poor immune response (lack of amino acid and thus protein synthesis)
Where in the hepatocytes does the urea cycle occur?
Mitochondrial matrix
Where in the hepatocytes does the urea cycle occur?
First bit in mitochondrial matrix
second bit in cytosol
(Changes compartments halfway through)
In the urea cycle what is the control step?
The first step that occurs - the formation of carbamoyl phosphate from ammonia and bicarbonate (CO2)
What steps of the urea cycle occur in the mitochondrial matrix?
1) Carbamoyl phosphate formed from ammonia and bicarbonate - CONTROL STEP
2) Carbamoyl group transferred to ornithine to form citrulline
What steps of the urea cycle occur in the cytosol?
(the second half of the cycle)
3) Second amino group added to citrulline from aspartate
4) Argininosuccinate and then arginine is formed
5) UREA IS RELEASED
6) Ornithine produced goes back into mitochondrial matrix to be combined with carbonyl phosphate
When is the urea cycle activated?
When levels of amino acids are high
How is the urea cycle activated?
Carbomyl phosphatase synthase 1 is the enzyme that catalyses the control step of the cycle, this is allosterically activated by N-acetylglutamat which is formed when glutamate levels are high (signalling high levels of protein catabolism)
What is the difference between urea and uric acid?
They are not the same thing! But both do contain nitrogen, uric acid is derived from purine nucleotides rather than proteins
What it hyperuricaemia and what can it lead to?
Excess uric acid in the blood, it can lead to deposition of sodium urate crystals in the kidneys (kidney stones) and in the joints (gout)
What is the cause of hyperuricaemia?
Either due to over production of urate or poor excretion via the kidneys, high purine food (Red meat, seafood, yeast containing foods including beer) should be avoided
Name 3 common pathways that the carbon skeletons of amino acids can be fed into?
1) Krebs cycle used to synthesise ATP
2) Fatty acid and ketone synthesis
3) Glucose synthesis (gluconeogenesis)
What are the 2 common amino acids which cannot be made into glucose but are solely ketogenic - can only be made into acetyl CoA & ketone bodies?
Lysine and Leucine
What is gluconeogenesis?
Synthesising glucose from non carbohydrate intermediates - during fasting or exercise
Where does gluconeogenesis mainly take place?
Mainly in the cytosol of the liver and kidneys
What are the 3 main non carbohydrate intermediates used in gluconeogenesis?
1) Keto acids - derived from amino acids (particularly alanine)
2) Lactate - derived from anaerobic glycoslysis
3) Glycerol - from triacylglycerol breakdown
Many reactions in gluconeogenesis are simply reversal of glycolysis reactions, but 3 steps in glycolysis are irreversible, which 3 steps are catalysed by different enzymes in gluconeogenesis?
1) Pyruvate -> phosphoenolpyruvate (requires several stages)
2) Fructose 1,6 bisphosphate -> fructose 6 phosphate (fructose 1,6 bisphosphatase)
3) Glucose 6 phosphate -> glucose (glucose 6 phosphatase)
Nb. in gluconeogenesis 6ATP are required
How are gluconeogenesis and glycolysis controlled?
They are reciprocally regulated:
- High glucose and/or low energy = glycolysis
- Low glucose and/or high energy = gluconeogenesis
What are the effects of glucagon and insulin on glycolysis and gluconeogenesis?
- Glycolysis is inhibited by glucagon and activated by insulin
- Gluconeogenesis is activated by glucagon and inhibited by insulin
Other than insulin and glucagon which substances activate/inhibit gluconeogenesis?
Inhibited by AMP and ADP
Activated by citrate and acetyl coA
What is the core cycle?
The core cycle converts lactate from rapidly respiring muscle back to glucose
Where does the core cycle take place?
Glucose converted to lactate (via pyruvate) in MUSCLE
Lactate carried in the blood to the LIVER where the lactate is converted to glucose (via pyruvate) and the glucose is carried in the blood back to the muscle where it can be used again
What is the purpose of the glucose-alanine cycle?
To sustain transamination in peripheral tissue, by providing a safe way to transfer nitrogen in the blood to the liver and also a way of regenerating a-ketoglutarate (cells that are rapidly breaking down amino acids run out of a-ketoglutarate)
What happens in the glucose-alanine cycle?
Some glutamate produced in peripheral
What happens in the glucose-alanine cycle?
1) Some glutamate produced in peripheral tissues transfers its amino group to pyruvate to produce alanine and regenerate a-ketoglutarate
2) Alanine travels in the blood to the liver where it transfers its amino group on to a-ketoglutarate to regenerate glutamate and pyruvate
3) Pyruvate is converted to glucose in the liver, the glucose travels in the blood to the peripheral tissues where it is converted to pyruvate and the whole cycle can start again
Why does alcohol make you hungry?
1) Ethanol metabolism produces large amounts of NADH
2) High levels of NADH tend to cause conversion of pyruvate (including that produced from alanine) to lactate (reaction is reversible)
3) high levels of NADH also prevent conversion of glycerol to G3P (glyceraldehyde 3 phosphate - which would become glucose)
4) thus high levels NADH inhibit gluconeogenesis and thus lower blood sugar making you hungry
What do deficiency in and excess growth hormone lead to in children?
Deficiency = dwarfism Excess = gigantism
What does excess growth hormone lead to in adults?
Epiphyses are closed so bones cant increase in length so there is no change to stature, however excess growth hormone in adults leads to acromegaly: bones become excessively thickened, other tissues overgrow
What does deficiency in growth hormone lead to in adults?
No obvious disease but replacement increases lean body mass, decreases fat and increases vigour
GRH (growth hormone-releasing hormone) is released from where in response to what?
Released from the arcuate nucleus of the hypothalamus
Released in response to: Low glucose, amino acids, TRH, Ghrelin, sex hormones, sleep, exercise and stress
Where is growth hormone released from and in response to what?
Growth hormone is released from the anterior pituitary
Release is stimulated by GRH and inhibited by Somatostatin aswell as IGF’s (insulin like growth factors)
What are the target organs of GH?
Fat, Cartilage and Bones, Liver
What is the role of somatostatin in GH release, where is it released from, stimulated by what and inhibited by what?
Somatostatin released from the paraventricular nucleus of the hypothalamus
Somatostatin released in response to GH and it inhibits the release of GH from the anterior pituitary (-ve feedback)
Somatostatin also inhibits the release of GRH (-ve feedback) and the release of somatostatin is inhibited by GRH to keep a balance
Which 3 hormones act on the anterior pituitary to control the release of Growth hormone?
1) Somatostatin inhibits release
2) GRH (growth-hormone releasing hormone) stimulates release
3) IGF’s inhibit release
What is the pattern of secretion of growth hormone?
Pulsatile releases (lots of rapid pulses) with more released during sleep
What kind of receptor is the GRH (or GHRH) receptor at the anterior pituitary?
A GPCR, acts through adenylyl cyclase and cAMP
What kind of receptor is the Somatostatin receptor at the anterior pituitary?
A GPCR, acts through Gi
How many splice variants of growth hormone exist?
2 (Come from same DNA but different splicing)
22kDa = main form, some 20kDa
How is about 40% of growth hormone released carried in the blood and why?
Binds to plasma proteins made by cleaving its receptor - this buffers it and protects it from the proteases in the circulation
What kind of receptor does growth hormone act through>
Tyrosine Kinase ASSOCIATED receptor leading to protein phosphorylation
What are the rapid/acute effects of GH on liver muscle and fat?
Diabetogenic effects
1) Liver: increased gluconeogenesis
2) Fat: Increased lipolysis
3) Muscle: decreased glucose uptake
4) Insulin resistance
What hormone are the long term effects of GH on growth mediated via and where is it released from?
Mediated via insulin-like growth factor 1 (IGF1) (also called somatomedin), released from liver, cartilage and bones in response to GH
What are the 2 forms of IGF’s (somatomedins) and which one is more active and which one is not controlled by GH?
IGF1, IGF2
IGF 1 is more active
IGF 2 is not controlled by GH
What are the broad effects of IGF’s (somatomedins)?
Enhance protein synthesis and growth
Can cause hypoglycaemia (cross reactivity with insulin)
What is the role of insulin in growth?
Need insulin to facilitate growth, need growth hormone to make it happen but glucose say we have enough energy for it to happen (especially needed in utero)
What is the role of steroids in growth?
Sex steroids accelerate growth, but hasten maturity
Glucocorticoids typically slow growth
What is the role of thyroid hormones in growth?
Act like insulin as a facilitator, essential for normal growth and response to GH
How are thyroid hormones carried in the blood?
Tightly bound to proteins (especially thyroid binding globulin and transthyretin)
Why are thyroid hormones carried in the blood tightly bound to proteins?
Greatly prolongs half lives (T4 - 8 days, T3- 1 day)
Where are thyroid hormones released from and in response to what?
Released from the thyroid gland in response to TSH released from pituitary
What is the general effect of thyroid hormone on metabolism?
Increase metabolic rate and heat generation
What are the 3 forms of thyroid hormone, which has most activity and which is produced in the greatest amounts in the thyroid gland?
T3 - active form
T4 - little activity but 90% secreted is in this form
rT3 - inactive
What hormone stimulates nearly all the steps in the production of thyroid hormone?
TSH
What is iodination in the production of thyroid hormone and what process follows?
In the lumen of the gland - Iodine (taken up by the follicular cells from the blood and released into the lumen) is added to thyroglobulin (secreted into lumen from follicular cells)
Conjugation follows then endocytosis, then proteolysis then secretion of T3 or T4 into blood
What happens to T4 in the periphery to make T3?
T4 gets deiodinated by 2 enzymes to form T3
Where are Type 1 and 2 enzymes that deiodinate T4 to T3 found?
Type 1 - found in liver kidney and thyroid, inhibited by stress and caloric restriction
Type 2 - found in pituitary, CNS and placenta, is constitutive (works all the time)
What receptor does Thyroid hormone act through?
Nuclear receptor which initiates gene transcription (may be additional non genomic effects)
What are the acute effects of thyroid hormone?
1) Increases basal metabolic rate and heat production via ‘futile cycles’ (forward and backward reactions at the same time) and mitochondrial uncoupling
2) Causes both lipolysis and lipogenesis
3) Increases proteolysis but also protein synthesis - net muscle wasting
4) Increases Na+/K+ATPase and leak
5) increases Beta receptor expression
6) usually no hyperglycaemia (insulin control normal)
What are the chronic effects of thyroid hormone, what does deficiency in infancy or in later childhood lead to and what does low TH lead to which is common in areas with low environmental iodine?
1) Crucial for normal brain development and growth
2) Deficiency in infancy leads to cretinism and dwarfism
3) Later in childhood there is severe impairment of growth: catch-up growth is possible
4) TSH drives thyroid hypertrophy, so low TH (And lack of feedback) leads to a goitre: common in areas with low environmental iodine
How can auto immunity cause hyperthyroidism?
antibodies against the TSH receptor may activate it, driving excess thyroid hormone production and cause hyperthyroidism (eg. graves disease)
What are the symptoms of graves disease?
(all hyperthyroidism): weight loss, tremor, sweating , tachychardia, dislike hot weather
(Graves disease): exophthalmos (eyes stick out), double vision, pretibial myxoedema (growth of tissue in front of shin, feels woody)
How can auto immunity cause hypothyroidism?
Ab that destroy TSH receptors or other targets cause hypothyroidism (eg. Hashimoto’s thyroiditis)
What is myxodema?
Another name for hypothyroidism
What are the symptoms of hypothyroidism?
Weight gain, hypothermia, tiredness, constipation, skin thickening and oedema, bradychardia, dislike of cold weather, secondary anovulation (don’t ovulate, lose menstruation cycle)
What is the main natural glucocorticoid in man?
cortisol
Where is CRH (corticotrophin releasing hormone) released from?
Hypothalamus integrates diurnal rhythm, physical, environment and biochemical stress factors to release CRH
What does CRH act on and what does it cause?
Acts on GPCR receptors in the anterior pituitary to cause the release of ACTH (adrenocorticotropic hormone)
What does ACTH act on and what does it cause?
ACTH stimulates the adrenal cortex hypertrophy and cortisol production
How is the release of ACTH inhibited?
Iatrogenic steroids suppress ACTH release and cause adrenal atrophy
What are the acute effects of glucocorticoids in general, in liver, in fat and in muscle?
1) Inhibit insulin response and enhance SNS responses (target glucose to the brain, other organs use fats)
2) In liver: promotes gluconeogenesis and glucose release
3) In fat: lipolysis (glycerol for gluconeogenesis and FFA for energy)
4) In muscle: protein breakdown for gluconeogenesis
What kind of receptor do glucocorticoids act via?
Nuclear receptor, inducing gene transcription
What are the chronic effects of glucocorticoids?
1) Immunosuppression
2) Reduction in inflammation and cytokine production
3) Stimulate haematopoiesis and GI tract mucosae
4) Fat redistribution - peripheral to central
5) Skin thinning, muscle wasting, osteoporosis
6) Complex CNS effects: euphoria to psychosis
What is disease is caused by excess glucocorticoids?
Cushing’s sydrome
What disease is caused by adrenocortical insufficiency?
Addison’s disease (high ACTH gives slaty pigmentation)
GH, TH and insulin work together to increase growth, in the simplest terms when do they allow growth?
Restrict growth when food is short and enhance growth when food is plentiful
Are GLUT 1- 5 glucose transporters passive of Na+ symporters?
Passive
Are SGLT-1 and 2 glucose transporters passive or Na+ symporters?
Na+ symporters
What is the affinity of GLUT 2 for glucose and which tissue is it found in?
Has low affinity and found in kidneys, ileum, liver and pancreatic beta cells
What is characteristic of GLUT 4 for glucose and which tissues is it found in?
insulin responsive (inserted into the membrane in response to insulin), found in skeletal muscle, heart and adipocytes
Where are SGLT 1 and 2 glucose transporters found?
In apical brush border of the small intestine
Which cells of the islets of Langerhans of the pancreas release insulin?
Beta cells found mostly in the core
Which cells of the islets of Langerhans of the pancreas release glucagon>
alpha cells found mostly on the periphery of the gland
Which cells of the islets of Langerhans produce somatostatin?
delta cells
What do the F cells of the islets of Langerhans release?
pancreatic polypeptide
Through what transporter does glucose enter the beta cells of the islets of Langerhans?
GLUT 2 (which is insulin insensitive and low affinity)
After the entry of glucose into the beta cells of the pancreas how is insulin released?
1) Beta cells sense glucose (and AA) in the blood by using it to make ATP
2) ATP closes K+ATP channels (Stopping it moving out) depolarising the membrane
3) Depolarisation causes Ca2+ influx (from outside) and CICR (Calcium induced calcium release from the SER)
4) The high levels of calcium induce exocytosis of insulin
Which deliver of glucose induces higher release of insulin: IV or oral?
Oral
What is significant about the pattern of insulin release with a rapid load of glucose?
Its biphasic (2 peaks)
What is the action of the ANS (autonomic nervous system) on insulin release?
PNS drives insulin secretion
SNS inhibits insulin secretion
What else acts on insulin release aswell as ANS and glucose?
Secretagogues (incretins) act via cAMP or PLC pathways to increase exocytosis
Inhibitors can antagonise eg. via Gi
What is the role of C peptide (from insulin production) in terms of markers?
C peptide is inactive, but clinically is a useful marker of endogenous insulin production
What is the rough process (in terms of protein chain etc.) of the production of insulin?
1) Insulin is produced as a preprohormone which is quickly cleaved to a prohormone
2) Internal disulphide bonds fold it up
3) During processing in the Golgi it is cleaved to an A and B chains which are linked and a free C peptide
What kind of receptor is the insulin receptor?
Receptor itself is an enzyme - tyrosine kinase receptor
How does the insulin receptor work?
The TK domains phosphorylate eachother and nearby proteins, in particular a family of insulin receptor substrates
What are the 2 basic pathways that occur once insulin reaches the insulin receptor?
1) Signal and lead to an acute response: GLUT 4 transporters put in membrane and glucose taken up into cells
2) Slower, gene expression is altered, transcription activated (via MAPK pathway) and various proteins made
Through which transporter is glucose taken up into the liver?
The GLUT 2 transporter, its non insulin sensitive and has a low affinity for glucose so only takes up a decent amount of glucose when glucose v high
What reactions in liver cells are stimulated by insulin?
1) Glycogen storage increased
2) VLDL production increased
What reactions in liver cells are inhibited by insulin?
1) Gluconeogenesis inhibited
2) Ketone body production inhibited
In response to insulin, through what transporter is glucose taken up into muscle cells and adipose cells?
GLUT 4 inserted and glucose taken up via GLUT 4 - GLUT 4 favours use of glucose
What reactions increase in muscle cells in response to insulin?
1) Glycogen synthesis increase
2) Protein synthesis increase
(3) Break down of fatty acids inhibited)
Other than insulin what else induces GLUT 4 insertion into the muscle cell membrane?
Exercise via adrenaline
What reactions in fat cells are increased and decreased in response to insulin?
1) Triglyceride storage increased
2) Export of FFA (for energy) and glycerol (for gluconeogenesis) reduced
3) LPL exported to endothelium, where it extracts FFA from VLDL (just released by liver in response to insulin)
What is glucagon release from alpha cells antagonised and driven by?
Antagonised by glucose and driven by amino acids
Proglucagon can be turned into 2 things during primary processing, where does the processing of each take place?
1) Processed to glucagon in the alpha pancreatic cells
2) Processed to GLP1 in intestinal L cells, a potent incretin (as is glucagon itself)
What kind of receptor is a glucagon receptor?
GPCR linked to Gs
What are the effects of glucagon on liver cells?
1) Glycogen breakdown and gluconeogenesis
2) Presence of G6Pase allows G6P to be broken to glucose and then exported
3) Fatty acids used as an energy source and for ketone body production
(At high levels) what are the effects of glucagon on muscle cells and adipocytes?
1) Adipocytes: Lipolysis
2) Muscle: Proteolysis to free up amino acids for gluconeogenesis
Why is there no effect of glucagon on muscle and adipocytes normally?
First pass metabolism of liver
What is the shift in metabolism to do with when glucose in the blood falls?
Largely due simply to a decrease in insulin as glucose falls
Somatostatin is released from what cells in what 3 parts of the body?
Released from the D cells of the stomach, pancreas and duodenum (also released from the hypothalamus - suppresses GH release)
What is the main mode of secretion of somatostatin?
Acts in a paracrine fashion (and possibly in an endocrine fashion)
What is somatostatin released in response to and inhibited by?
1) release stimulated by [H+]
2) release is inhibited by ACh
What is the action of somatostatin?
1) Acts on G cells to inhibit the release of gastrin
2) Inhibits the release of CCK and secretin (and insulin and glucagon, if it can get into cells)
(3) Inhibits release of GH from anterior pituitary)
What hormone is released during exercise that causes the metabollic effects of exercise?
Adrenaline (acts through cAMP) (cortisol also has same effects)
What are the effects of exercise (ie. adrenaline) on metabollism?
1) Glucose production in liver (inc. via Cori cycle)
2) Glycogen breakdown in muscle and GLUT 4 insertion (also via intrinsic AMPK)
3) Fatty acids released from adipocytes
Polyuria, polydipsia, weight loss, blurred vision and ketoacidosis are symptoms of what disease and why?
Diabetes
Polyuria - increase in urine production (glucose lost in urine and pulls water with it)
Polydipsia - more thirsty
Weight loss - losing energy in urine
Blurred vision - high glucose = difficult to focus eyes
Ketoacidosis - liver fooled by lack of insulin so produces ketones (despite high glucose) and brain uses glucose in liver so ketones build up
What is the cause of diabetes mellitus (type 1)?
Inability to produce insulin,
autoimmune cells, in which beta cells are destroyed
What imbalance in the blood leads to lipolysis, proteolysis, gluconeogenesis and ketogenesis in the liver?
Excess glucagon or glucagon: insulin imbalance
What is the cause of diabetes mellitis (type 2)?
Impaired cellular response to insulin - receptor down regulation, reduced signalling
strongly associated with obesity
Is ketoacidosis common in diabetes type 2?
no
Which kind of diabetes mellitis require exogenous insulin?
Type 1 (type 2 rarely does)
What is the treatment for diabetes type 2?
1) diet to reverse the problem
2) Drugs to enhance insulin secretion (sulphonylureas, incretins)
3) Drugs to enhance insulin sensitivity (piaglitazone)
4) Drugs to inhibit gluconeogenesis (metformin)
What problems are poor control of diabetes mellitis associated with?
Poor control associated with serious long-term vascular, ocular, renal and neurological problems (glucose binds to stuff and messes it up)
Why can IGFs cause hypoglycaemia?
Cross reactivity with insulin
