Metabolism S4 - Lipids, Glycogen and Fat Flashcards
What are the different classes of lipids?
- Fatty acid derivatives - Hydroxy-methyl-glutaric acid derivatives (C6 compound) - Vitamins: can’t make A, D, E or K ourselves
Name some fatty acid derivatives
- Fatty acids (fuel molecules) - Triacylglycerols/triglycerides (fuel storage and insulation) - Phospholipids (components of membranes and plasma lipoproteins) - Eicosanoids (local mediators: signal between cells to coordinate a generalised tissue response)
Name some hydroxy-methyl-glutaric acid derivatives
- Ketone bodies C4 (water soluble fuel molecules) - Cholesterol C27 (membranes and steroid hormone synthesis) - Cholesterol esters (cholesterol storage) - Bile acids and salts C24 (lipid digestion)
Describe some features of lipids
- Structurally diverse - Generally insoluble in water (hydrophobic) - Most only contain C, H, O (phospholipids also contain P, N) - More reduced than carbohydrates so release more energy when oxidised, and complete oxidation requires more oxygen
Describe the weight and energy content of triacylglycerols in a healthy 70kg man compared to an obese 135kg man
- 70kg: TAG ~15kg, ~600,000kJ - 135kg: TAG ~80kg, ~3,000,000kJ - Hence obese man has 2,400,000kJ excess
Describe the structure of triacylglycerols (TAG)
2 hydrogens on every carbon, so highly reduced
Describe some features of triacylglycerols (TAG)
- Hydrophobic so stored in an anhydrous form - Stored in specialised tissue: adipose tissue - Utilised in prolonged exercise, starvation and during pregnancy (switch to fatty acid metabolism) - Storage/mobilisation under hormonal control
Describe the tissues involved in triglyceride metabolism
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Describe the metabolism of triacylglycerol
- GI tract: lipids (TAG) in diet. Extracellular hydrolysis of lipids in small intestine by pancreatic lipases to fatty acids and glycerol - These are recombined in small intestine and transported as TAG by lipoproteins (chylomicrons) to either adipose tissue (stored as TAG) or consumer tissues (fatty acid oxidation to energy, not cells without mitochondria like RBCs, not brain as fatty acids do not easily pass blood-brain barrier) - Fat can be mobilised from adipose to consumer tissue FA-albumin, using hormone-sensitive lipase. Glucagon and adrenaline increase, insulin decreases
Describe the role of fatty acids in metabolism
- Converted back to triglycerides in GI tract - Packaged into lipoprotein particle (chylomicrons) - Released into circulation via lymphatics - Carried to adipose tissue and stored as triglyceride - Released as fatty acids when needed - Carried to tissues as albumin: fatty acid complex
What is the result of low extracellular [glucose]?
Fatty acid release as alternative fuel
Describe some features of fatty acids (FA)
- CH3(CH2)nCOOH where n=14-18 (e.g. 16-20 C in total) - Saturated or unsaturated (one or more carbon-carbon double bonds) - Amphipathic (contain hydrophobic and hydrophilic groups) - Certain polyunsaturated FA, e.g. linoleic acid, are essential (required in diet) because mammals cannot introduce a double bond beyond C9
Describe fatty acid catabolism
Mitochondrial 1. FA is activated (by linking to coenzyme A) outside the mitochondrion 2. Transported across the inner mitochondrial membrane using a carnitine shuttle 3. FA cycles through sequence of oxidative reactions, with C2 removed each cycle
Describe fatty acid activation
- Occurs outside the mitochondria, in cytoplasm - Fatty acids are activated by linking in coenzyme A (via high energy bond) by the action of fatty acyl CoA synthase: - Fatty acid + ATP + CoA ➡️ fatty acyl~CoA + AMP + 2Pi - Pi unstable and spontaneously hydrolysed. Energy used to attach CoA - Activated fatty acids (fatty acyl~CoA) do not readily cross the inner mitochondrial membrane
Describe the carnitine shuttle
- Transports fatty acid acyl~CoA across mitochondrial membrane - Regulated, so controls rate of FA oxidation - Inhibited by malonyl~CoA (biosynthetic intermediate) - Defects can occur in this transport system (exercise intolerance, lipid droplets in muscle) PIC
What is beta-oxidation?
Catabolism of fatty acids
Summarise beta-oxidation
- All intermediates are linked to CoA (FA activation) - More energy derived from FA oxidation than glucose oxidation - Stops in absence of O2 (no substrate-level phosphorylation) - No ATP synthesis PICS
Describe glycerol metabolism
Glycerol can be transported in the blood to the liver, where it is metabolised
What is the main convergence point for catabolic pathways?
Acetyl-CoA - CH3CO group linked to coenzyme A - Linked via S-atom: high energy of hydrolysis - Therefore, activated acetyl group - CoA contains vitamin B5: panthenoic acid (deficiency leads to impaired metabolism)
What are the functions of acetyl~CoA?
A most important intermediate in both catabolic and anabolic pathways
What are the three ketone bodies produced in the body?
- Acetoacetate: CH3COCH2COO- (liver) - Acetone: CH3COCH3 (spontaneous non-enzymatic decarboxylation of acetoacetate) - Beta-hydroxybutyrate: CH3CHOHCH2COO- (liver)
What are the normal and elevated levels of ketone bodies in the body?
- Normal plasma ketone body concentration: less than 1mM - Starvation: 2-10mM (physiological ketosis) - Untreated Type 1 diabetes: greater than 10mM (pathological ketosis; fruity smell of breath due to release of acetone)
How are ketone bodies synthesised?
By liver mitochondria
Describe control of ketone body production in the liver
- Low blood glucose levels result in release of fatty acids from adipose tissue, leading to: - Low NAD+ substrate availability, NADH product inhibition - Inhibition of enzymes isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase due to lack of substrate and negative feedback by NADH, inhibiting TCA - Acetyl-CoA build up: can’t get into TCA cycle due to high NADH levels caused by breakdown of triglycerides to fatty acids which are converted to acetyl-CoA with NAD+ ➡ NADH - Acetyl-CoA diverted from TCA cycle to production of ketone bodies, which supply energy needs preserving depleted circulating glucose levels PIC
Describe the metabolism of ketone bodies
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Describe the regulation of ketone body synthesis by the insulin/glucagon ratio
- When the insulin/glucagon ratio is high e.g. fed state: lyase is inhibited, reductase is activated, so cholesterol is synthesised - When the insulin/glucagon ratio is low e.g. starvation, diabetes: lyase is activated, reductase is inhibited, so ketone bodies are synthesised PIC
What is the advantage of ketone bodies in starvation/diabetes?
They spare glucose and conserve it for utilisation in the brain
Describe the features of ketone bodies
- Water soluble molecules - Permits relatively high plasma concentrations - Alternative substrate - Above renal threshold, excreted in urine, leading to ketonuria - Acetoacetate and beta-hydroxybutyrate are relatively strong organic acids and can lead to ketoacidosis - Volatile acetone may be excreted via the lungs - Characteristic smell of acetone (nail varnish remover) on breath
What happens with fatty acids with an odd number of carbon atoms?
- Beta-oxidation until 3C unit (proprionyl CoA) - Also arises from several amino acids (Met, Ile) 1. Carboxylation to methyl malonyl CoA with carboxylase (Biotin cofactor) 2. Rearranged to succinyl CoA with mutase (Vitamin B12 cofactor)
Some tissues have an absolute requirement for glucose as an energy source. Which are they?
- Erythrocytes and leukocytes - Testes - Kidney medulla - Lens and cornea of eye To enable blood glucose to be kept at required levels, a store of glucose is required: glycogen (a polymer of glucose)
What is absolutely essential for normal brain function?
Stable blood glucose level. Brain can utilise ketone bodies as fuel, but it prefers glucose, and takes 10-14 days to switch over to ketone bodies. Maximum 50% energy provided
Describe the consequences of hypoglycaemia at different blood glucose levels (mmol/L)
- 2.8: confusion - 1.7: weakness, nausea - 1.1: muscle cramps - 0.6: brain damage, death Heavy people never normally get hypoglycaemia
How is glycogen stored?
As granules - Muscle glycogen: present as both intra- and intermyofibrillar glycogen granules - Liver glycogen: glycogen storage granules within hepatocytes
Describe glycogen structure
- Branch-like: broken down quickly - Glycogen is a polymer consisting of chains of glucose residues - Chains are organised like the branches of a tree, originating from a dimer of the protein glycogenin (acts as a primer at core of glycogen structure) - Glucose residues are linked by alpha-1-4 glycosidic bonds (join chains) with alpha-1-6 glycosidic bonds forming branch points every 8-10 residues
Give the reactions involved in glycogenesis (glycogen synthesis)
- Requires energy - Glucose + ATP ➡️ Glucose 6-phosphate + ADP. Enzyme: hexokinase (glucokinase in liver). Anabolic process - Glucose 6-phosphate ↔️ Glucose 1-phosphate. Enzyme: phosphoglucomutase - Glucose 1-phosphate + UTP + H20 ➡️ UDP-glucose + 2Pi - Glycogen(n residues) + UDP-glucose ➡️ Glycogen(n+1 residues) + UDP. Enzyme: glycogen synthase for alpha-1-4 glycosidic bonds or branching enzyme for alpha-1-6 glycosidic bonds
Describe glycogenolysis (glycogen degradation)
- Glycogen(n residues) + Pi ➡️ Glucose 1-phosphate + glycogen(n-1 residues). Enzyme: glycogen phosphorylase for alpha-1-4 glycosidic bonds or de-branching enzyme for alpha-1-6 glycosidic bonds - Glucose-1-phosphate ↔️ glucose 6-phosphate. Enzyme: phosphoglucomutase - Glucose 6-phosphate goes to either muscle (glycolysis used by muscle for energy production) or liver (glucose released by liver into blood for use by other tissues)
Is glycogenolysis a simple reversal of glycogenesis?
No. Different enzymes allow for simultaneous inhibition of one pathway and stimulation of another
Glycogen stores serve different functions in liver and muscle. What are they?
- Liver: Gluconeogenesis. Glycogenolysis, then G6P converted to glucose by glucose-6-phosphatase and exported to blood. Liver glycogen is a buffer of blood glucose levels - Muscle: glycolysis. Glycogenolysis, but muscle lacks enzyme glucose-6-phosphatase so G6P enters glycolysis for energy production
Give an overview of glycogen metabolism
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Describe the regulation of glycogen metabolism
- Glycogen synthesis: rate limiting enzyme is glycogen synthase - Glycogen degradation: rate limiting enzyme is glycogen phosphorylase - Muscle stores differ from liver in that glucagon has no effect. Also AMP is allosteric activator of muscle glycogen phosphorylase but not of the liver form of the enzyme TABLE
What are glycogen storage diseases?
- Inborn errors of metabolism (inherited diseases) - Arise from deficiency or dysfunction of enzymes of glycogen metabolism - 11 distinct typed. Incidence varies from ~1 in 20,000 to ~1 in 1,000,000. Severity depends on enzyme/tissue affected - Liver and/or muscle can be affected - Excess glycogen storage can lead to tissue damage - Diminished glycogen stores can lead to hypoglycaemia and poor exercise tolerance Examples: - von Gierke’s disease: glucose 6-phosphatase deficiency - McArdle disease: muscle glycogen phosphatase deficiency
What is gluconeogenesis?
- The production of new glucose - Beyond ~8 hours of fasting, liver glycogen stores start to deplete and an alternative source of glucose is required: gluconeogenesis - Occurs in livers and to a lesser extent in the kidney cortex - N.B.: Acetyl-CoA cannot be converted into pyruvate (pyruvate dehydrogenase reaction is irreversible) so there is no net synthesis of glucose from acetyl-CoA
What are the three major precursors (substrates) of gluconeogenesis?
- Lactate from anaerobic glycolysis in exercising muscle and red blood cells (Cori cycle) - Glycerol released from adipose tissue breakdown of triglycerides - Amino acids: mainly alanine. Essential and non-essential amino acids whose metabolism involves pyruvate or intermediates of TCA cycle can be converted to glucose - (Also lactate)
What are the key control enzymes of gluconeogenesis?
Three reactions are not simple reversals of their corresponding steps in glycolysis. Enzymes that control them are: 1. Phosphoenolpyruvate carboxykinase (PEPCK) 2. Fructose-1,6-bisphosphatase 3. Glucose-6-phosphatase 1+2 are major control sites of pathway
Describe the regulation of gluconeogenesis
2 key enzymes (PEPCK and fructose 1,6-bisphosphatase) regulated in response to starvation/fasting, prolonged exercise and stress TABLE
Describe the time course of glucose utilisation
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Describe the use of triacylglycerols (TAG) as an energy store
- Energy intake in excess of requirements is converted to TAG for storage - Highly efficient energy store. Energy content per gram twice that of carbohydrate or protein - Storage and mobilisation of TAGs is under hormonal control
Describe some features of adipocytes
- Typical adipocyte ~0.1mm in diameter. Cells expand as more fat added - Average adult has ~30 billion fat cells weighing ~15kg - Can increase in size (hypertrophy) about fourfold on weight gain before dividing and increasing total number of fat cells (hyplasia) PIC
Give an overview of dietary triacylglycerol metabolism
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Describe fatty acid synthesis (lipolysis)
- Mainly in liver (a bit in adipose tissue too). Dietary glucose as major source of carbon - Glucose ➡️ pyruvate in cytoplasm (glycolysis) - Pyruvate enters mitochondria and forms acetyl-CoA and oxaloacetate (OAA) which then condense to form citrate - Citrate ➡️ cytoplasm and cleaved back to acetyl-CoA and OAA - Acetyl-CoA carboxylase (key regulator) produces malonyl-CoA from acetyl-CoA - Fatty acid synthase complex builds fatty acids by sequential addition of 2 carbon units provided by malonyl-CoA - Process requires both ATP and NADPH
Give an overview of liver lipogenesis
Acetyl-CoA carboxylase is key regulatory enzyme: - Insulin (covalent dephosphorylation) and citrate (allosteric) increase activity - Glucagon/adrenaline (covalent phosphorylation) and AMP (allosteric) decrease activity DIAGRAM
Compare fatty acid synthesis and beta-oxidation: C2 added/removed and how, involvement of acetyl~CoA, where occurs, enzymes, oxidative/reductive, ATP, intermediates, regulation, effect of insulin and glucagon/adrenaline
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Describe fat mobilisation (lipolysis)
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Describe the pathway of gluconeogenesis from pyruvate
Uses some steps of glycolysis and overall process can be represented by: 2pyruvate + 4ATP + 2GTP + 2NADH ➡️ glucose + 2NAD+ + 4ADP + 2GDP + 6Pi + 2H+
How do ketone bodies spare glucose and conserve it for utilisation in the brain?
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