F: CELL Lipid synthesis and Degradation

Question 1

What are lipids?

Answer 1

Monosaccharides soluble in non-polar solvents

Question 2

Why is fat an important energy store?

Answer 2

Fats synthesised and stored when calorific intake exceeds immediate needs of body

Energy content of fat per gram is over twice that of either carb or protein

1g fat - 37kjoules
1g protein - 17kjoules
1g carbohydrate - 16kjoules

Question 3

Describe the fate of glycerol

Answer 3

• Breakdown of TGs gives acetyl-CoA and glycerol
• In liver, glycerol used to synthesise glucose by glucongeogenesis
• In muscle, glycerol used in glycolysis and oxidative phosphorylation to produce ATP

Question 4

What different reactions can glucose undergo/be involved in?

Answer 4

• Glycolysis
• Gluconeogenesis
• Glycogenesis
• Glycogenolysis

Question 5

Describe fatty acids

Answer 5

• Fats most often made from dietary carbs, though some amino acids can be used
• Not all fats stored, as are preferred energy source for cardiac muscle
• Fats stored in adipose tissue as TGs but majority synthesised in liver
• TGs formed from glycerol + 3 FAs
• FAs:
  
  • Chains of methyl groups
  • Terminal carboxyl group
  • Double bonds if present are usually cis
  • Humans unable to create double bonds less than position 9
  • Essential FAs obtained from diet

Question 6

Describe the synthesis of fats

Answer 6

• From excess glucose taken up in diet, in liver
• glucose → G-6-P [enzyme: glucokinase]
• G-6-P further metabolised in glycolysis to make pyruvate
• pyruvate is converted into Acetyl-CoA
• Acetyl-CoA reacts with oxaloacetic acid to form citrate [tricarboxylic acid cycle]
• when ATP levels are high, need for glucose is low → excess citrate is transported out of mitochondria
• it is converted back to Acetyl-CoA
• then synthesised into fatty acids
  
  • some retained in liver
  • majority are transported in the blood
• alternatively, Acetyle CoA can be used to synthesis cholesterol which is transported around the body in blood to non-hepatic tissue

Question 7

Describe FA synthesis

Answer 7

Takes place in cytosol, requires:

• Acetyl-CoA
• NADPH
• ATP
• Takes place in fed state, when glucose levels high, demand for ATP low

Involves sequential addition of 2 carbon units derived from acetyl-coA

Citrate malate shuttle provides 40% NADPH needed for fatty acid synthesis 60% comes from the pentose phosphate pathway

Step 1 :

• Acetyl-coA + ATP + HCO3- → Malonyl-coA + ADP + Pi (catalysed by acetyl-coA carboxylase)
  
  • Acetyl-coA carboxylase forms malonyl-CoA, then malonyl residue is transferred to ACP (acyl carrier protein), part of multienzyme complex of FA synthase. Second acetyl molecule from acetyl molecule is then transferred to ACP where the 2 condense to form acetoacetyl-ACP
  • Acetyl-coA carboxylase is inhibited by phosphorylation. Glucagon stimulates phosphorylation, so inhibits this enzyme
  • Expression of the enzyme increases with high carbs and low fats, and decreases if there’s low carbs and high fats
• Important irreversible regulatory step, activated by citrate (positive feed forward) and inhibited by palmitic acid (negative feedback)
• Requires vitamin biotin

Step 2:

• Elongation - Cytosolic, addition of 2 carbons

Question 8

How is the acetyle CoA transported to the cytosol where it is needed for fatty acid synthesis?

Answer 8

• citrate-malate antiporter
• acetyl coa + ocaloacetete → citrate
• citrate transported out to cytosol
• this is where acetyl coa, oxaloacetete is regenerated
• the oxaloacaetete + NADH → malate
• malate is converted to pyruvate [forms NADPH in process]
• pyruvate moves back to mitochondria

Question 9

Describe the action of fatty acid synthase

Answer 9

• Responsible for FA synthesis
• Multienzyme complex
• Intermediates covalent linked to ACP
• Enables efficient + rapid movement of growing FA chain to be passed from 1 active site to next
• Efficiency of reaction further enhanced as enzyme exists as a dimer arranged head to tail

Question 10

Describe cholesterol

Answer 10

• Rigid hydrophobic molecule, virtually insoluble in H2O
• Precursor of sterols, steroids, bile salts
• Important in membranes
• Transported in circulation as cholesteryl esters
• Cannot be used to provide energy
• Imbalance can cause significant health issues

Question 11

Describe cholesterol synthesis

Answer 11

• Synthesised mostly ER
• Starts with activation of acetate, acetyl-coA
• Major regulatory step is conversion of 3-hydroxyl-3-methylglutaryl CoA (HMGCoA) to mevalonate
• Cholesterol inhibits HMGCoA reductase, enzyme involved in its own synthesis
• Dieting doesn’t help to reduce circulating cholesterol, as endogenous synthesis increases

Question 12

Describe ketogenesis

Answer 12

• In liver:
  
  • Fasting, uncontrolled diabetes + prolonged exercise stimulate FA breakdown, producing acetyl-CoA
  • Metabolism shifts towards maintaining blood glucose leading to reduction in OAA
  • Loss of OAA limits energy production from acetyl-CoA
  • Excess acetyl-CoA used to form ketone bodies
  • Ketone bodies are acetoacetate, 3-beta-hydroxybutyrate and acetone
  • Synthesis ketone bodies regulated by insulin/glucagon ratio, ketogenesis high when ratio low, as this inhibits acetyl-CoA carboxylase
  • Ketone bodies used preferentially by cardiac muscle and renal cortex, and brain during starvation

Question 13

Describe fatty acid degradation

Answer 13

Release of energy from reserves stored in adipose tissue requires 3 steps

• Mobilisation - apidocyte
  
  • Hormones that stimulate FA mobilisation: glucagon and adrenaline → act through 7TM receptors, which stimulates increase in cAMP intracellularly
  • Activates PKA
  • PKA phosphorylate triacylglycerol lipase
  • This then breaks down triacylglycerol into diacyloycerol and into free FAs, transported to liver
• Activation - liver cytosol
  
  • Long chain FA activated on the OMM to form acyl-CoA
  • Transported to inner mitochondrial matrix for oxidation using carnitine
  • Carnitine deficiency can cause muscle weakness or even death
  • Transport inhibited by malonyl-CoA
• Degradation - liver mitochondria - Stimulated by glucagon, adrenaline, norad, inhibited by insulin
  
  • Fatty acid beta oxidation - Acyl-CoA degraded by sequential removal of two carbon units. As a result FADH2, NADH and acetyl-CoA are produced
  • FADH2, NADH form ATP
  • In the liver Acetyl-CoA does not enter citric acid cycle
  • In non-hepatic tissue complete oxidation of palmitate yields 106 molecules of ATP
  • Odd chain length yield propionyl-CoA in the last round of oxidation
  • Propionyl-CoA is converted to oxaloacetate and used for gluconeogenesis
  • Odd numbered double bonds are removed by isomerase and even double bonds by reductase and isomerase

FAs transported to liver, activated by acyl-CoA synthase in cytoplasm, forms fatty acyl-CoA

Fatty acyl-CoA reacts with alcohol carnitine to form fatty acyl-carnitine

Fatty-acyl-carnitine is then transported across the inner mitochondrial membrane

Question 14

Describe the hormonal regulation of fat metabolism

Answer 14

• Insulin:
  
  • ↑ glycolysis in the liver
  • ↑ Fatty acid synthesis in the liver
  • ↑ TG in adipose tissue
  • ↓ b-oxidation
• Glucagon and adrenaline:
  
  • ↑ TG mobilisation