Energy Production: Lipids

Question 1

What are lipids

Answer 1

• Structurally diverse 
• Generally insoluble in water (hydrophobic) 
• Most only contain  C, H, O
– (phospholipids contain P, N) 
• More reduced than carbohydrates
– release more energy when oxidised
– complete oxidation requires more O2

Question 2

What are 3 classes of lipids

Answer 2

1. Fatty acid derivatives: Fatty acids – fuel molecules. Triacylglycerols (triglycerides) – fuel storage and insulation
   Phospholipids – components of membranes and plasma lipoproteins
   Eicosanoids – local mediators
2. Hydroxy-methyl-glutaric acid derivatives (C6 compound) 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
3. Vitamins A, D, E and K.

Question 3

What is a triacylgygerol

Answer 3

Glycerol backbone with 3 fatty acid side chains
Formed by esterification
Broken by lipolysis

• Triacylglycerols are hydrophobic
• Therefore stored in an anhydrous form
• Stored in specialised tissue – adipose tissue
• Utilised in prolonged exercise, ‘starvation’, during pregnancy
• Storage / mobilisation under hormonal control

Question 4

What tissues are involved in triglyceride metabolism

Answer 4

GI tract
Lipids (TAG) in diet Extracellular (stage1) hydrolysis of lipids in small intestine by pancreatic lipases
Triglycerides -> glycerol or fatty acids
Recombined in small intestine and transported as TAG by lipoproteins (Chylomicrons)

Blood
Carries glycerol to liver
Fatty acids -> chylomicrons 
Released into circulation via lymphatics 
Fatty acids to muscle

Tissues
FA oxidation -> energy
Liver contains glycerol
Stored as TAG in adipose 
NOT cells w/o mitochondria, not brain; FA do not pass blood-brain barrier easily

Question 5

What are the stages of the tag/fatty acid cycle in adipose tissue?

Answer 5

1 = Glucose transport,   
2 = Glycolysis
3 = Esterification
4 = Lysis
5 = Re=esterification

Low extracellular glucose results in fatty acid release as alternative fuel

Question 6

What is the general formula of fatty acids and what are their properties

Answer 6

CH3(CH2)nCOOH
• saturated or
• unsaturated ( ie one or more double bonds C=C)
• amphipathic (contain hydrophilic & hydrophobic groups)
• certain polyunsaturated FA are essential (i.e. required in diet (because mammals cannot introduce a double bond beyond C9), e.g. linolenic acid 18 : 3 (9,12,15)

Question 7

Where does fatty acid catabolism occur and what are the stages

Answer 7

• Occurs in mitochondria

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

Question 8

What is fatty acid activation?

Answer 8

Occurs outside the mitochondria, in cytoplasm

• Fatty acids activated by linking to coenzyme A (via high energy bond) by the action of fatty acyl CoA synthase :
CH3(CH2)nCOOH + ATP + CoA -> CH3(CH2)nCO~CoA + AMP + 2Pi

• Activated fatty acids (fatty acyl~CoA) do not readily cross the inner mitochondrial membrane

Question 9

What is the carnitine shuttle?

Answer 9

Transports fatty acyl~CoA across the membrane

Cat transfers activated acyl group into carnitine - removing acyl from coa onto intermediate carnitine to produce acyl carnitine
Allows transport in of that molecule
Returnsafree carnitine back into molecule
Acyl carnitine into matrix where carnitine removed and CoA re attached ready for metabolism
This is done by a second cat

• Regulated, so controls the rate of FA oxidation
• Inhibited by malonyl~CoA (biosynthetic intermediate)
• Defects can occur in this transport system (exercise intolerance, lipid droplets in muscle)

Question 10

What is beta oxidation of fatty acids?

Answer 10

Stage 4
Chop of 2 carbon units - add to acetyl CoA
Produces lots of acetyl CoA - these can then go round tca - 9

Most tissues and WBC

Question 11

What are the key points in fatty acid metabolism?

Answer 11

Cycle of reactions 
• Removal of 2C units per cycle 
• CH3CH2/ CH2CH2/ CH2CH2/////////CH2COOH 
• Oxidation 
• H+ and e- transferred to NAD+ and FAD 
• Stops in absence of O2 
• No ATP synthesis

Question 12

Where is glycerol metabolised?

Answer 12

Glycerol can be transported in the blood to the liver, where it is metabolised

Question 13

Where is the main convergence point for catabolic pathways?

Answer 13

• CH3CO group linked to coenzyme A 
• Linked via S-atom - high energy of hydrolysis 
• therefore, activated acetyl group 
• CoA contains vitamin B5
- panthenoic acid

Question 14

What are the functions of acetyl CoA

Answer 14

Most important intermediate in both catabolic and anabolic pathways
Can be converted to ketone bodies or cholesterol

Question 15

What are ketone bodies

Answer 15

• Three ketone bodies produced in the body
– Acetoacetate: CH3COCH2COO-
– Acetone: CH3COCH3 - spontaneous (non-enzymatic) decarboxylation of acetoacetate
– β-hydroxybutyrate: CH3CHOHCH2COO (liver)

• Normal plasma ketone body concentration < 1 mM
• Starvation 2-10 mM (physiological ketosis)
• Untreated Type 1 diabetes > 10 mM (pathological ketosis)
• synthesised by liver mitochondria

Question 16

Describe control of ketone body production in the liver

Answer 16

G1p not produced - fatty acids oxidised and released into circulation
Metabolised to produce nadh and acetyl coa
Nadh signals high energy to tca to inhibit 2 regulated enzymes
Signals to enzymes to stop which inhibits TCA
Citrate builds up
OAA levels fall
Acetyl CoA no lomger gets into cycle
CoA builds up and is diverted into ketone body pathway

Question 17

What is ketone body synhthesis regulated by

Answer 17

Ketone bodies synthesis regulated by the insulin/glucagon ratio: fed state

When the insulin/glucagon ratio is high, i.e. fed state: Lyase is inhibited, reductase activated -> cholesterol synthesis

When the insulin/glucagon ratio is Low, i.e. starvation state: Lyase is activated, reductase inhibited -> ketone body synthesis

Question 18

What happens in early and late starvation/diabetes

Answer 18

Early:
Brain using glucose - 
adipose tissue 
Maintaining circulating glucose
Mininumsing use of glucose
Ketone body utilisation -> Acetyl CoA -> CO2 + H2O

Late:
Muscle breaking down protein
Gluconeogenesis
Yield of glucose in liver - maintains circulating glucose concentrations
Aim is to maintain circulating glucose and hence brain function
Ketone body utilisation -> Acetyl CoA -> CO2 + H2O

Question 19

What are ketone bodies

Answer 19

• Water soluble molecules
• Permits relatively high plasma concentrations
• Alternative substrate
• Above renal threshold, excreted in urine -> ketonuria
• Acetoacetate and β-hydroxybutyrate are relatively strong
organic acids -> ketoacidosis
• Volatile acetone may be excreted via the lungs
• N.B. characteristic smell of acetone (nail varnish remover) on breath