W5 Lipid synthesis + degradation

Question 1

Why is fat such an important store of energy?

Answer 1

The energy content of fat per gram is over twice that of either carbohydrate or protein

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

Question 2

Fatty acid synthesis summary

Answer 2

Takes place in the cytosol and requires:

Acetyl-CoA

NADPH (from transporting acetyl CoA from MC to cytosol)

ATP

It involves the sequential addition of 2 two carbon units derived from acetyl-CoA

Question 3

Transfer of acetyl CoA to the cytosol

Answer 3

Pyruvate → oxaloacetate → acetyl CoA → citrate

Citrate → acetyl CoA → oxaloacetate → malate (using NADH) → pyruvate (producing NADPH)

Citrate-malate antiport

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

Question 4

Fatty acid synthesis first step

Answer 4

Acetyl-CoA + ATP + HCO3- → malonyl-CoA + ADP + Pi

Acetyl-CoA carboxylase

This requires the vitamin biotin

Important irreversible regulatory step, activated by citrate (positive feed forward) and inhibited by palmitic acid (negative feedback)

Question 5

Acetyl-CoA carboxylase

Answer 5

Acetyl-CoA carboxylase is inhibited by phosphorylation. Glucagon stimulates phosphorylation and therefore inhibits the enzyme

Expression of Acetyl-CoA carboxylase is increased by high carbohydrate and low fat

Expression of Acetyl-CoA carboxylase is decreased by low carbohydrate and high fat

Question 6

Fatty acid synthesis - elongation

Answer 6

Reaction with ACP – acyl carrier protein

Step 2 Elongation

Cytosolic

Addition of 2 carbons

First step is acetyl-CoA carboxylase to form malonyl-CoA then the malonyl residue is transferred to the acyl carrier protein (ACP) part of the multienzyme complex of fatty acid synthase.

A second acetyl molecule from Acetyl CoA is then transferred to ACP where the two condense to form acetoacetyl-ACP

Acetoacetyl-ACP into butyryl-ACP (after reduction, dehydration + reduction again) NADPH produced at each reduction

Combines w/malonyl-ACP to form 6 carbon compound (CO2 released)

Question 7

Fatty acid synthesis cycle

Answer 7

Intermediates are covalently linked to acyl carrier protein (ACP)

All enzymes required form a multi-functional complex called Fatty acid synthase (Many ASs so easy flow of reactants to products)

Fatty acid synthase exists as a dimer

Each cycle = +2 carbon

Question 8

Cholesterol

Answer 8

Rigid hydrophobic molecule virtually insoluble in water

Precursor of sterols, steroids and bile salts

Transported in the circulation as cholesteryl esters

Cannot be oxidised to O2 and H2O so provide no energy

Important membrane components

Question 9

Cholesterol synthesis

Answer 9

Cholesterol is synthesised mostly in the ER

Over 30 steps are involved

Starts with the activation of acetate, acetyl-CoA

Major regulatory step is the conversion of 3-hydroxyl-3-methylglutaryl CoA (HMGCoA) to mevalonate

Cholesterol inhibits HMGCoA reductase (targets for drugs designed for regulation of CL synthesis) the enzyme involved in its own synthesis

Difficult to reduce circulating cholesterol by diet alone as endogenous synthesis is increased

Question 10

Mobilisation

Answer 10

Triacylglycerol to Diacylglycerol by triacylglycerol lipase

Diacylglycerol to free fatty acids (by other lipases) also producing glycerol

Important when food is not readily available ie starvation or exercise stimulated by glucagon and adrenalin but inhibited by insulin

FA synthesis + degradation are seperated by a biological membrane (MC membrane)

Question 11

Fate of glycerol

Answer 11

Absorbed by the liver

Glycerol → G3P (phosphorylated)

G3P → Dihydroxyacetone phosphate (oxidised)

Dihydroxyacetone phosphate → Glyceraldehyde 3-phosphate (isomerised)

Glyceraldehyde 3-phosphate then either grows through glycolysis or gluconeogenesis

Question 12

Fatty acid degradation

Answer 12

Fatty acids are transported to the liver and activated by acyl-CoA synthase in the cytoplasm

Acyl-CoA produced is transported across the inner mitochondrial membrane bound to the alcohol carnitine

Question 13

Activation (Liver)

Answer 13

Long chain FA activated following reaction with CoA to give acyl-CoA – ATP OMM

Transported to inner mitochondrial matrix for oxidation using carnitine

Carnitine deficiency can cause muscle weakness or even death

Transport is inhibited by malonyl-CoA (reciprocally regulated)

Question 14

Fatty acid oxidation (liver mitochondria)

Answer 14

Acyl-CoA degraded by sequential removal of two carbon units

As a result FADH2, NADH and acetyl-CoA are produced

Question 15

Fatty acid oxidation (beta-oxidation)

Answer 15

FADH2, NADH form ATP

Acetyl-CoA will enter the citric acid cycle only in the presence of glycolysis (only non-hepatic tissue)

Complete oxidation of palmitate (other FA) yields 106 molecules of ATP

Odd chain length yield propionyl-CoA in the last round of oxidation

Odd numbered double bonds are removed by isomerase even double bonds by reductase and isomerase

Question 16

Ketogenesis

Answer 16

Acetyl-CoA converted to acetoacetyl-CoA

Acetoacetyl-CoA converted to HMG-CoA
(β-hydroxy β-methylglutaryl-CoA)

HMG-CoA converted to acetoacetate

Acetoacetate can be reduced to 3-β-hydroxybuterate or non-enzymatically to acetone

Question 17

Regulation of ketogenesis

Answer 17

The synthesis of ketone bodies are regulated by the insulin/glucagon ratio

Ketongenesis is high when the ratio is low as this inhibits acetyl-CoA carboxylase (rate limiting step in fatty acid synthesis)

Question 18

Fate of ketone bodies

Answer 18

Major energy source for cardiac muscle and renal cortex (dependent on the flow of carbohydrate in glycolysis)

In non hepatic = krebs always continuing

During starvation up to 75% of the brains energy is derived from acetoacetate

Acetoacetate → acetoacetyl CoA by CoA transferase (Succinyl CoA → Succinate)

Acetoacetyl CoA → 2 acetyl CoA by thiolase (using CoA) (Will enter krebs)

Question 19

Hormonal regulation of fat metabolism

Answer 19

Insulin
		↑ glycolysis  in the liver
		↑ Fatty acid synthesis in the liver
		↑ TG in adipose tissue
		↓ b-oxidation

Glucagon and adrenalin
↑ TG mobilisation