Energy from Fat, Chapter 14

• Energy is released from fat by Dr. Rachel Hunt, Chapter 14.
• This information is available as an e-textbook.

Learning Outcomes

• Indicate the importance of triglyceride fat for long-term fuel storage
• Describe the role of adipose tissue lipase in the breakdown of triglyceride into fatty acids and glycerol
• Describe how fatty acids are activated to their CoA esters, and how they are transported into mitochondria via the carnitine shuttle system
• Describe the enzyme reactions of the β-oxidation pathway that yield acetyl-CoA, NADH, and FADH2
• Summarize the factors regulating fatty acid oxidation
• Outline how odd-numbered carbon-chain fatty acids are metabolized
• Explain the term 'ketone bodies' and outline the significance of ketogenesis in starvation

Biological functions of lipids

• Lipids are components of cell membranes such as phospholipids and cholesterol
• Lipids are precursors of hormones like cholesterol and steroid hormones
• Lipids are long term fuels in the form of triglycerides

Efficiency of Triglycerides as Fuel

• Triglycerides are stored as large fat droplets in the fat cells of adipose tissue
• A 70 kg adult has 11 kg of fat as TG, 120 g of glycogen in the liver and 10 g of glucose
• 1 gram of fat yields 38 kJ on a weight basis
• 1 gram of protein yields 21 kJ, and 1 gram of carbohydrate yields 17 kJ

Structure of triglyceride fat (triacylglycerols)

• Triacylglycerol is formed by three fatty acids linked to a glycerol backbone via ester bonds
• Common fatty acids include palmitic acid (C16:0), stearic acid(C18:0), oleic acid (C18:1), linoleic acid(C18:2) and linolenic acid (C18:3)

Breakdown of stored triglyceride fat in adipose tissue

• Lipase is activated by adrenaline and glucagon
• Triacylglycerol lipase is active and forms fatty acids
• Free fatty acids then travel in plasma bound to albumin
• They act as fuels for muscles, heart, and liver
• Glycerol diffuses in the bloodstream to all tissues.

Metabolism of glycerol

• Glycerol is water-soluble and is taken up by all tissues
• In most tissues, glycerol enters the glycolysis pathway for conversion to pyruvate, then into the TCA cycle for oxidation to CO₂
• In starvation, glycerol enters the glycolysis pathway and is converted to glucose by gluconeogenesis

Fatty acid metabolism by β-oxidation pathway

• All reactions occur in the mitochondrial matrix, requiring transport across the membrane
• Intermediates are present as CoA thioesters
• Conserves the biological energy of a fatty acid molecule by transferring 2 H atoms to the cofactors NAD+ and FAD to form NADH & FADH₂
• There is no direct ATP synthesis
• A series of four enzyme reactions occurs

Activation of long-chain fatty acids

• Long chain fatty acids are activated in the cytosol by the addition of CoA
• Fatty Acyl-CoA synthetase converts Fatty acids into Fatty Acyl-CoA

Coenzyme A

• CoenzymeA (CoA) is actually a dinucleotide with a vitamin and sulphur

Energetics

• Energetically, the activation of fatty acids requires 2 ATP for the recreation of ATP
• Recreation of ATP is not part of the β-oxidation pathway.

Transport of fatty acyl-CoA into mitochondria: carnitine shuttle

• Fatty acyl-CoA freely diffuses across the mitochondrial membrane
• A fatty acid group is transferred to carnitine by carnitine acyltransferase I, which releases fatty acyl-carnitine
• Fatty acyl-carnitine crosses the inner mitochondrial membrane via a translocase
• Carnitine is switched back for CoA by carnitine acyltransferase II, recreating fatty acyl-CoA.
• Carnitine is transported back into the intermembrane space
• This process is energetically neutral.

Overview of β-oxidation pathway

• The β-carbon undergoes oxidation which produces a carbonyl group
• One round of β-oxidation produces acetyl-CoA and a fatty acyl-CoA that is 2 carbons shorter

Beta Oxidation Reactions

• Reaction 1 involves removing 2 H atoms. Acyl-CoA dehydrogenase converts Fatty acyl-CoA into FADH2
• Reaction 2 involves the addition of water. Enoyl-CoA hydratase turns Enoyl-CoA into Hydroxyacyl-CoA
• Reaction 3 involves the removal of 2 H atoms
• Hydroxyacyl-CoA dehydrogenase converts Hydroxyacyl-CoA into NADH + H+
• Reaction 4 involves the removal of 2 C units, while Ketoacyl-CoA thiolase converts Ketoacyl-CoA into Acetyl-CoA

Summary of β-oxidation pathway

• A fatty acid is activated by converting it into Fatty Acyl-CoA
• The shorted fatty acid re-enters the reactions
• A fatty acid with 16 carbons will pass through 7 repeats of α-oxidation pathway
• This leads to the production of NADH and FADH2

Energy yield from fatty acid oxidation

• Oxidation of NADH + H+ produces 2.5 ATP
• Oxidation of FADH₂ produces 1.5 ATP
• The total ATP in energy yield is 106

Regulation of fat metabolism

• Lipase enzyme is activated by adrenaline & glucagon, which releases fatty acids from adipose tissue
• Regulation happens via the entry rate into mitochondria via carnitine shuttle
• Regulation happens by regulating the reoxidation rate of cofactors NADH & FADH₂ by Electron Transport Chain

Metabolism of odd-numbered fatty acids

• β-oxidation results in C15 → C13 → C11 → C9 → C7
• Further metabolism results in C5 & C3
• Odd numbered fatty acids deal with the last 3 carbons -
• Propiónyl-CoA-carboxylase converts CO2 into Methylmalonyl-CoA
• Methylmalonyl-CoA mutase then becomes Succinyl-CoA enters the TCA cycle

Ketone body formation

• Ketogenesis occurs when fat metabolism is the main source of energy during starvation as seen in type I diabetes
• Fatty acid oxidation in hepatocytes leads to high concentrations of Acetyl Co A
• This exceeds the capacity of the TCA cycle
• Excess Acetyl CoA is converted into 'ketone bodies' in the liver
• Acetoacetate and β hydroxybutyrate are released into the bloodstream.
• Acetoacetate and β hydroxybutyrate are released into the bloodstream
• Most cell types can convert acetoacetate and β hydroxybutyrate back into TCA cycle intermediates
• Most tissues oxidise a mixture of fatty acids and ketone bodies
• The liver cannot utilise ketone bodies
• The brain cannot utilise fatty acids; the brain uses glucose and a small amount of ketone bodies ('emergency fuel')