Session 3: Energy Production from Lipids (NEW)

Features of Lipids

- Hydrophobic

- Mostly contain C, H and some O

- More reduced than carbohydrates = release more energy when oxidised

The three classes of lipids

1) Fatty acid derivatives

- Fatty acids = fuel molecules

- Triacylglycerols from diet = fuel storage, insulation

- Phospholipids = membranes, lipoproteins

- Eicosanoids = Fatty acid metabolite, local mediator

2) Hydroxy-methyl-glutaric acid (HMG) derivatives

- Ketone bodies (alternative hydrophilic fuel molecule)

- Cholesterol = membrane and steroid hormone synthesis

- Cholesterol esters = cholesterol storage

- Bile acids and salts = lipid digestion

3) Vitamins

ADEK

Triacylglycerol function

Fuel storage and insulin

Phospholipid function

Component of membrane

Plasma lipoproteins

Eicosanoid function

Fatty acid metabolites

Local mediators

Triglyceride structure

Glycerol backbone + 3 fatty acid side-chains

Triglycerides stored in an anhydrous form in ___ tissue

Adipose

Triglycerides are utilised during what specific situations?

- Prolonged exercise

- Starvation

- Pregnancy (increased metabolic load on woman)

The metabolism of triglycerides is under hormonal control.

Which hormones promote TG mobilisation?

- Glucagon

- Adrenaline

- Growth hormone

- Cortisol

- Thyroxine

The metabolism of triglycerides is under hormonal control.

Which hormones promote TG storage?

- Insulin

Stage 1 of triglyceride metabolism

Extracellular (GI tract)

- TGs digested into = fatty acids + glycerol

- Fatty acids + glycerol absorbed from GI into circulation

- No ATP produced

What enzyme catalyses the breakdown of triacylglycerols into glycerol and fatty acids in stage 1 of triglyceride metabolism in the GI tract?

Pancreatic lipase enzyme

Low extracellular [glucose] results in ___ ___ release as an alternative fuel

Fatty acid

Stage 2 of triacylglycerol catabolism focuses on the breakdown of fatty acid constituent

Where does this stage take place in the cell?

Intracellular (mitochondria)

- Fatty acids transported to tissues (especially adipose, liver, skeletal muscle) where they are oxidised

- This process requires H+ carriers which are reduced

- Reducing power released

Fatty acids contain hydrophilic and hydrophobic groups - they are ___

Amphipathic

Example of a saturated fatty acid

Palmitic fatty acid

Stearic acid

Example of mono-unsaturated fatty acid

Oleic acid

Example of poly-unsaturated fatty acid

Arachidonic acid

Give two examples of polyunsaturated fatty acids which are ESSENTIAL fatty acids?

- Alpha-linolenic acid (omega 3)

- Linoleic acid (omega 6)

Stages of fatty acid catabolism

Enzyme which catalyses activation of fatty acids (linking of coenzyme A to fatty acid)?

Fatty acyl CoA synthase

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

What is used to help these fatty acyl CoA cross the inner mitochondrial membrane?

Carnitine shuttle transporter

Molecule that inhibits fatty acid transport by carnitine shuttle transporter?

Malonyl CoA-intermediate in FA synthesis

Is fat a higher energy fuel than glucose?

Yes

C6 fatty acid = 41 ATP

C6 glucose = 32 ATP

Glycerol metabolism occurs in the ___

Liver

- Intracellular (cytosol)

Glycerol metabolism process

Enzyme which catalyses conversion of glycerol to glycerol-3-phosphate in glycerol metabolism

Glycerol kinase

Intermediate of glycerol metabolism which enters glycolysis?

Dihydroxyacetone phosphate (DHAP)

CoA is derived from what vitamin?

Vitamin B5 (pantothenic acid)

Ketone bodies are an alternative ___ molecule

Fuel

Normal plasma ketone body concentration

< 1 mM

Ketone body concentration during physiological ketosis (starvation)

2-10 mM

Ketone body concentration during pathological ketosis (Type 1 Diabetes)

> 10 mM

Ketoacidosis

Excessive production of ketones, making the blood acidic

- Acetoacetate and Beta-hydroxybutyrate at high concentrations in the blood

Ketonuria

Ketones in the urine

- Occurs when the renal threshold of ketones is exceeded so ketone bodies excreted in the urine

Why may volatile acetone be excreted via the lungs of type 1 diabetics?

Acetoacetate spontaneously breaks down to acetone

- Characteristic smell of acetone can be smelt on the breath of T1D patients

When are ketone bodies synthesised by the liver mitochondria?

- When glycolysis is low e.g., prolonged exercise

- When glucose is low e.g., in starvation (physiological ketosis)

- In untreated type 1 diabetes (pathological ketosis)

What hormones influence ketone body synthesis (ketogenesis)?

Insulin/Glucagon ratio

In the fed state - how is ketogenesis affected?

Fed State = High Insulin/Glucagon Ratio

- Lyase inhibited

- Reductase activated

- Hydroxymethyl glutaryl-CoA (HMG-CoA) + Reductase react

- Production of Mevalonate which forms Cholesterol

- Cholesterol synthesis favoured in the fed state

In the fasted state - how is ketogenesis affected?

Fasted State = Low Insulin/Glucagon Ratio

- Lyase activated

- Reductase inhibited

- Hydroxymethyl glutaryl-CoA (HMG-CoA) + Lyase react

- Production of acetoacetate which forms B-hydroxybutyrate (ketone bodies)

Acetoacetate can also break down spontaneously to form acetone (volatile acetone on the breath of T1D patients)

Ketogenesis in the fed state

Ketogenesis in the fasted state (starvation)

What enzyme does statins drugs inhibit to decrease cholesterol?

HMG-CoA reductase

Ketogenic diet benefits

- Epilepsy = reduces seizures

- Obesity = weight loss

- Diabetes = improved insulin sensitivity

- General health = improves endurance and performance

Note =

Ketogenic diets can also benefit individuals who have an X-linked pyruvate dehydrogenase (PDH) deficiency.

Ketogenic diet short-term side effects

- Nausea

- Vomiting

- Headache

- Dizziness

- Insomnia

- Constipation

Ketogenic diet long-term side effects

- Hepatic steatosis

- Kidney stones

- Nutrient deficiencies

- High cholesterol

Triacylglycerols are mainly water soluble

True or false?

False

Name the enzyme which hydrolyses dietary triacylglycerols to fatty acids and glycerols in the gastrointestinal tract?

Pancreatic lipase

Unlike fatty acid which is converted to acetyl CoA in order to enter TCA cycle, glycerol needs to enter glycolysis to be processed to pyruvate and then be converted to acetyl CoA

True or false?

True

Name the active transporter which allows transported of activated fatty acids to mitochondria

Carnitine

Fatty acids yield more energy than C6 glucose as they are more reduced.

How many moles of ATP are produced from oxidation of C6 fatty acid?

41 ATP

Where are ketones synthesised in the body?

Liver

Name the volatile ketone which is excreted via lungs in patients with type 1 diabetes

Acetone