FAT METABOLISM

Introduction

Another major fuel used as a source of bond energy for the synthesis of ATP is fat - specifically fatty acids. These may be oxidised immediately following absorption from the gut or stored as triglycerides and used later.

Fatty acids are an important metabolic fuel particularly for muscle tissue. They are used by all tissues (except the brain) under normal dietary circumstances and are used exclusively by some tissues under altered dietary conditions such as starvation.

Storage and mobilisation of fatty acids

Dietary fat (which is digested and then re-synthesised into triglycerides) is non-polar and must be carried in the circulation as lipoproteins. The protein molecules provide a polar coat for the non-polar lipid and thus enable transportation in the polar (water based) bloodstream. The lipoproteins which transport triglycerides derived from the diet to adipose tissue are called chylomicrons.

Storage in the adipose tissue is catalysed by lipoprotein lipase, the activity of which is stimulated by insulin (the same hormone which stimulates storage of glucose as glycogen).

Hormonal control of storage and mobilisation

When required, the stored triglycerides are released from the adipose tissue, a process catalysed by mobilising lipase which is stimulated by adrenaline and glucagon, the same hormones which stimulate release of stored glycogen as glucose.

When released from the adipose tissue, the fatty acids are transported attached to the major protein in the circulation, which is albumin. Fatty acids are transported to various tissues by this means and then oxidised.

Triglyceride makes up about 70% of the body's energy reserve for two reasons :

because they are non-polar, they are stored in the absence of water (termed anhydrous)

Because of the absence of water, they are compact and light and a relatively large amount of triglyceride is stored in a relatively small space compared to glycogen.

because of the structure of triglycerides being largely a hydrocarbon chain (16-20 covalently linked methyl groups), they are highly reduced.

Because they are highly reduced, there is a large energy yield when they are oxidised.

The relative energy yield from fat and carbohydrate is :

approximately 40 kJ/g triglyceride

approximately 18 kJ/g glycogen

ß-oxidation of fatty acids

This is a cyclic series of reactions (occurring within the mitochondria) with the end result of two carbon units being hydrolysed from the fatty acid chain with each cycle. These two carbon units are molecules of acetyl CoA.

With each oxidation cycle, a molecule of NAD is reduced to NADH and one FAD is reduced to FADH. These are re-oxidised by the electron transport chain with the energy released coupled to ATP synthesis.

The acetyl CoA molecules formed in each cycle are oxidised to CO₂ in the citric acid cycle, with the oxidation/reduction reactions coupled to the electron transport chain and further ATP synthesis.

These events occur in liver and muscle. During sustained exercise the cells of slow twitch muscle fibres (which possess mitochondria) utilise ß-oxidation as the major source of ATP.

Ketone bodies

An alternative method of utilising the acetyl CoA formed by ß-oxidation is via the synthesis and subsequent oxidation of four-carbon units known collectively as ketone bodies.

Acetyl CoA is converted in the liver into acetoacetate (essentially two acetyl groups covalently linked). Acetoacetate can be further reduced to form ß-hydroxybutyrate. These two compounds are referred to as ketone bodies. Their synthesis occurs in the liver.

They diffuse from the liver into the circulation and are used as fuels by several tissues. Heart muscle and renal cortex, in particular, use acetoacetate in preference to glucose. In contrast, glucose is the major fuel for the brain and erythrocytes in a human on a balanced diet. The brain has the capacity to adapt to the use of acetoacetate during starvation (and in the metabolic disease diabetes mellitus). In starvation of long standing, acetoacetate meets more than 70% of the energy needs of the brain.

This ability of the brain to adapt to the use of acetoacetate is important because fatty acids cannot enter neural tissue. Acetoacetate is regarded as a water soluble and readily transported form of acetyl CoA.

The efficiency (amount of ATP produced) of oxidation of fatty acids directly or via formation of ketone bodies is approximately the same - there is no penalty to the body in converting acetyl CoA to this water soluble form.

It is important to be aware that there is no mechanism in animals for the conversion of fatty acids to glucose.

Fatty acid synthesis

This occurs in the cytoplasm of cells (compared to ß-oxidation which occurs inside the mitochondria).

The process begins with acetyl CoA and cyclic reactions join two-carbon units to the growing fatty acid chain. The completion of the synthesis and the formation of unsaturated fatty acids is complex.

The role of fatty acid synthesis is to :

supply the body's needs for particular fatty acids not supplied in the diet AND

to convert excess dietary glucose to fatty acids for storage

Glucose is converted to pyruvate (glycolysis), then to acetyl CoA which, when ATP is required, is oxidised by the citric acid cycle. If the glucose intake exceeds the body's energy needs (and after saturation of glycogen stores) the acetyl CoA can be used for fatty acid synthesis (in the liver) and storage as triglyceride in adipose tissue.