Lipid Metabolism And Associated Inborn Errors Biology Essay


Fatty acid oxidation (FAO) is an essential metabolic process which provides energy, in the form of ATP, in times of fasting and metabolic stress. (Nelson and Cox 2008); its importance is reinforced by the fact that in many organs such as the mammalian liver and heart, FAO yields as much as 80% of the energy required for efficient physiological function (Nelson and Cox 2008).The release of free fatty acids, from dietary sources or via the catabolism of stored triglycerides, into the bloodstream is predominantly metabolised in the intracellular compartments of the mitochondria (Vockley and Whiteman 2001). Here the fatty acids undergo three stages of respiration via β-oxidation, the citric acid cycle and oxidative phosphorylation of the electron transport chain (Hames and Hooper 2005). The following essay however will delve deeper into the metabolic pathways which are specific to lipid metabolism and so for this purpose will exclude the citric acid cycle and electron transport chain. The purpose of this article is to review some of the vast literature produced on the oxidation of fatty acids, whilst discussing the vital role of the many enzymes which drive these metabolic pathways and hence why inborn errors in these enzymes can result in loss of function and health in the human body.

Activation and Transport of Fatty Acids into the mitochondria

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Before entering the matrix of the mitochondria fatty acids must first become activated which takes place on the outer mitochondrial membrane. Adenosine triphosphate forms a thioester linkage between the sulfhydryl group of a coenzyme A and a carboxyl group of a fatty acid, catalysed by acyl CoA synthetase (Berg 2007). Small and medium chain acyl CoA molecules (i.e. up to 12 carbon atoms in length) are able to passively diffuse through the inner mitochondrial membrane, long chain fatty acids on the other hand need a specialised transport mechanism (Hames and Hooper 2005). These fatty acids are conjugated to a zwitter ionic alcohol known as carnitine; Carntine acyltransferase I catalyses the reaction which transfers a sulphur atom on coenzyme A to the hydroxyl group of carnitine to form acyl carnitine, this is then shuttled across the inner mitrochondrial membrane by a translocase shown by figure 1, (Berg et al 2007).

Figure 1: A translocase mediates the entry of acyl carnitinewhich returns back to cytoplamic side of the inner mitrochondrial membrane in a reverse reaction for the exchange of acyl carnitine, catalysed by carnitine acyl transferase II, taken from Berg et al 2007.

B oxidation

Figure 2: Mitrochondrial β-oxidation of fatty acids, taken from Brookes.S.J 2009Once inside the matrix of the mitochondria, degradation of saturated fatty acids occurs via the β-oxidation pathway shown by figure 2 (Hames and Hooper 2005). This involves four enzyme catalysed reactions; the initial reaction is dehydrogenation catalysed by three isoforms of fatty acyl Co-A dehydrogenase, each specific for either short chain (4-8 carbons ), medium chain (4-14 carbons ) and long chain fatty acids (12-18 carbons), this dehydrogenates between the β-carbon and α-carbon to give a trans-∆2-enoyl-coA and a FADH2 (Berg 2007).

The second reaction, which is catalysed by enoyl CoA hydratase, is a hydration reaction where water is added to the double bond of the trans-∆2enoyl-CoA which forms a L stereoisomer to give the product 3-hydroxyacyl CoA (Nelson and cox 2008). The third reaction is an oxidation reaction catalysed by β-hydroxyacyl -CoA dehydrogenase which dehydrogenates L-B-hydroxyacyl CoA to form β-ketoacyl-CoA with the formation of NADH (Nelson and Cox 2008) The final reaction which is catalysed by β-ketothiolase involves the attack of a nucleophillic thiol sulphur of coenzyme A on 3-ketoacyl-CoA which is electron poor, this results on cleavage of the α-β bond and acetyl CoA is released, a second product is formed which is a fatty acyl-CoA shortened by two carbons and is ready to begin the whole cycle again, hence why β-oxidation is a cyclic process ( Matthews 1998).

B-oxidation in peroxisomes

Under normal physiological conditions the body will utilise the B oxidation metabolic pathway of the mitrochondria, however peroxisomes also contain enzymes which are capableof producing aceyl-CoA from the oxidation of fatty acids shown by figure 3 (Nelson and Cox 2009). The process similarly involves four enzymatic reactions but in contrast produces dicarboxylic acid as a bi product (Matthews et al 2000). This metabolic pathway becomes of particular importance when mitrochondrial B oxidation becomes saturated or is not functional due to an inborn error of metabolism, in fact during periods of prolonged fasting the peroxisome can account for up to as much as 20% of total cellular FAO (Hale 1992).

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Figure 3: Comparison of B-oxidation in peroxisomes and the mitrochondria. There are two main differences: Firstly during the first oxidative step electrons pass directly to o2 and secondly the NADH produced in the second reaction is not reoxidised, taken form Nelson and Cox 2008.

Mitrochondria Peroxisome

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Oxidation of unsaturated fatty acids

The oxidation of unsaturated fats utilises a slightly different metabolic pathway. These unsaturated fats have a high monounsaccarhide content with a cis configured double bond ( William et al 2009). The double bonds present in unsaturated fatty acids cannot be acted upon by enoyl-CoA hydratase which catalyses the addition of H20 to the trans double bond of ∆2-enoyl-CoA and so, as shown in figure 4, an extra isomerise enzyme is required to shift the double bond; this generates a trans-isomer which can then continue down the main pathway of fat degragation (Nelson and cox 2008). Polyunsaturated fatty acids require a second enzyme named 2,4-dienoyl CoA reductase which forms a cis-∆3-enoyl CoA which is converted by an isomerise enzyme so that it can continue down the main metabolic pathway (Hames and Hooper 2005).

Figure 4: The oxidation of a diunsaturated fatty acid named linoleoyl CoA, taken fron Berg et al 2007.

Oxidation of odd-chain fatty acids

Odd numbered fatty acid chains, although rare in abundance, are also oxidised by β-oxidation, the difference being that in the last pass through the β-oxidation cycle the resultant substrate is a fatty acyl-CoA with a five carbon fatty acid; This is then cleaved and oxidised to form acetyl CoA and propionyl-CoA (Nelson and Cox 2008). Propionyl-CoA is then converted to succinyl CoA as shown by figure 5, which, along with the acetyl CoA, then enters the critic acid cycle for further oxidation (Berg et al 2007).

Figure 5: Propionyl CoA is a generated from the oxidation of fatty acids with odd numbered carbon chains, it is convereted to succinyl CoA before entering the citric acid cycle, taken from Berg et al 2007.

Inborn errors of lipid metabolism.

Inborn errors of mitochondrial fatty acid oxidation result from mutations in the genes coding for the enzymes involved in FAO, figure 6 represents some of many inborn errors of FAO that have identified as of present. They have become increasingly identified and thought of as an important class of neurometabolic diseases, with severe clinical consequences such as cardiomyopathy, liver dysfunction, metabolic acidosis and hypoglycaemic seizures ( Kompare 2008). The presence of unique biochemical markers and technological advances in clinical application of mass spectrometry, newborn screening and molecular genetics has been crucial for the development of a timely diagnosis (Kompare et al 2008). Individual enzymatic defects in FAO are rare however collectively common as a consequence of the large variety of different enzymes involved in FAO, table 1 represents the variety of enzymes that are involved in FAO and whether they have an associated metabolic disorder.(Kompare et. al 2008). In order to give an in depth understanding of just how these disorders biochemically are deficient and the consequences that result from them, Medium Chain Acyl-Coenzyme A Dehydrogenase (MCAD) deficiency will be used as an exemplar (Mckinny 2004).

Figure 6: A timeline to show the discovary of the many different metabolic disorders of fatty acid oxidation. CPTII: carnitine palmitoyltransferase II deficiency, CAT: carnitine transporter deficieny, MAD (GAII): multiple acyl-CoA dehydrogenation deficiency, CTPI: carnitine palmitoyltransferase I deficiency, RR-MAD: riboflavin multiple acyl-CoA dehydrogenation disorder, SCAD: short-chain acyl-CoA dehydrogenase deficiency, LCHAD: lon-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, MTP: MTP deficiency, CACT: carnitine/acylcarnitine translocase deficiency, VLCAD:very long chain acyl-CoA dehydrogenase deficiency, SCKAT: short chain 3-oxoacyl-CoA thiolase deficiency, FATP: fatty acid transport protein deficiency, SCHAD: short chain 3-hydroxyacyl-CoA dehydrogenase deficiency and ACAD9: long chain acyl CoA dehydrogenase deficiency, taken from Gregerson et al 2008.

Enzymes involved in mitrochondrial fatty acid oxidation.


Fatty acid transport and activation

Fatty acid transporter(s) (Plasma membrane)

Acyl CoA synthetase(s)

Carnitine Cycle

Plasma membrane carnitine transporter

CPTI (liver)

CPTI (Muscle)

Carnitine/acylcarnitine translocase


Mitrochondrial B-oxidation

Very long chain ACD (membrane)

LCAD (matrix)

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Trifunctional Protein

Long chain 3-hydroxyacyl- CoA dehydrogenase

Crotonase (short chain 2-enoyl-CoA hydratase


Short chain 3-ketoacyl-CoA thiolase

Medium chain 3-ketoacyl-CoA thiolase

Table 1: Some of the many enzymes involved in fatty acid oxidation showing that the majority have associated metabolic disorders, taken and adapted from Vockley and Whiteman 2001.

Medium Chain Acyl Dehydrogenase Defciency

MCAD deficiency is a potentially fatal disorder resulting from a mutation in the gene which encodes for the enzyme medium chain acyl-CoA dehydrogenase in mitochondrial B-oxidation (Nelson and Cox 2008). Affected individuals produce an abnormal protein product which results in inefficient enzyme activity to metabolise medium chain fatty acids(Dietrich 2005); consequently medium chain fatty acids accumulate which are metabolised to acylcarnitine intermediates and toxic dicarboxylic acid which can lead to organ dysfunction (Kompare et al 2008). It is the most commonly diagnosed inborn error of FAO with prevalence rates of up 1 in 10000 to 1 in 27000 of mainly European descent and is usually presented during childhood triggered by a period of catabolic stress such as fasting, exercise or febrile illness (Smith et al 2010). Patients are usually asymptomatic between episodes until they experience metabolic stress when their impaired oxidative capacity is overwhelmed and hence will present with a variety of episodic symptoms such as encephalopathy, hypoglycaemia, lethargy, seizures and respiratory arrest (Smith et al 2010). If undiagnosed 20-25% of cases result in death on the first metabolic crisis, with 30-40% of these survivors having irreversible neurological impairment with varying degrees of disability(Smith et al 2010).

MCAD defciency is an autosomal reccesive condition caused by a mutation in the ACADM gene (Gregerson 2008); this is nuclear gene which consists of 12 exons, spans over 44kb and encodes a precursor monomer of 421 amino acids, figure 7 shows the variety of different mutations of the gene which cause MCAD defciency with the most frequent mutation being lactated on exon 11 and is a 985A>G transition which results in a lysine to glutamate substition (Dietrich 2005). The ACADM genotypes can also vary between severe: c.985A>G/c985A>G, intermediate: c199T>C/c.985A>G and carrier: c.985>G/wildtype, forms of the disease (Smith et al 2010).

Figure 7: gene variation of the ACADM gene of symptomatic patients with MCAD deficiency and newborns with suspected MCAD deficiency, taken from Gregerson et al 2008.

MCAD disorder is identified via DNA based tests through the use of PCR and consequently is diagnosed as one of the battery of newborn screening tests via the analysis of a newborn blood spot, figure 8 shows the testing procedure of newborn babies (Sim et al 2002). More commonly however testing is usually conducted using tandem mass spectrometry for the detection of abnormal metabolites such as dicarboxylic acid, cartinine and glycine esters in urine and blood via the use of stable isotope dilution gas chromatography mass spectrometry which allows the diagnosis of asymptomatic individuals, figure 9 shows the clinical indictors of MCAD defciency (Rector and Ibdah 2009). Futher confirmation can be obtained from an organic acid profile or DNA mutation analysis, which involves the measurement of MCAD enzyme activity in fibroblasts and molecular genetic testing of the ACADM gene (Dietrich 2005).

Figure9 : Investigation procedure following on from clinical indicators off fatty acid oxidation defects, obtained through testing , taken from Sim et al 2002.

Figure8 : Investigation procedure for the diagnosis of fatty acid oxidation defects in newborns, taken from Sim et al 2002.

Once diagnosed the prognosis for the disease is very positive with treatment consisting of the avoidance of long periods of fasting together with dietry modifications of a high carbohydrate/ low fat diet. Sufferers are advised to frequently feed in order to avoid the accumulation of toxic metabolites resulting from hypoglycaemia and peripheral lipolysis; it is also recommended for toddlers to have 2g/kg of uncooked corn starch, which is slowly released into the blood to prolong sufficient stores of glucose overnight and hence prevent the body from metabolising fats (Dietrich 2005).


It is clearly evident that mitochondrial FAO is a crucial metabolic process which provides the energy required for efficient physiological function of the human body, even more so in newborn babies whom have limited glycogen reserves and hence rely heavily on the release of energy from fatty acids (Hammond and Wilcken 2002). Consequently in view of the requirement to oxidise fatty acids efficiently it is vital that we understand how this finely tuned intricate metabolic pathway proceeds so that we can maintain metabolic function in patients who suffer from inborn errors of lipid metabolism. This is reinforced by the fact that there are still enzymes of mitochondrial FAO to which defects and gene mutations have not yet been diagnosed and so it is likely that further disorders remain to be found and hence new challenges for science to solve