Fatty Acid Oxidation Defects

1. The disorders of oxidation of fatty acids by mitochondria has been major focus of research for the past 10-20 years. Based on these studies clinicians are now beginning to understand symptoms of Reyes-like syndrome, cardiomyopathy, hypotonia, hypoglycemia, developmental delay, and in some cases sudden infant death syndrome (SIDS). These are all related to defects in FAO.

2. Panel of assays in neonates now include quantization of FAO enzymes specifically MCAD.

Fatty Acids are preferentially oxidized

1. During periods of extended exercise e.g. aerobics, running on a treadmill, running for long distances.

2. In diabetic patients in whom glucose metabolism is low.

3. During periods of starvation.

4. By heart muscle which almost exclusively depends on FA oxidation for energy.

Sequential Steps in the oxidation of Fatty Acids

• Mobilization of Fat from adipose tissue• Transport of fatty acids in plasma and their

activation in the cells• Transport of activated fatty acids to

mitochondria and oxidation• Formation of ketone bodies (excess oxidation

in starvation and diabetes)• Regulation of fatty acid oxidation

Mobilization of Triacylglycerols That are Stored in Adipocyte Cells

Free fatty acids and glycerol are released into the blood stream

Lipolysis inducing hormones: Epinephrine, glucagon, adrenocorticotropic hormones -> Insulin inhibits lipolysis

Free fatty acids are bound by serum albumin -> serves as carrier in blood

FA Bound to FABP

FA in Plasma

FAO Cycle

Steps in the oxidation of Palmitoleic Acid (C:16:1)

1) CH3-CH2-CH2-CH2-CH2-CH2-CH=CH-CH2-CH2-CH2-CH2-CH2-CO-SCOA +CH3-CO-CoA + FADH2 +NADH

2) CH3-CH2-CH2-CH2-CH2-CH2-CH=CH-CH2-CH2-CH2-CO-SCoA + CH3-CO-CoA + FADH2 +NADH

3) CH3-CH2-CH2-CH2-CH2-CH2-CH=CH-CH2-CO-SCoA+

CH3-CO-CoA + FADH2 +NADH

4) CH3-CH2-CH2-CH2-CH2-CH=CH-CO-SCoA + CH3-CO-CoA + FADH2 +NADH

5) CH3-CH2-CH2-CH2-CH2-CO-SCoAA + CH3-CO-CoA +NADH

6) CH3-CH2-CH2-COA+ CH3-CO-CoA + FADH2 +NADH

7) CH3-CO-CoA + CH3-CO-CoA + FADH2 +NADH

After the 7th round you are left with an 8th acetyl CoA (CH3-CO-CoA) + 6FADH2 + 7NADH

8

Oxidation of Odd Chain FA

11

Omega Oxidation of Fatty Acids

Fattyacyl CoA

Regulation of FAO

1. Enzyme CPTI (carnitine-palmitoyl transferase I) is the rate limiting enzyme. It is inhibited by Malonyl CoA, a product formed during fatty acid synthesis

2. Hormonal Regulation of FA oxidation

• Glucagon

• Epinephrine

• Insulin

Triacyl glycerol or Hormone sensitive lipase

Spectrum of FAO deficiencies

1. Carnitine deficiency

2. Fattyacyl CoA synthetase deficiency

3. Short chain (SCAD), medium chain (MCAD), long chain (LCAD) and multi-chain (MCAD) dehydrogenase mutations

4. Acyl Carnitine-Carnitine translocase mutations

Another report from England: Of 62 affected individuals identified, 57 were from England, giving an incidence of 4.5 cases/100 000 births. Forty six cases presented with an acute illness (10 of whom died), 13 cases were identified because of family history, and three for other reasons. Six of the survivors were neurologically impaired. Undiagnosed, MCAD deficiency results in considerable mortality and morbidity. However, current management improves outcome.

The clinical entity known as MCAD deficiency was biochemically defined about 20 years ago; however, some believe the condition to be at least as common in newborns as phenylketonuria, with an incidence approximating 1 per every 12,000 live births. A recent report from Europe indicates an incidence in Bavaria of 1:8456 in more than 500,000 newborns screened

Examples of Clinical Findings

A Child has MCAD deficiency

Will this child be:

A. Hypoglycemic

B. Hyperglycemic

C. Normal glucose

Will this child be:

A. Severely ketotic

B. Mildly ketotic

C. Not ketotic

Will this child have:

A. Acidosis

B. Alkalosis

C. Normal pH.

Learning ObjectivesThis lecture links defects in catabolism of lipids to a variety of

pathological states. Following this lecture students should understand that

1. oxidation of lipids is an important energy source

2. oxidation requires mobilization of fat from adipose cells in response to hormones like glucagon and epinephrine by a mechanism in which cellular cAMP is increased

3. fatty acids transported in plasma have to be activated

4. activated fatty acids need to be transported from cytosol to mitochondrial matrix where oxidation takes place and this regulation has important implications for energy production and pathology

5. in diabetics excess fatty acids oxidized produce ketone bodies as metabolites which are important source of energy for muscle , heart and brain

6. the presence of ketone bodies in plasma leads to acidosis which affects oxygen saturation of Hb and resultant delivery of oxygen to tissues