Fatty Acid Oxidation & Lipolysis

• Fatty acids are stored in white adipose tissue.
• Carbohydrates are the main energy source for the body.
• Complete fatty acid oxidation yields 9 kcal/g.

Lipolysis

• Hormone-sensitive lipase is responsible for lipolysis of free fatty acids (FFA).
• Catecholamines and glycerol activate lipolysis.
• Insulin inhibits lipolysis.
• Lipolysis produces glycerol and free fatty acids.
• Glycerol is transported to tissues containing glycerol kinase.
• Free fatty acids are oxidized for energy production.

FFA Oxidation

• FFA are oxidized in the mitochondrial matrix.
• Red blood cells cannot oxidize FFA.
• The brain does not use FFA for energy.
• Beta oxidation involves successive shortening by 2-carbon fragments.
• Beta oxidation occurs through saturated (even-numbered) fatty acids.
• Beta oxidation yields Acetyl CoA, NADH, and FADH2.
• The rate of beta oxidation increases during prolonged fasting, starvation, diabetes mellitus, and ketogenic diets.
• Fatty acids are activated for beta oxidation in the cytosol.
• Fatty acids are activated by attaching CoA to form acyl CoA.
• Acyl CoA synthetase (thiokinase) is an enzyme of the outer mitochondrial membrane.
• Activation of fatty acids consumes 2 high-energy bonds (ATP to AMP).
• The carnitine shuttle is the rate-limiting transportation process in beta oxidation.
• Malonyl CoA inhibits CAT1, which inhibits beta oxidation.
• An increase in the acetyl CoA/CoA ratio decreases thiolase reactions that require CoA.
• Carnitine is mainly obtained through diet (meat).
• Lysine and methionine synthesize carnitine in the kidney and liver.
• Skeletal muscle contains 97% of the body's carnitine.
• Skeletal and cardiac muscles do not synthesize carnitine.
• Carnitine deficiency decreases the ability of tissues to use long-chain fatty acids as fuel.
• Carnitine deficiency presents with hypoglycemia during fasting, muscle weakness, and myoglobinemia.
• Treatment for congenital cases includes a diet high in carbohydrates and low in fats, avoiding fasting, and supplementing with medium-chain fatty acids (coconut).
• The sequence of four reactions in beta-oxidation releases FADH2 (oxidation), then involves hydration, NADH release (oxidation), and Acetyl CoA (thiolytic cleavage).
• The number of cycles in beta-oxidation is calculated as (n/2)-1.
• The end energy yield is calculated as (No. of cycles x 17) + 10.

Medium Chain Fatty Acyl CoA Dehydrogenase Deficiency

• Medium-chain fatty acyl CoA dehydrogenase deficiency is an autosomal recessive disorder.
• It is the most common inborn error of beta oxidation.
• It is more common in Caucasians of Northern European descent.
• It involves a decreased ability to oxidize fatty acids with 6-10 carbons, leading to their accumulation.
• Patients present with hypoglycemia and hypoketonemia.
• Treatment involves avoiding fasting.

Oxidation of Fatty Acids

• Oxidation of fatty acids with an odd number of carbons produces Propionyl CoA (3 carbons).
• Propionyl CoA metabolism requires Vitamin B12 and Biotin.
• Propionyl CoA metabolism results in Succinyl CoA production, which enters the citric acid cycle.
• Unsaturated fatty acids require extra enzymes to break double bonds, and NADH may be needed (produces less energy).
• VLCFA (>22 carbons) undergo peroxisomal beta oxidation.
• Peroxisomal beta oxidation products include shortened fatty acids linked with carnitine, which move to the mitochondria & produces H2O2 without NADH or FADH2.

Syndromes

• Zellweger syndrome (peroxisomal biogenesis disorder) and X-linked adrenoleukodystrophy (adrenocortical insufficiency, abnormality in white matter of the cerebrum) are syndromes that lead to the accumulation of VLCFA.
• Branched very long chain fatty acids undergo peroxisomal alpha oxidation.
• Peroxisomal alpha oxidation releases carbon dioxide.
• Peroxisomal alpha oxidation occurs in the brain and nervous tissue.
• Omega oxidation of fatty acids occurs in the endoplasmic reticulum.
• Omega oxidation requires Cytochrome p450, NADPH, and molecular O2.
• Omega oxidation occurs at both ends of the fatty acid.