Lipids as Fuel
After a meal, chylomicrons containing TAG and apo C-II are acted upon by lipoprotein lipase, located in the capillaries of muscle and adipose tissue and activated by insulin. FFAs can be taken up directly or transported on albumin.
During fasting, proteins are used as an energy source following glycogen depletion, generating carbon skeletons following deamination that can be used at various points in the TCA Cycle.
Levels of total urinary nitrogen, a measure of deamination, peak early during fasting and fall of during the proceeding weeks. In order to maintain levels, TAG stores are therefore mobilized.
Release of TAG Stores in Adipose Tissue
In the fat, a high epinephrine/insulin ratio activates hormone-sensitive lipase via cAMP and PKA, liberating FFAs and glycerol to the blood.
Glycerol cannot be metabolized in adipose tissue, and so it must return to the liver to be metabolized by glycerol kinase for future use in TAG synthesis. It can also be used as a substrate for gluconeogenesis.
FFAs diffuse through the plasma membrane and bind to albumin, where they are transported to the tissues and are oxidized for their energy. Active transport across membranes is mediated by fatty acid binding protein. FAs can also be transported to the liver, where they can contribute to the formation of ketone bodies.
Fatty Acid Oxidation
Fatty acid oxidation is used as an important energy source for tissues including skeletal and heart muscle. Fatty acid oxidation occurs in the mitochondrion, while fatty acid biosynthesis occurs in the cytoplasm.
Accumulation of malonyl CoA, an intermediate of fatty acid synthesis, inhibits beta- oxidation of fatty acids.
Fatty acid oxidation occurs in the mitochondrial matrix through a number of steps and requires carnitine. Through the beta-oxidation spiral, the fatty acid chain is sequentially shortened by 2 carbons through the action of three acylCoA dehydrogenases to produce acetyl CoA molecules which enter the TCA cycle.
Oxidation of FAs with odd numbers of C produce a 3 carbon structure, propionyl CoA. This is oxidized in a three step process which involves L-methylmalonyl CoA and succinyl CoA, and requires Vitamin B12.
Beta oxidation of FAs produces energy from FADH2, NADH, and Acetyl CoA. The energy output is high: for each palmitoyl CoA, 131 ATPs are produced.
Fatty Acid Oxidation Defects
FA oxidation can be blocked by failure to enter the mitochondria, usually due to some defect with carnitine.
Genetic defects may also be present in one of the three acylCoA dehydrogenase enzymes, with the medium chain deficiency being the most common. This results in the excretion of dicarboxylic acids and leads to increasing use of glucose and often profound hypoglycemia.
Vitamin B12 deficiency leads to urine buildup of methylmalonic acidemai and aciduria, leading to metabolic acidosis and developmental disability.
Zellweger Syndrome occurs due to a loss of functional peroxisomes, which oxidize very long fatty acids. Their accumulation leads to death within 6 months of age.