Fatty Acid Oxidation Flashcards
Three stages of fatty acid oxidation (β oxidation)
- Release of fatty acid from TAGs
- Transport into the mitochondrial matrix.
- Repeated cycles of oxidation
Describe the release of fatty acid from TAGs
This process is initiated by hormone-sensitive lipase (HSL), which removes a fatty acid from carbon 1 and/or 3 of the TAG.
HSL is activated by epinephrine
Describe fatty acid transport into the mitochondrial matrix
In cells, fatty acids are converted into their CoA derivatives in the cytosol. Fatty acid degradation occurs in the mitochondria.
However Acyl-CoA molecules cannot enter the mitochondrial matrix, so the long chain acyl (fatty acid) group is transferred temporarily to the small, zwitterionic alcohol carnitine (catalyzed by carnitine-palmitoyl transferase or CPT). This is also a MAJOR REGULATORY STEP in fatty acid oxidation.
Once inside the matrix, the Acyl-CoA is resynthesized.
Short and medium-chain (
Deficiencies in carnitine production or utilization
Massive amounts of triacylglycerol deposits in the liver
Cause muscle cramping, weakness or worse because oxidation of long-chain fatty acids is a primary source of energy.
Describe how repeated cycles of oxidation happen
β oxidation is the major pathway of fatty acid oxidation. It is named β because the β carbon gets oxidized. Each cycle has 4 steps and results in one 2 carbon Acetyl CoA, one FADH2 and one NADH.
Step 1. Acyl CoA Dehydrogenase:
Located in the mitochondrial matrix.
Oxidizes acyl CoAs.
Four forms of the enzyme exist specific for short (4-8), medium (4-14) and long (12-18) and very long carbon chains.
The enzyme uses FAD and introduces a trans-double bond.
Step 2. Enoyl CoA Hydratase:
Adds water across the trans double bond created in
reaction 1.
Step 3. β-Hydroxy-CoA Dehydrogenase:
Oxidizes the hydroxyl generating β-keto acyl-CoA
and NADH from NAD.
Step 4. Thiolase:
Releases acetyl CoA and transfers the fatty acid
shortened by two carbons to CoA-SH for another
round of β-oxidation.
Regulation of CPT-1
Malonyl CoA, intermediate in fatty acid synthesis, inhibits it and keeps it from shuttling fatty acids into the mitochondria
Genetic defects in Acetyl CoA Dehydrogenases
Genetic defects in all four enzymes have been described. Results in severe hypoglycemia provoked by fasting.
Medium-chain fatty acyl CoA dehydrogenase (MCAD) deficiency has been identified as the cause of some cases of SIDS, likely because infants rely on milk for nutrition and milk contains mostly medium chain fatty acids.
Oxidation of fatty acids with odd number of carbons
Odd-chain length fatty acids occur rarely in the diet. They are oxidized by β-oxidation until a 3-carbon proprionyl CoA remains.
In 3 steps (that include a biotin-requiring and a vitamin B12-requiring step), the proprionyl CoA is converted to succinyl CoA, an intermediate in the TCA cycle.
Oxidation of very long chains
Some very long chain fatty acids are oxidized to C8 fatty acids in peroxisomes (cellular organelles that generate peroxide (H2O2) in the process of fatty acid oxidation).
Ketones
Produced in liver from excess acetyl CoA
Acetoacetate, β hydroxybutarate and acetone
Water-soluble fuels exported to the brain and other tissues when fuel is not available
Substrates for oxidative metabolism when glucose is low (fasting and low-carb diets)
High levels of NADH during fatty acid oxidation promotes conversion of aceoacetate into 3-hydroxybutyrate
Ketone bodies are the main energy source for cardiac muscle and the renal cortex.
Ketoacidosis
Extremely high levels of ketone bodies can be released during periods of extreme metabolic stress such as starvation.
When the rate of formation of ketone bodies is greater than the rate of their use, their levels begin to rise in the blood
(ketonemia) and eventually in the urine (ketonuria). These two conditions are seen most often in cases of uncontrolled type 1 diabetics. The patients are insulin – resistant due to failure to take insulin, illness or other stress. Under these conditions, the hormone sensitive lipase is highly activated, releasing large quantities of fatty acids from adipose. Fatty acid oxidation produces high levels of NADH, which
inhibits the TCA cycle and forces the excess acetyl CoA generated from fatty acid oxidation into the ketone body pathway.
Since two of the ketone bodies (acetoactate and 3-hydroxybutyrate) are moderately strong acids, they lower the blood pH, resulting in metabolic ketoacidosis.
Acetone is highly volatile, which can sometimes be smelled (a fruity odor) on the breath. This is a common symptom of diabetic ketoacidosis.
What are the products of each cycle of beta-oxidation?
1 acetyl CoA (can then feed into the TCA cycle and oxidative phosphorylation)
1 NADH and 1 FADH2 for electron transfer chain reaction
And the fatty acid chain is then 2 carbons shorter and continues cycling through
Peroxisomal beta- oxidation
Peroxisomes are also a major site of b-oxidation.
Very long chain and branched (phytanic acid from plants) fatty acids are preferentially oxidized in peroxisomes.
Although the intermediates are the same the enzymes are unique to peroxisomes.
Some medium chain fatty acids are exported from peroxisomes to the mitochondria for further oxidation.
Zellweger syndrome and X-linked adrenoleukodystrophy are related to defects of peroxisomal b-oxidation
What happens when you have excess Acetyl CoA
It’s converted into ketone bodies and exported from the liver
Acetoacetate and beta-hydroxybutyrate
Ketones produced primarily in the liver
Diffuse in blood to other peripheral tissues
Reconverted to acetyl CoA (enzyme missing in liver, but containing in brain)
Primarily transported to muscles and brain
