Fatty Acid Degradation Flashcards
What form of fatty acid is stored in adipose?
Muscle? (2)
Body fluids?
Liver?
Triglycerides
Glycogen/protein
Free glucose
Glycogen
In the liver, what can be used to produce ketone bodies?
Acetyl CoA
Why does the brain have a limited capability to beta-oxidation of fatty acids?
Because FAs cannot pass the blood-brain barrier
What are the two main sources of fatty acids in the well fed state? What’s the difference?
Chylomicrons – formed in the intestinal epithelium from FA in diet, they go in the circulation where FAs are removed through the peripheral tissues
Very low density lipoprotein – from glucose synthesized to become FAs, packaged in the liver
What is the source of FAs in the fasting or exercising state? What is FA broken down from? What enzyme is used? How is it regulated?
FA is taken from adipose tissue, it is broken down from triglycerides by hormone sensitive lipase. High glucagon/insulin ratio and high epinephrine levels activate this
What happens to the FAs released from adipose tissue?
They are bound to albumin (transporter) and delivered to target tissues. Fatty acid binding protein in the plasma membrane transports them inside the cell to be degraded mainly in the mitochondria
Describe the long chain FA transport into mitochondria
Acyl CoA will be added to FA through acetyl CoA synthetase
Fatty acyl CoA will cross the outer membrane, the CoA will be removed to be replaced by carnitine to form fatty acyl carnitine using CTP-1
It will cross the inner membrane through carnitine translocate
Carnitine will be removed and replaced by CoA to form fatty acyl CoA all by CPT-2
Fatty acyl CoA will go on to beta-oxidation
How is carnitine synthesized? What is required as a donor?
Where is it synthesized? Where is it stored afterwards?
What is it used for?
It is synthesized from protein-bound lysine, synthesis requires S-adenosyl-methionine (SAM) as methyl donor
Synthesis starts in the skeletal muscle, completed in liver and kidney, stored in skeletal muscle afterwards
Used as dietary supplement to speed up FA oxidation
What happens in the deficiency of carnitine metabolism?
What does it lead to?
What is elevated?
How is it treated?
Unable to degrade long chain FA, manifests during fasting or infections
Leads to hypoketotic hypoglycemia during fasting, ketone bodies not produced in liver, gluconeogenesis will be deficient, glucose is not spared in circulation
Blood levels of liver enzymes and ammonia
High carb, low fat diet rich in medium chain length fatty acids (does not require carnitine)
What is low/elevated in the following carnitine deficiencies:
Primary carnitine deficiency
CPT-1 deficiency
Acylcarnitine translocase deficiency
CPT-2
Low plasma carnitine and acyl carnitine level, elevated carnitine in urine
Elevated free carnitine plasma level, elevated free carnitine/acyl (C16-18) carnitine ratio
Low plasma free carnitine level/elevated acyl(C16-18) carnitine levels
Low plasma free carnitine levels/elevated acyl(C16-18) levels
What comes out of one cycle of beta-oxidation?
How do you calculate what is produced?
1 molecule of FADH2, NADH, and Acetyl CoA
Half the molecule, subtract by one
Where are medium-chain fatty acids formed?
Some are produced in peroxisomes from very long chain of fatty acids, they are transported into the mitochondria where beta-oxidation proceeds
What is elevated in Medium Chain Acyl CoA DH (MCAD) deficiency? How is it treated?
C6-C10 acyl carnitine levels and C6-C10 dicarboxylic acids in urine (due to omega oxidation)
Treated with glucose and carb rich diet
How is beta-oxidation regulated?
Malonyl CoA, which forms from acetyl CoA formed though acetyl CoA carboxylase, inhibits CPT-1. Acetyl CoA carboxylase is activated by insulin and inhibited by AMP-PK. NADH as well as FADH2 inhibits beta oxidation
Where does omega oxidation take place?
What is produced?
When is it activated?
It takes place in the SER
Dicarboxylic acid is produced
It is activated when beta-oxidation is deficient
Explain paroxysmal degradation of fatty acids. What are oxidized? How?
What is generated?
What is the main product in peroxisomal degradation of fatty acid?
Long (C>22) and branched chains are oxidized here. Branched chains are first oxidized in the alpha position, beta-oxidation then follows. Long chains go straight through beta-oxidation
H2O2, NADH, and Acetyl CoA (cannot be used for TCA yet, has to be conjugated to carnitine, transported to mitochondria, then can be used for TCA)
C6-C10 acyl carnitines
What is classic refsum disease? What is deficient?
What is elevated?
What are some of the symptoms?
Nervous system disorder. It is the deficiency of phytanic acid hydrolase, which is involved in the alpha-oxidation of phytanic acid
Elevated plasma phytanic levels
Symptoms include retinitis pigmentosa (can lead to blindness), deafness, ataxia, lack of ability to smell, and neuropathy
What is defective in X-linked adrenoleukodystropy (X-ALD)?
What is elevated
How is it manifested?
Defective peroxisomal very long chain FA transporter
Elevated C>22 FA in plasma
Neurological manifestation and demyelination (can be seen in MRI)
What is defective in PBR and ZSS?
How is it manifested?
What is elevated?
Defects in peroxins, which are proteins needed for peroxisome assembly
Demyelination occurs, liver dynsfunction
C>22 and phytanic acid is elevated in plasma
Where are ketone bodies synthesized?
Why must acetyl CoA be converted to ketone bodies?
Ketone bodies are synthesized in the liver
Acetyl CoA must be converted to ketone bodies because they cannot be transported in the bloodstream as Acetyl-CoA, they can however, be transported as ketone bodies, they are converted back to acetyl CoA in the tissue to be used in the TCA cycle
What are the three types of ketone bodies produced in the liver?
Which one is the most prominent? Why? What is the enzyme responsible for its synthesis?
Acetoacetate, D-B-hydroxybutyrate, and acetone
D-B-hydroxybutyrate is the most prominent because NADH levels in the liver are high, so they are favored. The enzyme responsible is D-B-hydroxybutyrate
What is the enzyme that is absent in the liver, which causes its inability to convert D-B-hydroxybutyrate to acetyl CoA to be used in the TCA cycle?
Succiny CoA: acetoacetate CoA transferase
How is ketone body synthesis regulated?
The rate of beta-oxidation, which determines the amount of acetyl CoA
NADH/NAD+ levels, when the ratio is high, this reverses malate –> oxaloacetate action, acetyl CoA cannot enter the TCA cycle
What is the effect of hypoketotic diseases?
Deficiency in carnitine metabolism
Deficiency in beta-oxidation
What can cause ketoacidosis? How?
Chronic alcohol consumption – TCA is inhibited because Acetyl-CoA is being used for ketone body synthesis
Type I diabetes – lack of insulin and high glucagon/insulin ratio, adipose and liver thinks that the body is fasting, releases a lot of ketone bodies
