Degradation of Fatty Acids and B-Oxidation Flashcards
How does acetyl CoA feed the KB synthesis instead of entering TCA
When NADH/NAD is high then malate –> OAA is reversed. Acetyl CoA can not enter the TCA
B ox of unsaturated fa
Dietary unsaturated fatty acids contain cis double bonds. Cis-double bonds cannot be processed by the β oxidation machinery. β oxidation proceeds until the cis bond is reached. The cis bond is isomerized to trans bond and β oxidation can proceed further
The main diff of peroxisomal degradation from mitochondrial B oxidation
No FAD(2H) production in peroxisomes- instead H2O2 is produced
Regulation of B oxidation Insert pic
High I/g (during fed) stimulates acetylCoA carboxylase - then malony CoA inhibits CPTI (IN THE LIVER)
allostric inhibitor of CPTI
malonyl CoA (formed from acetyl Coa by acetyl CoA carboxylase)
fa activation
In order to be metabolized, fatty acids must be converted to fatty acyl CoA
Tx or deficiency of carnitine metabolism
H. Carb, L fat diet: rich in medium chain length fa
Hypoketotic diseases
Deficiencies in carnitine metabolism Deficiencies in β-oxidation (such as MCAD) Both cause hypoketotic hypoglycemia
sources of fa during fed state
chylomicrons and VLDLs VLDLs are made by liver
Intercellular localization of fa
Mitochondria Main site of b-oxidation Degradation of long, medium and short chain fatty acids Peroxisomes- very long and branched chain SER omega-oxidation in dicarboxylic acid
MCAD deficiency
Hypoketotic hypoglycemia Elevated C6-C10 acylcarnitine levels in plasma and urine. Elevated C6-C10 dicarboxylic acids in urine (due to ω oxidation). (adipic and subaric acids are most diagnostic in urine). Similar onset (fasting, infection) and symptoms as in carnitine deficiency. Responsible for some of the sudden death during infancy. Treatment with glucose and carbohydrate rich diet.
Transport of long chain fatty acids into mitochondria
carnitine-conjugated (longer than 12C) smaller than 12C carnitine is not required.
Oxidation of medium chain fatty acids
Dietary medium chain fatty acids are not stored in triglycerides in the human body They do not need to form fatty acyl CoA or carnitine conjugates to enter mitochondria Once they are in the mitochondria, they are conjugated with CoA. Some medium chain fatty acids are produced in the peroxisome from very long chain fatty acids, conjugated to carnitine and then transported into mitochondria. β oxidation then proceeds similarly to the long chain fatty acids.
carnitine storage
skeletal muscle
carnitine
Synthesized from protein-bound lysine. Synthesis requires S-adenosyl-methionine (SAM) as methyl donor. Synthesis starts in skeletal muscle and completed in liver and kidney. Most carnitine is stored in skeletal muscle in the human body. Transported into cells by specific carnitine transporter. Carnitine can be used as a dietary supplement to accelerate fatty acid oxidation.
w oxidaiton
Takes place in the smooth ER. Produces dicarboxylic acids. The dicarboxylic acids can undergo mitochondrial β oxidation. Normally, a minor process. Increases if β oxidation is deficient (see MCAD deficiency previously)
deficiency of carnitine metabolism
Consequences of failure to degrade long chain fatty acids - during fasting or infection -leads to hypoketotic hypoglycemia during fasting -elevated liver enzymes and ammonia lipid droplet accumulation in: liver hear Sk. m.
site of omega oxidation of fatty acids into dicarboxylic acids
SER
CPTII deficiency
Plasma acylcarnitine- high Plasma free carnitine-low urine free carnitine- normal
because of missing this enzyme, the liver can not produce acetyl Co A from KB
Succinyl CoA- acetoacetate transferase
MCAD deficiency treatment
glucose and carb rich diet
enzyme deficiencies that cause organic acidemias (priopionic or methyl malonyl acidemia)
enzyme defeciencies in the propionyl CoA degradation.
CAC deficiency
Plasma acylcarnitine- high Plasma free carnitine-low urine free carnitine- low
blood transport of fa
In fed state, dietary fatty acids are transported as triglycerides inside lipoprotein particles (chylomicrons). In fed state, fatty acids synthesized in the liver from glucose are transported as triglycerides inside lipoprotein particles (VLDLs). Fatty acids released from the adipose tissue (during fasting or exercise) are bound to albumin and delivered to target tissues.
CPTIA deficiency (liver)
Plasma acylcarnitine- Low Plasma free carnitine-High urine free carnitine- Low
Two conditions with high acylplasma carnitine, and normal urine free carnitine
CPTII and CAC deficiency
Primary carnitine deficiency (transport into the cell)
Plasma acylcarnitine- low Plasma free carnitine-low urine free carnitine-elevated
Condition under which w-oxidation increases
When B oxidation is deficient
sources of fa during fasting or exercise
Triglycerides are degraded in the adipose tissue into fatty acids and glycerol by hormone sensitive lipase. The process is stimulated by elevated glucagon/insulin ratio and high epinephrine levels.
Oxidation of odd fatty acids
The last cycle of β oxidation produces 1 acetyl CoA (2 carbon) and 1 propionyl CoA (3 carbon). Propionyl CoA is degraded to succinyl CoA which enters the TCA cycle. Enzyme deficiencies in the propionyl CoA degradation pathway cause organic acidemias (propionic or methyl-malonyl acidemia).
Ketoacidosis
elevated KB in blood Type I diabetes – (lack of insulin, high glucagon/insulin ratio) adipose and liver “thinks” the body is fasting Acute consumption of large amounts of alcohol: Alcohol metabolism increases NADH, the malate–OAA reaction is reversed, acetyl-CoA is used for ketone body synthesis
There are only few tissues/cells that do not use fatty acids during fasting as energy source
RBC Brain-most fa cant pass through
