L40-41 Fatty Acid Oxidation and Ketogenesis Flashcards
Systemic fatty acid oxidation disorders:
Caused by: 1) MCAD deficient 2) CPT-1 deficient 3) Systemic carnitine deficient 4) Jamaican vomiting sickness Leads to: Hypoglycemia and Hypoketosis
Myopathic fatty acid oxidation disorders:
Caused by: 1) Myopathic carnitine deficiency 2) CPT-2 deficiency Leads to: Muscle cramps during exercise (a biopsy would show high muscle TAGs as lipid droplets)
MCAD Deficiency
1) 6-24 months 2) can’t oxidize fatty acids 6-10 carbons 3) severe hypoglycemia during fasting because over-reliance on glucose (due to not being able to break down fatty acids in liver/muscle) 4) Long chain fatty acids oxidized to medium chain acCoa (8-10 C’s) - medium chain acyl carnitines excreted in urine 5) dicarboxylic acids also found in urine due to increased flux through w-oxidation
Carnitine deficiency
1) Can’t uptake carnitine into tissues 2) Transport of long chain fatty acids into mitochondria is impaired and b-oxidation is decreased 3) Systemic carnitine deficiency presents at early age (hypoglycemia due to impaired gluconeogenesis because acCoa is activator of pyruvate carboxylase) and ketogenesis is decreased if liver carnitine is deficient 4) myopathic carnitine deficiency is characterized by muscle weakness and cardiomyopathy (presents at later age) - presence of CK-MM and myoglobin in urine to indicate skeletal muscle damage 5) reduced serum carnitine
CPT 2 deficiency
Cardiomyopathy and muscle weakness (myopathic form) Lipid deposits (triglycerides) found in skeletal muscle Prolonged exercise = myoglobinuria and high ck-MM levels in serum
Treating systemic fatty acid oxidation disorders
Manage hypoglycemia w IV glucose and avoid fasting and fats in diet (but keep lots of carbs!)
Treating myopathic fatty acid oxidation disorders
Stop muscle activity and give glucose and carnitine supplementation
Jamaican vomiting sickness…
* unripe ackee fruit has hypoglycin A to inhibit MCAD * results in hypoglycemia and inhibits b-oxidation * medium chain acyl carnitines found in urine
Oxidation of odd chain fatty acids…
Produces propionyl CoA (3C) in final round of b-oxidation This ultimately becomes succinyl coA
Regulating b-oxidation
Free fatty acid levels in serum regulate rate of oxidation Fatty acid levels in serum regulated by insulin/glucagon ratio - low ratio (fasting) activates hormone sensitive lipase in adipose tissue for lypolysis Entry of fatty acids into mitochondria is regulated by CPT1 - malonyl CoA (formed during fatty acid synthesis) and it inhibits cpt1 - this ensures that b-oxidation and fatty acid synthesis dont take place simultaneously
Peroxisomal oxidation of fatty acids
Very long chains (22-26C) first oxidized in peroxisomes - then short results sent to mitochondria for more oxidation
Zellweger syndrome
Defective peroxisomal biogenesis mainly affecting liver and brain Increased levels of C26 fatty acids in circulation Neuro defects like delayed development and extensive demyelination Hepatomegaly and hepatocellular failure Fatal in infancy
Phytanic acid
Dietary branched chain fatty acid found in dairy products - alpha oxidation done in peroxisomes
Refsum disease
deficient peroxisomal phytanyl coA a-hydroxylase (so defect in a-oxidation) Phytanate accums in tissues (esp neuro tissues) Visual defects, ataxia and polyneuropathy and skeletal manifestations Treat with dietary restriction of branched chain fatty acids
what is omega oxidation?
This is a minor pathway for oxidation of fatty acids in the ER omega oxidation results in oxidation of omega-C atom of fatty acid to form dicarboxylic acid In disorders where beta oxidation is defective like in MCAD deficiency, dicarboxylic acids can be found in circulation and urine
Further fate of AcCoA
