Fatty Acid Oxidation Flashcards
1
Q
Why do we need beta oxidation? what is it?
A
- primary source of fatty acids for oxidation are dietary and mobilization from cell stores
- fatty acids from diet are delivered from gut to cells via transport in the blood
- fatty acids are stored in the form of TGs within adipocytes of adipose tissue
- in response to energy demands, the fatty acids of stored TGs can be mobilized for use by peripheral tissues
- release of metabolic energy, in the form of fatty acids, si controlled by a complex series of interrelated cascades that result in activation of hormone sensitive lipase
2
Q
Process of hormone induced fatty acid mobilization in adipocytes? (4)
A
- hormone sensitive lipase is activated by glucagon, epinephrine, or beta corticotropin
- these hormones bind to the receptor and leads to the activation of adenylate cyclase
- the resultant increase in cAMP activates PKA which then phosphorylates and activates hormone sensitive lipase
- hormone sensitive lipase hydrolyzes fatty acids from TGs and DGs
- DGs are substrates for either hormone sensitive lipase or for the non inducible enzyme DG lipase - the final fatty acid is released from MGs through the action of MG lipase (enzyme active in the absence of hormonal stimulation)
- net result of action of these enzymes is three moles of free fatty acid and one mole of glycerol
- free fatty acids diffuse from adipose cells, combine with albumin in blood and are transported to other tissues, where they passively diffuse into cells
- when fatty acids are transported through cytoplasm, their oxidation proceeds in both peroxisomes (non oxidative phosphorylation) and mitochondria (by oxidative phosphorylation)
3
Q
Table of metabolism of different length fatty acids? (5)
A
see pic
4
Q
Beta oxidation of short and medium chain fatty acids, less than 12 C?
A
- capable of diffusing directly into the mitochondria and are then activated by the matrix enzymes in the matrix
- they cross the inner mitochondrial membrane without the aid of carnitine shuttle
- once inside the mitochondria matrix, they are activated to their Coenzyme A derivatives by acyl coenzyme A synthetases (thiokinase)
5
Q
Beta oxidation of very long chain fatty acids, more than 21 C? (7)
A
- may be first metabolized down to octanyl CoA in peroxisomes
- then transported to the mitochondria for the remainder of oxidation
- carnitine may be involved in the transfer of shortened fatty acyl to mitochondria
6
Q
activation of long chain fatty acids in cytosol? (8)
A
-one molecule of ATP used to form one long chain fatty acyl CoA molecule
7
Q
Importance of carnitine and its function?
A
- in mammals, carnitine is considered a conditionally essential nutrient, so it can be synthesized by the organism but it mostly comes from diet
- 75% of total body carnitine levels come from diet
- 25% from endogenous synthesis
8
Q
Carnitine sources?
A
- animal based foods (meat and dairy) contain high levels
- food sources derived from plants contribute very little
- endogenous synthesis in liver and kidneys
9
Q
Carnitine synthesis? (10)
A
- carnitine is synthesized from lysine in liver and kidney, but not in skeletal or heart muscle
- carnitine uptake is mediated by OCTN2 transporter in humans
- Vit C required
10
Q
Transport of long chain fatty acids in mitochondrial matrix? (11)
A
- long chain fatty acyl CoA can pass through the outer mitochondrial membrane but cannot pass through the inner membrane
- carnitine is the carrier in the translocation of long chain fatty acyl groups across the inner mitochondrial membrane into the matrix
- carnitine acyl transferase 1 and 2 (CAT 1 and 2) transfer a fatty acid between thiol of CoA and hydroxyl of carnitine
- carnitine acyl carnitine translocase is the transporter
11
Q
What inhibits the carnitine shuttle? (12)
A
- Malonyl CoA
- when fatty acid is synthesized in the cytosol, malonyl CoA inhibits CPT1 and entry of fatty acids into mitochondria for beta oxidation
- CPT1 (carnitine palmitoyl transferase 1) is a specific CAT1
- malonyl coa is made from acetyl coa by the enzyme acetyl coa carboxylase
12
Q
overall regulation of long chain fatty acid activation and transport into mitochondria?
A
- substrate availability
- CoA must be available for beta oxidation to proceed, since it is a substrate for the thiolase reaction - covalent modification by hormone
- hormone sensitive lipase in adipose tissue is activated by phosphorylation (glucagon)
- its activity is low when insulin levels are high - allosteric inhibition
- high levels of malonyl coa allosterically inhibit CAT1
- this prevents beta oxidation during fatty acid synthesis
13
Q
What is the main source of energy during periods of fasting?
A
- beta oxidation of fatty acids
- also plays major role in energy during prolonged exercise in heart and muscle
14
Q
Why is it called beta oxidation?
A
- it occurs through the sequential removal of 2 carbon units by oxidation at the beta carbon position of the fatty acyl CoA molecule
1. oxidation occurs at the beta carbon
2. follwed by the cleavage of the alpha beta bond
3. acetyl CoA is formed and fatty acyl CoA (2 C’s shorter)
15
Q
What does each round of beta oxidation produce?
A
- one NADH
- one FADH2
- one acetyl CoA
- in muscle, acetyl CoA enters the TCA cycle where it is further oxidized to CO2 with the generation of three NADH and one FADH2, and one ATP
- NADH and FADH2 can then enter the respiratory path for the production of ATP (ETC)
- in liver, acyl CoA is converted to ketone bodies
16
Q
Caloric values of glucose vs fatty acids? (15)
A
-oxidation of fatty acids yields more energy than glucose
17
Q
Beta oxidation of saturated fatty acids (palmitoyl CoA)? (16)
A
- in a cycle of reactions, carbons of fatty acyl CoA are released into two carbon acetyl CoA units
- this yields 36 ATP, equivalent to complete oxidation of glucose - in liver, acetyl CoA units are then used for synthesis of ketone bodies
- in other tissues, they are metabolized in TCA cycle to form ATP - complete oxidation of palmitate yields 129 ATP, after 2 mole of ATP is invested at the thiokinase reaction
- overall ATP from palmitate is about twice that per gram of glucose because it is already partially oxidized in comparison with palmitate
18
Q
What are the 4 enzymes and reactions used in beta oxidation of long chain fatty acids? (17)
A
1) Acyl Coa dehydrogenase- Dehydrogenation between the alpha and beta carbons (C2 and C3) in a FAD-linked reaction.
2) Enoyl CoA hydratase- Hydration of the double bond by enoyl CoA hydratase.
3) Hydroxyl acyl CoA dehydrogenase- A second dehydrogenation in a NAD-linked reaction.
4) Keto acyl thiolase- Thiolytic cleavage of the thioester by beta-ketoacyl CoA thiolase.
- fatty acid is now two carbons shorter and re-enters beta oxidation
- acetyl coa can go through the TCA cycle
19
Q
Overall equation of palmitoyl CoA? (18)
A
pic
20
Q
Overview of mitochondrial beta oxidation? what is the trifunctional protein complex? (19)
A
- 4 fatty acyl CoA dehydrogenase enzymes for oxidation of various lengths of fatty acids
- trifunctional protein complex with two subunits expresses the enzyme activities for steps 2-4 of beta oxidation path
- equivalent enzymes for shorter fatty acids are soluble proteins of the matrix
21
Q
What is medium chain acyl CoA dehydrogenase deficiency (MCADD)?
A
- in 1st years of life, this deficiency will become apparent following prolonged fasting
- one of the most common inborn errors of fatty acid oxidation (1 in 12,000 births in west, 1 in 40,000 world)
- autosomal recessive inheritance
- medium chain fatty acids may accumulate and damage tissues
- damage to liver and brain, muscle defects
- decrease in fatty acid oxidation
- severe hypoglycemia
- failure to produce ketone bodies during fasting
- maternal complications of pregnancy
- misdiagnosis of Reye syndrome or Sudden infant death syndrome (SIDS)
22
Q
Symptoms of MCADD?
A
- can be triggered once baby has stopped receiving nightly feeds
- vomiting, lethargy, frequently coma, hypoglycemia which occurs due to tissue dependence on glucose for energy
- excessive urinary excretion of medium chain dicarboxylic acids as well as their glycine and carnitine esters
23
Q
Treatments of MCADD?
A
- high carbohydrate and MC acyl CoA derivatives
- human milk is rich in long chain fatty acids
- frequent feeding, avoidance of fasting, carnitine supplements
- deficiencies in short and long chain fatty acyl dehydrogenases have similar features
24
Q
Jamaican vomiting sickness?
A
- the unripe fruit of Jamaican Akee tree contains a toxin, hypoglycin, which inhibits both short and medium chain acyl CoA dehydrogenases
- this inhibits beta oxidation and leads to nonketotic hypoglycemia
25
Q
Beta oxidation of saturated fatty acyl CoA that has an odd number of carbons? (24)
A
- produces acetyl CoAs and one mole of propionyl CoA
- the majority of natural lipids contain an even number of carbons
- propionyl CoA is converted in an ATP dependent pathway to Succinyl CoA
- Succinyl CoA enters the TCA cycle for further oxidation
- succinyl CoA is also produced during the catabolism of branched chain amino acids
26
Q
Process of the breakdown of propionyl CoA? (25)
A
- requires Vit B12 and Biotin
- propionyl CoA is a minor source of carbons for GNG
32
Q
Process of alpha oxidation? (28)
A
- branched chain fatty acids, phytanic acid is methylated, so it cannot act as a substrate for the first enzyme of the beta oxidation path (acyl CoA dehydrogenase)
- an additional mitochondrial enzyme, alpha hydroxyls, adds a hydroxyl group to the alpha carbon of phytanic acid
- this serves as a substrate for the remainder of normal oxidative enzymes - the first carbon is removed as CO2
- in subsequent cycles of beta oxidation, acetyl CoA and propionyl CoA are released alternately
33
Q
Refsum disease? (28)
A
- rare autosomal disorder caused by deficiency of alpha hydroxylase
- phytanic acid accumulates in the tissues and serum in large quantities
- leads to severe symptoms including cerebellar ataxia, retinitis pigmentosa, nerve deafness, peripheral neuropathy
- symptoms are neurologic
- treatments involved diet restrictions
- restrict dairy products and ruminant meat from diet can help symptoms
34
Q
Beta oxidation of very long chain fatty acids? (29)
A
- very long chains undergo preliminary beta oxidation in peroxisomes, when shortened to long chains, are then transferred to mitochondria
- many are metabolized to short chains, such as hexanoyl CoA, instead of completely being oxidized to acetyl CoA due to the lack of TCA cycle enzymes in the peroxisomes - shortened chains are exported to mitochondria to be completely oxidized to provide energy, ATP
36
Q
What is Zellweger syndrome? (45)
A
- congenital autosomal recessive disorder
- results in reduction of peroxisome in cells of liver, kidney, and brain
- damages white matter of brain and also how body metabolizes particular substances in blood and organ tissues
- rare disorder affecting infants (1 in 50,000 to 100,000)
- affects both male and female
40
Q
What is Adrenoleukodystrophy? cause? (45)
A
- neurological disorder due to defective peroximal oxidation of very long chain fatty acids
- most common peroxisomal disorder affecting males at early ages ( X linked)
- it is a fatal demyelinating disease caused by mutations in the ABCD1 gene
- this leads to absent or non functioning adrenoleukodystrophy protein (ALDP)
42
Q
Omega oxidation of fatty acids? (39,40)
A
- occurs in ER of kidney and liver
- alternative path of very long chain fatty acid metabolism
- failure of beta oxidation to proceed normally can result in increased omega oxidation activity
- lack of carnitine palmitoyltransferase (CPT) activity prevents fatty acids from entering mitochondria can lead to accumulation of fatty acids in cell and increased omega oxidation
- in vertebrates, the enzymes for omega oxidation are located in the ER of liver and kidneys
45
Q
Primary carnitine deficiency (systemic) causes?
A
- defective in endogenous biosynthesis of carnitine
- defect in the OCTN2 gene
46
Q
What is primary carnitine deficiency?
A
- defect in plasma membrane carnitine transporter (kidney, muscle) that prevents uptake of carnitine and causes urinary carnitine wasting
- autosomal recessive disorder with mutation of OCTN 2
- acute primary carnitine deficiency can be triggered by fasting or viral infections
51
Q
Secondary carnitine deficiency?
A
- manifested with a decrease of carnitine levels in plasma or tissues which are caused by other metabolic disorders:
- inadequate intake (fad diets, lack of access, vegetarians)
- deficiencies in mitochondrial mobilizing enzymes (CAT1 or CAT2)
- decreased endogenous synthesis of carnitine due to severe liver disorder
- excess loss of carnitine due to diarrhea, diuresis, hemodialysis
- hereditary disorder which carnitine leaks from renal tubes
- increased requirement for carnitine when ketosis is present or demands for fat oxidation is high (critical illness such as sepsis, burns, surgery of GI tract)
- decreased muscle carnitine levels due to mitochondria impairment (due to use of zidovudine or AZT)
54
Q
Diseases related to paths involved in fatty acids transported into mitochondria and peroxisomes? (45)
A
pic
56
Q
Lipid malabsorption problems? treatments? (47)
A
- results in loss of lipids (steatorrhea) in feces
- steatorrhea can be caused by numerous conditions
- problems:
1. liver
2. blocked bile duct
3. blocked pancreatic duct
4. defective absorptive cells - treatments:
- diet low in long chain fatty acids
- avoid starvation
- plenty of carbs
58
Q
What is Gauchers disease? (49)
A
- example of sphingolipidoses
- the most common genetic lysosomal storage disorder
- Type 1- does not affect nervous system
- Types 2 and 3- rare and neuronopathic
61
Q
Disorders associated with abnormal sphingolipid metabolism? (51, 52)
A
pics
62
Q
Sphingolipid disorders chart? (53)
A
pic
