Fatty Acids, Ketones B&B

Question 1

what enzyme is responsible for degrading triacylglycerol into fatty acids?

Answer 1

hormone sensitive lipoprotein lipase - found on endothelial surfaces of capillaries, abundant in adipose and muscle

Question 2

what are the basic steps of fatty acid synthesis (4)?

Answer 2

1. citrate shuttle transports excess acetyl CoA from mitochondria to cytosol
2. citrate converted back to acetyl CoA
3. acetyl CoA converted to malonyl CoA via acetyl-CoA carboxylase - rate limiting, requires biotin
4. synthesis of palmitate via fatty acid synthase - requires NADPH (from HMP shunt)

Question 3

fill in the steps regarding fatty acid synthesis:
1. ______ transports excess acetyl CoA from mitochondria to cytosol
2. ____ converted back to acetyl CoA
3. acetyl CoA converted to malonyl CoA via ________ - rate limiting, requires ______
4. synthesis of ______ via fatty acid synthase - requires _____

Answer 3

1. citrate shuttle transports excess acetyl CoA from mitochondria to cytosol
2. citrate converted back to acetyl CoA
3. acetyl CoA converted to malonyl CoA via acetyl-CoA carboxylase - rate limiting, requires biotin
4. synthesis of palmitate via fatty acid synthase - requires NADPH (from HMP shunt)

Question 4

which 2 tissues do NOT use fatty acids for energy?

Answer 4

1. RBC - no mitochondria, anaerobic glycolysis only
2. brain - glucose and ketones only

Question 5

what are the basic steps of beta oxidation of fatty acids? (4)

Answer 5

1. convert FA to fatty acyl CoA
2. carnitine shuttle transports fatty acyl CoA to inner mitochondria
3. beta oxidation removes 2 carbons - generates NADH, FADH2, acetyl CoA
4. 3C propionyl CoA remains, converted to succinyl CoA for TCA via propionyl-CoA carboxylase - requires biotin

Question 6

fill in the blanks regarding beta oxidation:
1. convert FA to fatty acyl CoA
2. ________ transports fatty acyl CoA to inner mitochondria
3. beta oxidation removes 2 carbons - generates ___, ____, _____
4. 3C _______ remains, converted to succinyl CoA for TCA via _______ - requires _______

Answer 6

1. convert FA to fatty acyl CoA
2. carnitine shuttle transports fatty acyl CoA to inner mitochondria
3. beta oxidation removes 2 carbons - generates NADH, FADH2, acetyl CoA
4. 3C propionyl CoA remains, converted to succinyl CoA for TCA via propionyl-CoA carboxylase - requires biotin

Question 7

what is carnitine required for and what results from deficiency?

Answer 7

carnitine: required to shuttle fatty acyl CoA to inner mitochondria in FA beta oxidation (basically, you need this to utilize FA for energy!)

deficiency (malnutrition, liver disease, hemodialysis, etc) —> muscle weakness, cardiomyopathy, hypoketotichypoglycemia when fasting (tissues overuse glucose and ketone synthesis is low without FA breakdown)

Question 8

how does MCAD (medium chain acyl-CoA dehydrogenase) deficiency present?

Answer 8

MCAD required for beta-oxidation of medium-chain fatty acids

MCAD deficiency: AR, severe hypoglycemia (overuse of glucose) without ketones (ketone synthesis requires acetyl CoA from beta oxidation)

gluconeogenesis shut down (lack of acetyl CoA) - fasting can be life-threatening

Question 9

which organs/tissues use ketones, which does NOT?

Answer 9

muscle/heart mainly use ketones to spare glucose for brain, though brain can also use ketone bodies

liver cannot use ketones - forces liver to release the ketones it makes into plasma for use by other tissues

Question 10

explain why there is high ketone production in diabetes

Answer 10

diabetes - low insulin causes higher utilization of fatty acids (not responding to glucose)

fatty acids broken down to acetyl CoA, which is diverted to ketone synthesis when in excess !

Question 11

explain why there is high ketone production with heavy alcohol intake

Answer 11

ethanol metabolism generates a lotttt of NADH

this causes TCA cycle to be halted at the place where NADH is made (converting malate to oxaloacetate)

the step after (which cannot be reached) is the point at which acetyl CoA enters TCA - since it cannot enter stalled TCA, acetyl CoA accumulates —> diverted to ketone production

Question 12

how does the citrate shuttle transport acetyl CoA out of the mitochondria?

Answer 12

citrate synthase combines acetyl CoA and oxaloacetate to make citrate

citrate can enter TCA (first substrate) or leave mitochondria for fatty acid synthesis - this is favored when energy is high and mitochondria citrate concentration rises

in cytoplasm, citrate is split into oxaloacetate and acetyl CoA again

Question 13

what is the committed step of fatty acid synthesis?

Answer 13

acetyl CoA carboxylase converts acetyl CoA to malonyl CoA with input of CO2 and ATP

(analogous reaction to pyruvate carboxylase)

Question 14

what are the 4 reaction phases of fatty acid synthase (FAS)?

Answer 14

1. condensation
2. reduction (using NADPH)
3. dehydration
4. reduction (using NADPH)

*note every cycle of fatty acid synthesis requires 2 NADPH!

Question 15

how does the catabolism of very long chain fatty acids differ from that of short/medium chain fatty acids?

Answer 15

very long chain fatty acids are first broken down in peroxisomes, prior to beta oxidation

peroxisomes also contain enzymes necessary for alpha-oxidation of some fatty acids with methyl branches

Question 16

how are long chain fatty acids transported into the mitochondria for beta oxidation?

Answer 16

via carnitine shuttle

1. FA converted to fatty acyl-CoA via acyl CoA synthetase
2. CPT-I transfers acyl group from CoA to carnitine = acylcarnitine
3. acylcarnitine is transported into mitochondrial matrix in exchange for free carnitine via CACT
4. CPT-II transfers acyl group from carnitine to CoA in the matrix, regenerating free carnitine

Question 17

fill in the blank regarding the carnitine shuttle:
1. FA converted to fatty acyl-CoA via _____
2. _____ transfers acyl group from CoA to carnitine = acylcarnitine
3. acylcarnitine is transported into mitochondrial matrix in exchange for free carnitine via ____
4. ____ transfers acyl group from carnitine to CoA in the matrix, regenerating free carnitine

Answer 17

1. FA converted to fatty acyl-CoA via acyl CoA synthetase
2. CPT-I transfers acyl group from CoA to carnitine = acylcarnitine
3. acylcarnitine is transported into mitochondrial matrix in exchange for free carnitine via CACT
4. CPT-II transfers acyl group from carnitine to CoA in the matrix, regenerating free carnitine

Question 18

malonyl CoA regulates fatty acid breakdown (beta oxidation) via inhibitor of _____

Answer 18

CPT-I: enzyme located in outer mitochondrial membrane, transfers acyl group from CoA to carnitine to form acylcarnitine and free CoA

part of the carnitine shuttle for long chain fatty acids

Question 19

what are the 4 cyclic reactions of beta oxidation?

Answer 19

1. oxidation (dehydrogenase)
2. hydration (hydratase)
3. oxidation (dehydrogenase)
4. cleavage (thiolase)

each cycle produces 1 acetyl CoA, 1 NADH, 1 FADH

Question 20

2 truths and a lie:
a. alpha oxidation initiations oxidation of branched-chain fatty acids
b. unsaturated fatty acids yield more FADH2 when they are oxidized
c. odd-numbered fatty acids are broken down by beta-oxidation to acetyl-CoA and propionyl CoA

Answer 20

a. alpha oxidation initiations oxidation of branched-chain fatty acids
b. unsaturated fatty acids yield LESS FADH2 when they are oxidized (already partially oxidized)
c. odd-numbered fatty acids are broken down by beta-oxidation to acetyl-CoA and propionyl CoA

Question 21

what are the only fatty acids that can generate glucose?

Answer 21

fatty acids with an odd number of carbons

broken down to acetyl CoA and propionyl CoA, requiring biotin as cofactor

succinyl CoA is produced downstream which can enter TCA (anapleurotic reaction)

Question 22

what kind of receptors are that of glucagon vs insulin?

Answer 22

glucagon - GPCR
insulin - tyrosine kinase

Question 23

how do CPT-I vs CPT-II deficiencies differ?

Answer 23

CPT-I and CPT-II both enzymes in carnitine shuttle for beta oxidation

CPT-I deficiency: primarily affects liver —> high free carnitine in blood, low acylcarnitines in blood —> hepatomegaly

CPT-II deficiency: primarily affects skeletal muscle —> low free carnitine, high acylcarnitines —> rhabdomyolysis

Question 24

MCADD, aka sudden infant death syndrome (SIDS)

Answer 24

MCAD (medium chain acyl CoA dehydrogenase) deficiency: hypoketotic hypoglycemia triggered by fasting/vomiting —> elevated medium chain acyl carnitines in serum, dicarboxylic acids due to omega oxidation in urine, hyperammonemia (via liver damage)

treat with frequent feeding + carnitine supplements, high carb/low fat diet

[recall MCAD is first step of medium chain FA beta oxidation]

Question 25

which of the following hypoketotic hypoglycemic disorders present with high serum carnitine? (all deficiencies)
a. carnitine transporter
b. CPT I
c. CPT II
d. MCADD
e. HMG CoA lyase/ synthase

Answer 25

b. CPT I (first enzyme in carnitine shuttle to move long chain fatty acids into mitochondrial matrix for beta oxidation)

note serum carnitine is LOWEST (basically none) in carnitine transporter deficiency due to loss in urine via impaired renal reabsorption

Question 26

which of the following hypoketotic hypoglycemic disorders present with myopathy with myoglobinuria? (all deficiencies)
a. carnitine transporter
b. CPT I
c. CPT II
d. MCADD
e. HMG CoA lyase/ synthase

Answer 26

c. CPT II (second enzyme in carnitine shuttle to move long chain fatty acids into mitochondrial matrix for beta oxidation)