Fatty acid metabolism

Question 1

Overview of fatty acids

Answer 1

Carboxylate + hydrocarbon chain
Desaturation = double bonds
- omega 3, 6 = essential (can’t synthesize)
- cis vs trans -> atherosclerosis
3 F.A. + glycerol -> triglyceride (storage)

Synthesis = cytoplasm
 -  liver and mammary
Oxidation = mitochondria
 - liver (-> ketogenesis, gluconeo)
 - muscle (-> fuel)

Question 2

ATP citrate ligase

Answer 2

ACL
First major step of fatty acid synthesis
Cytoplasmic

Citrate + ATP -> Ac-CoA + ADP + oxaloacetate

Oxaloacetate to malic enzyme (recycled)
AcCoA -> ACC -> synthesis
(or cholesterol, etc)

Question 3

Ac-CoA Carboxylase

Answer 3

ACC
Major regulatory step for F.A. synthesis and oxidation! (Rate limiting)
Ac-CoA + ATP -> Malonyl CoA + ADP
Contains biotin

Isoenzymes
ACC-alpha = cytosolic - liver, mammary
 (synthesis!)
ACC-beta = mitochondrial - liver, muscle
 (oxidation)

Question 4

Fatty acid synthase

Answer 4

Ac-CoA + Mal-CoA + NADPH -> palmitic acid + NADP
Only expressed in lipogenic (liver, mammary)
Pantothenic acid in ACP domain
NADPH reduces double bonds

Question 5

Malic enzyme

Answer 5

Malate + NADP -> Pyruvate + NADPH
(Malate from oxaloacetate from ACL enzyme)
Links NADPH regeneration to F.A. synthesis
Only lipogenic (liver, mammary)

vs pentose phosphate pathway in all tissues
-> NADPH

Question 6

Lipolysis

Answer 6

Triglyceride ->
Adipose triglyc lipase (ATGL) ->
Hormone sensitive lipase (HSL) ->
Monoglyceride lipase (MGL)

Perlipin positions lipid/enzyme junction

• > free fatty acids (bound to albumin)
  • > oxidative fuel
  • > ketones or gluconeo in liver

Question 7

Fatty acid oxidation

Answer 7

All cells except brain and RBCs
(preferred fuel for muscle)
Mitochondria

Uptake into cell -> F.A.CoA synthase
Requires ATP

Question 8

Transport of FA into mitochondria

Answer 8

Highly regulated!
Determines
- FA oxidation vs synthesis (liver)
- FA oxidation vs glycolysis (muscle)

CAT1 = Carnitine acyltransferase I = CPT1
FA-CoA + carnitine -> FA-carnitine + CoA
tightly regulated!
(-) malonyl CoA (via ACC-beta activity)
Transport (FA-carnitine)
CATII = reverse reaction in mitochondria

Question 9

Beta-oxidation

Answer 9

Within mitochondria
Stepwise (2C) oxidation of chain
-> Ac-CoA -> TCA if oxaloacetate available (glycolysis!)
-> FADH2 -> ETC -> ATP
-> NADH -> ETC -> ATP

Question 10

Ketogenesis

Answer 10

ONLY in liver
Converts Ac-CoA (fatty)-> ketone (water soluble)
- used by muscle, brain
Acetoacetat, beta-hydroxybutyrate

(+) excess Ac-CoA (FA oxidation)
(-) oxaloacetate (glucose availability)

Ac-CoA CANNOT be used for gluconeogenesis
(2C vs pyruvate is 3C -> oxaloacetate is 4C)

Question 11

Ketone oxidation

Answer 11

Brain (only fuel source other than glucose)
Muscle (skeletal and cardiac)

Requires oxaloacetate, succinyl-CoA (GLYCOLYSIS)
More energy, less oxygen than glucose
(preferred fuel if available)

Question 12

Transcriptional regulation of FA metabolism

Answer 12

Long-term coordinated regulation at ACL, ACC, FAS
(vs short-term allostery and phos of ACC)

Insulin -> SREBP1 -> SRE
Glucose -> phosphatase -> CHREBP -> “E box”
SREBP + CHREBP signaling -> FAS transcription
(both are necessary, insulin + glucose)

ex AIDS lipodystrophy:
persistent SREBP1c -> truncal obesity, high triglycerides