Lipogenesis

Question 1

Lipogenesis

Answer 1

Synthesis of fatty acids from acetyl CoA which can come from almost anything (mainly from glucose as insulin is the main stimulant). Need a reductant via NADH. Mainly in adipose tissue and liver.

Question 2

Steps

Answer 2

1. Acetyl-CoA activated by Acetyl-CoA Carboxylase which ads a CO2 from bicarbonate and consumes ATP. Forms malonyl-CoA. Highly regulated step.
2. Malonyl-CoA and acetate bound to fatty acid synthase removing CO2 and leaving a negative charge. As the acetate is closest to the negative charge, they combine at carbonyl C.
3. It is then reduced via NADPH which converts C=O to COH, dehydrated leaving a double bond a further reduced to get 4C hydrocarbon chain.
4. 4C hydrocarbon chain moved to RHS of FAs and process repeats.
5. FAs released as FA-CoA when chain length is C14-18 and at that point, any desaturation of CH2-CH2- to -CH=CH- is done after release.
6. Once 3 FA chains are formed, they are added to glycerol-3-phosphate

Question 3

Acetyl-CoA Carboxylase regulation

Answer 3

Goes through phosphorylation and dephosphorylation cycle. Insulin activates the phosphatases to activate acetyl-CoA. Also, allosterically activated by citrate where if lots of citrate travels to cytoplasm, it activates acetyl-CoA but switched off by fatty acyl-CoA.

Question 4

FAs key points

Answer 4

It doesn’t replace acetate, on FAs there’s a site for malonyl-CoA and acetate and the other is for the growing chain.

Question 5

Input and output

Answer 5

Each round of 2C addition requires 2 molecules of NADPH and the release of the CO2 that went on during the production of malonyl-CoA. We lack enzymes that introduce double bonds beyond C9. Long unsaturated omega 3/6 fatty acids are essential in diet.

Question 6

Selectivity of glycerol-3-phosphate location

Answer 6

Only liver has enzyme that converts glycerol to glycerol-3-phosphate otherwise in adipose, you go through half of glycolysis and glyceraldehyde-3-phosphate is reduced to glycerol-3-phosphate.

Question 7

servicing lipogenesis

Answer 7

FAs, ACC and esterification enzymes create the drive but still need substrate, need to increase PDH and transport acetyl-CoA into cytoplasm. Also need reductant, glycerol-3-P and ATP.

Question 8

Stealing acetyl-CoA from Kreb’s

Answer 8

Acetyl-CoA is first joined to oxaloacetate to form citrate, which can leave the mitochondria. This not only shuttles Acetyl-CoA into the cytoplasm but also frees CoA within the mitochondria, allowing PDH to continue producing more Acetyl-CoA. The fate of this Acetyl-CoA depends on the cell’s energy charge—when energy levels are high (reflected by high citrate), fatty acid synthesis is promoted.

Question 9

ATP-citrate lyase

Answer 9

In the cytoplasm, citrate is cleaved by ATP citrate lyase to regenerate Acetyl-CoA and oxaloacetate. Requires ATP input. ACL is inhibited by hydroxy-citrate (OHCit) which is found in the brindle berry. Doesn’t lead to weight loss as reactions are coupled.

Question 10

Acetyl-CoA transported as citrate

Answer 10

oxaloacetate needs to return to matrix, we will run out of carrier (applies to citrate too). Oxaloacetate is converted to malate (forms NADPH) which travels back into the matrix in the form of pyruvate which is then converted to oxaloacetate

Question 11

malonyl CoA inhibits beta oxidation

Answer 11

malonyl CoA inhibits CAT-2 preventing FA transport to mitochondria. Insulin inhibits beta oxidation through malonyl CoA.

Question 12

NADPH

Answer 12

NADPH is a form of NADH. Same chemical properties just bound by different enzymes.