3. Fatty acid metabolism

Fatty Acid Metabolism II

FA synthesis takes places in the cytoplasm but Acetyl-CoA is made in mitochondria (from pyruvate).

FA Synthesis
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Here’s how this problem is solved. When citrate is in excess, it’s exported out of mitochondria and into the cytosol. Once there, citrate is broken down into one molecule of oxaloacetate and–wait for it–one molecule of Acetyl-CoA. This costs 1 ATP.

Oxaloacetate is then converted to malate, which consumes 1 NADH. The reduction of malate back to pyruvate follows, which reduces an NADP+ to NADPH (yay, we need those!).

To prevent depletion of citrate, an alternate scenario occurs for Pyruvate entering the mitochondria. Here, pyruvate is converted into oxaloacetate (instead of Acetyl-CoA) via pyruvate carboxylase. This helps keep the CAC running by replenishing the citrate that exited the cycle.

Again, note the NADPH being produced.

Endoplasmic Reticulum

FA modifications that occur in the ER:

  1. Elongation of palmitate (growing it beyond 16 carbons)
  2. FA unsaturation (double bonds on FA carbon tail)


Take for example, stearoyl-CoA to Oleoyl-CoA. NADH is the initial donor, passing its electrons to FAD, converting it to FADH2, which is attached to NADH-cytochrome b5 reductase (NADPH could also be used as the donor). This reduces cytochrome b5, reducing its bound ferric iron to a ferrous iron–Fe3+ to Fe2+ . Those electrons are transferred to an iron atom bound to the Fatty acid desaturase. In its ferric state, it reacts with O2 releasing 2 H2O. This causes the unsaturation of the FA.

Regulation of FA Synthesis

Always a topic of concern in matters of metabolism.

Recall: Acetyl-CoA —(ACC)—> Manonyl-CoA —(FAS)—> FA

When nutrients and ATP are abundant, acetyl-CoA carboxylase (ACC) becomes activated leading to FA synthesis and storage. This is driven by the abundance of Citrate (an allosteric activator).

Conversely, when they’re low, ACC is inhibited. So, it won’t make FAs! ACC is switched off by the kinase, AMPK. Also switched off by too many FA via Palmitoyl-CoA.


ACC activity is under hormonal control

Insulin (post-eating, e.g.) triggers a signaling cascade that ultimately cleaves off a phosphate group attached to ACC, activating it.

Glucagon (low blood glucose), on the other hand, triggers a different cascade including AMPK, that inhibits ACC.

Similarly, epinephrine activates AMPK and inhibits ACC. Fight or flight.

A long-term high carbohydrate diet increases the expression of genes coding for ACC and thus increases fat storage. Storage over burning wins. Not good.



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