How much truth is there to the statement that Eating excess carbohydrate can make you fat? Let's find out!!

Triglyceride structure breakdown, again.

Recall, when we discussed Beta oxidation of fatty acids (FA), we also learned the structure of a triglyceride (TG) molecule. A TG molecule is made up of a glycerol backbone and 3 fatty acid chains. So to synthesize a TG molecules we need these building blocks first. We need to synthesize FA chains and we need to attach these chains to the glycerol backbone.

Fatty Acid Biosynthesis

Again let's recall, when we were breaking down FA chains, we were breaking them down into 2 carbon molecule compounds called Acetyl CoA. To synthesize a FA chain, we just need to rejoin the Acetyl CoA molecules back again and again until we reach the desired length of the chain.

So where do the Acetyl CoA to synthesize fatty acids come from? Now don't say they come from the breakdown of fatty acid!! Why not??

Let's look at this logically for a moment. Why do we break down fatty acids to Acetyl CoA in the first place? To produce energy. So, at a time when we are breaking down fatty acids into acetyl CoA, we need to use these Acetyl CoA for energy production. It just doesn't make sense to be using these to re-synthesize the FA chain, the one we just broke down!!

So, majority of the Acetyl CoA that comes from FA breakdown goes into energy production and is not a significant source for Acetyl CoA for FA synthesis. So now we ask again, where do the Acetyl CoA molecules come from?

Let's look at this diagram and maybe something might tickle your brain if you have been following the series from the start!!

Image from Kaplan USMLE Step 1, Biochemistry Lecture Notes. Annotations done by me.

Here we look at a simple information (the annotation) : A molecule called Pyruvate is being converted to our required molecule, Acetyl CoA via an enzyme called Pyruvate Dehydrogenase.

Simple enough. Wait. Did someone mention Pyruvate? Why does it sound so familiar?

Right on!! Where did we see pyruvate before? It was the end product of the pathway called Glycolysis, a pathway we used to metabolize glucose in an attempt to tap into the energy reserves. Now, if we need energy, i.e. the body's ATP supplies are low, most of the acetyl CoA will be dedicated to energy production and go into a pathway called Citric acid cycle, (will be discussed in future posts). But if you have produced enough energy reserves, these Acetyl CoA will be directed towards synthesis of Fatty Acids.

Now another interesting mechanism of how carbohydrate promotes fatty acid synthesis is, after you have eaten carbohydrates, your pancreatic beta cells will produce the famous hormone we call Insulin. Insulin has numerous activities, all of which can not be discussed in this post. One of the effects of insulin is to increase the activity of the enzyme PDH, thus promoting conversion of more Pyruvate to more Acetyl CoA. Given that these Acetyl CoA can go in either direction (energy production or fatty acid synthesis) this can not be considered a direct effect of insulin on promoting FA synthesis, but don't be disappointed. The fun is just getting started!!

Let's proceed.

Image from Kaplan USMLE Step 1, Biochemistry Lecture Notes. Annotations done by me.

If you looked carefully, you must have noticed, Acetyl CoA from Pyruvate is being produced inside the mitochondria, but FA synthesis occurs in the cytoplasm. So Acetyl CoA needs an exit route. But Acetyl CoA has no direct transporters on the mitochondrial membrane. So we use something called a citrate shuttle. To use this shuttle, we need to add a molecule called Oxaloacetate (OAA) to our Acetyl CoA molecule and disguise it as convert it to Citrate, which can now exit the mitochondia via the citrate shuttle.

Once in the cytoplasm, it's quickly broken down back into Acetyl CoA, which now officially enters the fatty acid synthesis pathway, and OAA.

Now Acetyl CoA will be acted upon by a very important enzyme called Acetyl CoA Carboxylase. This enzyme will add a molecule of carbondioxide (CO2) to Acetyl CoA and form malonyl CoA. But it is interesting that this CO2 never gets added to the actual FA chain, because when the next enzyme of the pathway, fatty acid synthase comes into action, it removes the CO2 before adding the acetyl group to the growing fatty acid chain. And this keeps repeating until the desired number of acetyl CoA has been added to the fatty acid chain. In humans, the enzyme fatty acid synthase can only synthesize fatty acid chains upto 16 carbon atoms long. A FA chain with 16 carbon atoms, as we've already learned in previous episodes, is called Palmitate or Palmitic Acid.

Note that, the enzyme fatty acid synthase uses something called NADPH. No point in confusing you guys too much, so just assume NADPH is similar to NADH. We said in episode 1, that these NADH will play a huge role in energy production. But if you have extra NADPH available in the cell, it means the body right now does not need anymore ATP, and the potential energy in the NADH/NADPH molecules can be stored away. And only when we have NADPH excess, we can synthesize fatty acids from the Acetyl CoA, and only then this pathway will proceed. The availability of NADPH will determine how much FA chains will be synthesized. This is how the cell knows whether to channel the Acetyl CoA into energy production or towards FA synthesis pathway.

But dude, what about the insulin you mentioned earlier?

Image from Kaplan USMLE Step 1, Biochemistry Lecture Notes. Annotations done by me.

This is where insulin exerts it's direct effect on increasing synthesis of fatty acid. It activates the first enzyme of the pathway Acetyl CoA Carboxylase and induces production of the second enzyme, Fatty Acid Synthase. In simple words, the more carbohydrates you eat, the more insulin will be produced and the more ready the enzymes of fatty acid synthesis pathway will be to convert those excess Acetyl CoA into fatty acid.

But let's not forget Glycerol!!

We have now successfully synthesized FA chains. All that's left to do is attach 3 of these chains on the glycerol backbone. The glycerol backbone in TG is in the form of a compound called glycerol-3-phosphate. Guess where we can get this glycerol-3-phosphate from??!!

Friggin' GLYCOLYSIS man!!!

If you don't still remember, we had an intermediate called DHAP in the pathway.

Image from Kaplan USMLE Step 1, Biochemistry Lecture Notes. Annotations done by me.

DHAP can be converted into Glycerol-3-P by the enzyme Glycerol-3P dehydrogenase. The other source of glycerol-3-phosphate can be direct phosphorylation of a glycerol molecule, but this can be done only by the liver.

Now that we have our fatty acid chains and glycerol backbone ready, all that's left to be done is to add 3 FA chains to the backbone and voilà!! You have yourself a Triglyceride molecule, ready to be stored as fat.

Make sure to enter the weekly smartcash giveaway contest and tune in for episode 5!!

Resources :
Lippincott's illustrated Reviews Biochemistry, 5th edition
Kaplan USMLE Step 1 Biochemistry Lecture Notes

If you enjoy medical topics, or want to learn how different things work in this amazing human body, please make sure to follow me at @simplifylife

Peace!!