Beta Oxidation and Gluconeogenesis

[justadream]

1) In diseases where you cannot break down fatty acids (like MCADD), why is gluconeogenesis impaired? Is it because gluconeogenesis requires ATP and without efficiently working fatty acid degradation, you lack the ATP?


2) Fatty acid degradation (Beta oxidation) produces Acetyl-CoA that can then enter the Krebs cycle and make ATP. It is often said that acetyl-CoA cannot be used for gluconeogenesis but I've always been confused about this because:

-Couldn't the acetyl-Coa just go through the Krebs cycle and eventually become Oxaloacetate (which is a substrate for gluconeogenesis)?

-If the above isn't possible (and it probably can't be but I just don't understand why), then why is it that Krebs cycle intermediates generated via other pathways (like the Fumerate made by the Urea cycle) can be used in gluconeogenesis?

---

Members don't see this ad.

 

[Polycherry]

Okay, so I'll try answering a part of your question - the second one. I had the same doubt for a long time and had to come up with a reasoning for myself.
Before going to my hypothesis, lets state some facts.

The total amount of lipids - FFA (free fatty acids) that enter from the blood stream to the liver can be either channelled into beta oxidation or formation of VLDL. The ones that undergo beta oxidation form acetyl-coA. This acetyl-coA can be channeled either to enter the citric acid cycle to produce ATP or to ketogenesis, where the ketone bodies act as a carrier of energy to other tissues. This can be seen very well in this picture from Harper's Biochemistry.

So why form ketones? Why not form glucose (gluconeogenesis) that can be sent to other tissues.
1. Ketones are better since the liver lacks the enzyme thiolase and can prevent the use of this energy for itself
2. The enzyme pyruvate dehydrogenase is irreversible.

Although it can enter pathways like glyoxylate cycle (not in humans) and pathways to make pyruvate from acetone (not economical) to form glucose, our question is why it can not do so directly via the Krebs cycle. Also odd chain fatty acids can form propionate that can enter gluconeogenesis.

Reason one could be understood and assimilated. But why reason 2?

See, the process of gluconeogenesis starts from various possible precursors - plausible entry points like, Pyruvate, OAA, Fumarate, Propionate (as succinate) and alpha-KG. It is important to note that, acetyl-coA is not an entry point for Gluconeogenesis.

-------My hypothesis(?) starts here. (The ones mentioned before this are facts and I hope I din't get any wrong)----------

This can be explained by the fact that all the entry points are an addition to the Kreb's cycle. They get on the boat, sail along, get off at oxaloacetate and leave. They don't bother the boat in any other way. Even Pyruvate, forms oxaloacetate via pyruvate carboxylase and then gets on the boat for gluconeogenesis.
On the other hand, Acetyl coA would be a part of the Kreb's cycle itself. Remember - It is not adding anything to it (2 carbons that are added are lost as CO2). So an Acetyl CoA added, can't leave as OAA. It would be analogous not sailing on the boat but eating it down itself. Slowly, it would lead to a decay and loss of the intermediates Kreb's cycle and it would come to a standstill (?)

 

[eklektikos]

1. As far as I understand, you're correct. Gluconeogenesis and fatty acid oxidation go hand in hand. I think the simple way to understand it is that if glucose and fat are the two main sources of energy available to the liver, it wouldn't make sense to use glucose during gluconeogenesis so the liver uses beta-oxidation of FAs. Without FAs, no gluconeogenesis.

To be more specific, in order for gluconeogenesis to occur there needs to be ATP and OAA that can be converted to PEP via PEPCK.

Beta oxidation will give you NADH, FADH2 and acetyl-CoA. NADH and FADH2 will provide the required ATP. NADH will also inhibit PDH, isocitrateDH, alphaketoDH allowing for OAA & pyruvate accumulation. Acetyl-CoA is an obligate activator of pyruvate carboxylase, often an important step of gluconeogenesis and will also inhibit PDH.