NADH as GNG and Glycolysis regulator

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OrangeMed

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Hello,

Can anyone explain how NADH regulates gluconeogenesis? TPR online exam solution states that NADH inhibits GNG because of reduction in concentration of pyruvate and OAA needed to produce glucose in GNG. I know that high NADH inhibits glycolysis as well by feedback inhibition. So does NADH inhibit both glycolysis AND GNG???

Thanks!

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http://www.ncbi.nlm.nih.gov/books/NBK22524/

This may be of interest to you. Basically, NADH inhibits gluconeogenesis because it shuts down the Cori cycle. Remember that lactate needs to be oxidized in order to make pyruvate. In other words, you need an oxidant, or a species that can be easily reduced, aka NAD+. Since the total NAD concentration is relatively constant, a high concentration of NADH means that you have a reducing agent present, not an oxidizing agent. Thus, lactate cannot be converted into pyruvate and instead accumulates.
 
Hello,

Can anyone explain how NADH regulates gluconeogenesis? TPR online exam solution states that NADH inhibits GNG because of reduction in concentration of pyruvate and OAA needed to produce glucose in GNG. I know that high NADH inhibits glycolysis as well by feedback inhibition. So does NADH inhibit both glycolysis AND GNG???

Thanks!

Answered pretty well but you can also tie this into the effects of alcohol on gluconeogenesis as well. I'll add it here.

Metabolizing ethanol leads to excess NADH and is why excess amount of ethanol can lead to hypoglycemia.

Ethanol is oxidized by the
alcohol dehydrogenase to acetealdehyde. This reaction needs consumes one molecule of NAD+ per molecule ethanol oxidized:

Ethanol + NAD+ <--> Acetaldehyde + NADH + H+

Acetaldehyde is oxidized by the
acetaldehyde dehydrogenase in a second reaction in the mitochondria to Acetyl-CoA, which produces another molecule of NADH:

Acetaldehyde + NAD+ # CoA <--> Acetyl-CoA + NADH + H+

If you now take a look on the Gluconeogenesis, there is one critical step which need NAD+: The oxidation of lactate to pyruvate ny the
lactate dehydogenase which then cannot be processed into oxalacetate, phosphorenolpyruvate and so on.

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Adding excess NADH shifts the reaction equilibrium completely to the side of lactate and also leads to the production of additional lactate, leading to hyperglycemia and lactic acidosis. Excess NADH from the ethanol oxidation inhibits the oxidation of fatty acids in the liver - this process also generates NADH for the production of ATP. NADH signals this process that enough energy is available in the cell. And finally excess NADH also inhibits the
malate dehydrogenase reducing the amount of oxalacetate for gluconeogenesis further.

hope this helps, good luck!
 
Thanks guys for your explanation. So, elevated NADH does inhibit BOTH glycolysis and GNG, right? I understood the mechanism but was having a hard coming to terms with one thing affecting two seemingly opposite processes in the same way.
 
Well, it doesn't really inhibit both in the same way. With these kinds of problems, it's more important to think about what you would want to happen with a certain scenario than simply memorizing all possible scenarios. For example, with high NADH in the cytosol, that means you're not able to regenerate NAD+ to carry out the GAPDH step and so glycolysis shuts down. On the other hand, when you have high NADH also means that you have less NAD+ for the lactate dehydrogenase step of gluconeogenesis. This is a critical component of the Cori cycle and so gluconeogenesis is inhibited.

However, some gluconeogenesis still occurs. Lactate to pyruvate is just one way to make pyruvate. Pyruvate could also be made from transamination of alanine. So the glucose-alanine cycle could still be working and you could make glucose that way. You could also shunt off TCA cycle intermediates directly into oxaloacetate, bypassing the lactate dehydrogenase step altogether. In fact, oxaloacetate is a great starting point for gluconeogenesis because there are many ways to make it, e.g. transamination of aspartate, any of the TCA cycle intermediates, pyruvate carboxylase, etc.

This paper has some good figures that may be of use to you: http://www.ncbi.nlm.nih.gov/books/NBK22423/
 
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