New Metabolic Pathways – Gluconeogenesis from Fatty Acids

This is a potential game changer:

In silico evidence for gluconeogenesis in humans from fatty acids

This study was technological and theoretical in nature. Using a flux model (to be described and linked to later) to determine conversion of one molecule into another (in this case, Acetyl-CoA into Glucose-6-Phosphate) it was determined that dietary fatty acids can be converted into glucose. This bolded claim is one that is taught as both false and fact in most educational institutions at the moment, thus this linked study is a huge paradigm shift in the nutritional world.

This blog post is essentially reviewing the linked article. I will be going through this summary in the same order (and same headings) as the article for easy following and to minimize my potential of getting lost in translation.

  • Elucidating an initial Pathway

The first step outlined in this paper was computing the elementary flux pattern of a subsystem just encompassing the inflow reaction of acetyl-CoA and the outflow reaction of G6P to see if a possible direct mechanism of converting Acetyl-CoA to G6P existed in humans.

Two fluxes were found. One of which consumes Acetyl-CoA and the other produces G6P. Evidence that there is a link between Acetyl-CoA (seen as the start of gluconeogenesis from fatty acids) and G6P (normally the first metabolite of glycolysis, can be seen as the final step in gluconeogenesis from fatty acids).

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Using the model outlined in this article, the authors then went to determine the feasible pathway of de novo gluconeogenesis from fatty acids. Please refer to figure 3 in the parent article for a pictorial representation (not sure if I can reprint it here) but essentially:

  • Fatty acids are first converted into Acetyl-CoA in the mitochondria. Acetyl-Coa turns into Acetone (a ketone body) via the intermediates Acetoacetyl-CoA and Acetoacetate.
  • Acetone is ejected into the cytosol, and via 4 intermediates turns into Pyruvate
  • Pyruvate re-enters the Mitochondria, and via Oxaloacetate turns into Phosphoenolpyruvic acid (PEP)
  • PEP is ejected back into the cytosol, and via 4 more intermediates ultimately turns into Glucose
This was the parent route hypothesized initially.
  • Determining alternate routes
Afterwards, alternate routes were hypothesized using the parent route. Three critical (needed) conversions were noted:
  1. Mitochondrial acetoacetate into cytosolic acetol (the first metabolite after acetone gets transported into the cytosol)
  2. Pyruvate’s conversion to Oxaloacetate in the mitochondria
  3. Cytosolic PEP turning into glucose (and all 4 intermediates)
Using these critical steps, alternate steps were hypothesized that would uphold the conversion of Acetyl-CoA into G6P.
9 possible pathways were discovered for conversion of Acetyl-CoA into mitochondrial acetoacetate. The conversion of acetoacetate to acetol is essential. The degradation of acetone (immediately prior to acetol) had 58 feasible pathways to pyruvate. The paper elucidates the reasoning of the following, but the 58 feasible pathways were reduced to 22 when applied, and running the possibilities through another model of metabolic pathways determination yielded 9 possible routines in which cytosolic acetone can turn into pyruvate.
In the end, 14 alternate pathways were considered. Some of which were reported earlier in the literature as hypothesises. [x] [x]
  • Discussion
I would like to direct those reading this to read the Discussion section in the paper. The authors do an incredible job tying past research together and filling in holes of acetone and ketone metabolism with these possible pathways such as increased capacity of enzymes involved in the pathways during periods of starvation and acetone not being accounted for in the past during pharmacokinetic studies (which could easily turn into glucose).
That being said, they also acknowledge the potential limitation of this pathway in vivo. One study in the past had 11% of acetone unaccounted for after 21 days of fasting, which is quite a small amount given the drastic time (assuming all 11% was used for gluconeogenesis; which is plausible now but still unproven). Some intermediates in the hypothesized pathways are cytotoxic in feasibly high doses, and mitochondrial transport competition could also occur and limit the maximal output. This pathway also requires 6-22 mols of ATP to turn fatty acid substrate into one mol of glucose, thus is catabolic in nature.
  • Conclusions
The authors leave these concluding remarks:
Summarizing our findings, it can be concluded that a thorough, systematic and detailed in-silico investigation of the stoichiometrically feasible routes from fatty acids to glucose based on an experimentally corroborated genome-scale metabolic network provides new insight into human metabolism under glucose limitation. It confirms earlier, anecdotal evidence and hypotheses about gluconeogenesis from fatty acids via acetone and provides hitherto unrecognized pathways for that conversion. This provides a plausible explanation for the surprising independence from nutritional carbohydrates over certain periods (e.g. upon the low-carbohydrate diet of inuit, in hibernating animals and embryos of egg-laying animals). Moreover, we provided a detailed analysis of the energetic balance of these pathways, which explains their limited capacity and their contribution to the particular efficiency of carbohydrate reduced and ketogenic diets.
In sum, via determining a flux between Acetyl-CoA and Glucose-6-Phosphate it was determined that one or multiple pathways of gluconeogenesis from fatty acids exist. Using different computer models, 14 plausible pathways via ketone metabolism were elucidated. Future studies will have to narrow down to see these possible pathways in humans.
And if you read this, got to here, and aren’t excited; this is kinda a big deal…

 

 

 

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