Here’s the big theory. Desaturase and cytochrome P450 enzymes in the ER compete for oxygen with the mitochondria. This is part of a switch to glycolysis that recycles the cytoplasmic NADH back to the NAD+ that glycolysis requires. If you’re going to do glycolysis, there is no need to allow oxygen into the mitochondria.
As I’ve said, the adipose cells of obese adults are glycolytic. (Jansson, 1994) Glycolysis is fundamentally anabolic and makes things growthy. The “state” of the adipose cell is one that favors retaining carbon rather than burning it. One of the levers an adipose cell can use to grow is to restrict oxygen from reaching the mitochondria. If you want the fuel to build up you have to close the damper.
In mammals, oxygen use in the ER is the damper.
The theory is speculative but has a lot of evidence supporting it. I’d like to prove it.
- PUFA desaturation allows ongoing glycolysis. (Kim, 2019)
- Activity of desaturase enzymes predict progression to diabetes in human adults; mendalian randomization suggests causality. (Janine, 2011) I haven’t heard a competing hypothesis as to why.
- Blocking desaturase enzymes in cancer cells causes a massive drop in both their oxygen consumption and rate of glycolysis. (Hasegawa, 2024; Luis, 2021; Zhou, 2021)
- Linoleic acid availability causes cells to increase oxygen consumption WHILE becoming glycolytic. (Arslan, 1984)
- Adipose tissue of obese humans has elevated desaturase activity. (Warensjo, 2009)
- Adipose tissue of obese humans is glycolytic. (Jansson, 1994)
- Reduced activity of any of SCD1, SCD2, D6D, D5D reduces insulin resistance and/or obesity in rodent models. (Ntambi, 2002; Hucik, 2019; Yashiro, 2016; O.Neill, 2020)
You were probably shown this lie in high school biology. Probably again if you took bio 101. In this image the various organelles all get their own space. The mitochondria are fat, sausage shaped organelles floating free from the Endoplasmic Reticulum (ER).
The REALITY is a bit different. The networks of ER and mitochondria are instead INTERTWINED. Here is a cross section of a cell taken with an electron microscope. You can see that the ER and the mitochondria (m) swim in the same waters.
We can zoom out and see this on a whole cell levels using confocal fluorescence microscopy. The red are mitochondria and the green is ER.
This is relevant because the mitochondria and the ER are the main consumers of oxygen within the cell. No one ever told you that the ER uses oxygen? The ER hosts a suite of oxygen consuming enzymes, including the fatty acid desaturases SCD1, SCD2, D6D and D5D; plus cytochrome P450s such as CYP4a11. Here is the general equation for how fatty acid desaturation works. A double bond is added to a lipid and in the process a molecule of NADH is converted to NAD+ and a molecule of O2 is converted to H2O.
As fatty acids (as acyl-CoAs) diffuse through the cytoplasm they have three possible fates (oversimplified, but…):
- Diffuse to the mitochondria where CPT1 activates them for mitochondrial oxidation by making them an acyl-carnitine.
- Same as 1, except on the way to the mitochondria, they get desaturated in the ER. This would be very common for stearic acid. SCD1 in the ER converts it to oleic acid as it diffuses in, directly competing for the oxygen that the mitochondria needs to burn the oleic acid.
- It gets converted to an oxylipin and exported from the cell for elimination in the urine. This is an oxidative fermentation.
In fermentation, electrons from NADH are transferred to an organic acceptor molecule, regenerating NAD⁺ without involvement of O₂ or the electron-transport chain.
Berg, Tymoczko & Stryer, Biochemistry (9th ed.)
Let’s dig into number three a little more. The pathway is below. Liver cells can take in linoleic acid via the fatty acid transporter CD36. D6D and D5D add double bonds to convert it to Arachidonic Acid (AA). Each desaturation step consumes an oxygen. CYP4A11 also consumes oxygen to convert the AA to 20-HETE. That is 3 molecules of oxygen consumed in the fermentation. The 20-HETE can then be glucuronidated to 20-HETE glucuronide and exported from the cell by MRP2.
Since the PUFA is fermented and exported, the rate of this process is not limited by the mitochondria’s ability to oxidize the incoming fatty acid. The process can go as fast as the enzymes allow it to go given the quantify of linoleic acid in the free fatty acid supply. This is ongoing.
The enzymes at every link of this pathway; CD36, D6D, ELOVL5, D5D, CYP4A11, UGT enzymes and MRP2; are controlled by PPARa. (Barbier, 2003; Goa, 2020; Kok, 2003; Hardwick, 2010) PPARa also controls two other oxygen consuming cytplasmic enzymes: SCD2 and ACOX. PPARa is the master regulator of oxidative fermentation of PUFA in the liver. Not coincidentally, animals increase expression of PPARa as winter approaches and as they become torpid. (Chayama, 2019) Also not coincidentally, the PPARa activating fibrate drug fenofibrate increased D6D activity, SCD activity and liver fat in humans. (Oscarrson, 2018)
Linoleic acid can power fermentation. As linoleic acid increases to (modern) physiological levels (Pelligrini, 2021) in cell culture, ATP production drops and lactate excretion increases. The cells become glycolytic. The stunning thing about this paper is that as the cells switched to glycolysis, oxygen consumption rates increased! Oxygen is supposed to be burned in the mitochondria for oxidative phosphorylation, not in the cytoplasm for glycolysis.
Could the oxygen stealing effects of oxidative fermentation of PUFA be physiologically relevant? How much oxygen can these processes really take? We don’t have a ton of data but the data points we do have are intriguing. Hasegawa showed that when SC26196 – an inhibitor of D6D – was applied to CHOL1 or TFK-1 cancer cells, their basal and maximum oxygen consumption rates dropped by between 20 and 40%. D6D and downstream reactions were using up to 40% of ALL oxygen consumed by the cells. This might actually understate the case since cells in culture are typically grown with very low linoleic acid.
Similarly, in activated B cells, inhibiting SCD1 and SCD2 with SSI-4 decreased oxygen consumption by two thirds while completely inhibiting glycolysis! Activated immune cells are typically highly glycolytic. Ongoing glycolysis requires fermentation to replenish NAD+. This comes from fermenting stearic acid to oleic acid. Stunningly, this fermentation and processes downstream of it consume two thirds of the total oxygen used by the cell. And they’ve been telling you glycolysis doesn’t consume oxygen. Not directly, I suppose.
What can we conclude about this? I am proposing a fundamentally new way to think about the health effects of dietary linoleic and linolenic acids. Both of these fats can be used for oxidative fermentation.
In my opinion, understanding the mechanism is crucial if you want to solve the problem. This looks to me like the primary mechanism by which PUFA effect our metabolisms. Sure, auto-oxidation of PUFA does some collateral damage, but it can’t be the root cause.
Desaturase enzymes can increase oxygen consumption, ie metabolic rate. Is higher metabolic rate always better?
Watch this space coming up, I’m just getting started. I’m going to introduce some scoring algorithms. Not computer algorithms, just “here’s how to think about these things in your head.” I’m going to dust off all of the very interesting feeding experiments done in mice, rats and pigs and see if we can build some rules that make sense of them.
Here’s a rule: PPARa activation is the spark, but linoleic acid is the fuel. Dietary oleic acid provides the spark via OEA, but linoleic acid fuels the fire. So when you combine those two, that’s probably going to go badly. High PUFA lard spiked with soybean oil in diet-induced obesity trials. Another thing that might go badly is if you increase seed oil consumption in an environment with rising environmental PPARa activators such as PFAs from nonstick coatings and phthalates from plastics.
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