Preamble: I started this current series of post about the ability of fatty acids with multiple double bonds to limit weight gain. To me, this is a paradox. Paradoxes are, without a doubt, the most productive sources for the development of an idea. Even as I started this current post I had no idea where it was going to end up and was bit surprised at where the metabolism took me. So be it. Let's begin.
Beta oxidation in peroxisomes does not consume oxygen and does not produce CO2.
The first step of oxidation of saturated fats runs like this:
R-CH2-CH2-COOH + FAD -> R-CH=CH-COOH + FADH2
In peroxisomes this is followed by
FADH2 + O2 -> FAD + H2O2
2xH2O2 -> Signalling -> Catalase -> 2xH2O + O2
The energy from FADH2 is released as heat and the oxygen is regenerated.
The NADH from beta oxidation is of no immediate use in a peroxisome and has to be transferred to mitochondria before it can be utilised. I suppose it could be phosphorylated to NADPH for anabolism but I have no data on that. It's not clear how reducing equivalents might be transferred from peroxisomes to mitochondria. There is speculation about something along the lines of the malate-aspartate shuttle used to import cytoplasmic NADH in to mitochondria.
It's also something of a truism that peroxisomes cease beta oxidation at C8 and then export this (by uncertain mechanism) to mitochondria for completion of oxidation. Digging back through the reference trail leads to the origin of this as the finding that isolated peroxisome preparations happily oxidise lauric acid but won't oxidise caprylic acid (much). Clearly oxidising DHA will never produce caprylic acid directly because there are double bonds within the residual eight carbon atoms. What exactly happens to truncated DHA at the C8 length appears to be an unasked question.
And there will be no CO2 production in peroxisomes as they do not have the TCA, that's limited to mitochondria.
So beta oxidation in peroxisomes produces heat, NADH, acetyl-CoA and signalling H2O2. And perhaps some caprylic acid from any saturated fatty acids being oxidised. It requires no oxygen consumption and results in no CO2 production, which gives an unchanged respiratory exchange ratio (RER).
Going back to
some of these things become clear. We have these measurements of oxygen consumption:
The round symbols are the fish oil fed groups. Average VO2 through 24h is reduced by fish oil from about 3500ml/kg/h to about 3000ml/kg/h, ie that's a just under 15% reduction.
Here are the RER figures, still fish oil as circles. As expected high fat diets show a low RER, low fat diets show the converse. The reduced O2 consumption is exactly balanced by a reduced CO2 production and the RER is still largely set by the dietary carbohydrate-fat ratio.
Clearly, under fish oil, approximately 15% of calories are being used to generate heat and anabolic substrate without consuming oxygen or being transferred to the ETC. Provided there is enough fish oil to stimulate peroxisomal proliferation the changes are quantitively independent of the absolute amount of fish oil.
So with fish oil at as low as 10% of calories, not all of which are PUFA, VO2 is dropped by 15% suggesting that the peroxisomes are activated and are oxidising more fatty acids than just the PUFA from the diet. Presumably on the low fat fish oil diet the peroxisomes are also metabolising palmitate and oleate derived from carbohydrate by de novo lipogenesis too.
If we go to this paper:
we can see, by clever carbon 13 labelling, that peroxisomal derived acetyl-CoA in cardiac muscle (and I would guess most other extra-hepatic sites) does not enter mitochondria, it all stays in the cytoplasm as malonyl-CoA.
These data are from perfusing hearts with docosanoate, a C24, fully saturated, fully peroxisome targeted fatty acid. We get lots of labelled malonyl-CoA in the cytoplasm, minimal labelled citrate in the mitochondria.
The next fascinating paper (HT to Peter Schmitt for the link) used erucic acid, another peroxisome targeted fatty acid.
In the liver peroxisomal oxidation of fatty acids generates acetate but that this is still converted to acetyl-CoA and then malonyl-CoA without entering mitochondria. We know from the Randle cycle that malonyl-CoA is an inhibitor of fatty acid oxidation so it should come as no surprise that erucic acid feeding to peroxisomes inhibits fatty acid oxidation in mitochondria. So we end up with lipid accumulation within the liver, progressing to fatty liver and NASH. I have mention before that in rodent models of alcoholic fatty liver disease fish oil is one of the most effective generators of alcohol induced liver damage...
But perhaps the best line from this last paper is:
"Peroxisomal metabolism of erucic acid also remarkably increased the cytosolic NADH/NAD+ ratio..."
It seems very, very unlikely that fish oil will be any different.
We find ourselves in a situation where peroxisomal oxidation of fatty acids generates benign heat combined with large amounts of anabolic substrate and a high NADH:NAD+ ratio without requiring oxygen while simultaneously inhibiting mitochondrial fatty acid oxidation while shifting metabolism to glucose.
Does that look like a recipe for cancer?
It does to me.
I had no idea that there is a large literature looking at the role of peroxisomes in all sorts of cancer types. Woohoo, they are a drug target! Perhaps avoiding peroxisome activating fatty acids and their derivatives might be a better approach. Apart from accepted Bad Things like drinking erucic acid or 4-HNE (a superb peroxisome activator) we might ask serious questions about drinking bulk fish oil.
Addendum: I recall this study (observational but not a food frequency questionnaire in sight), which I was fairly uncertain about back in 2013
Now I'm more convinced...