Overview
- Very Long Chain Fatty Acids (VLCFA) are those over 18 carbons in length
- VLCFA are an indicator of enzyme activity
- A dys-regulated SCD1-PPAR gamma-Elovl1-Elovl3-Elovl4-SREBP axis results in more saturated and monounsaturated VLCFA
- Nervonic acid, a monounsaturated VLCFA, is associated with Major Depressive Disorder and Psychosis
- The VLCFA increase steadily with the progression from healthy to diabetic to increasing severity levels of diabetic retinopathy
Very Long Chain Fatty Acids (VLCFA)
I’ve become very interested in very long chain fats – those weird ones that you ignored on your OmegaQuant test. Things like behenic acid, a 22 carbon length saturated fat. In Good PPAR, Bad PPAR, I pointed out that there is a positive feedback loop where too much SCD1 can lead to upregulated PPAR gamma, which upregulates elongases such as Elovl3 and Elovl6. All of these elongases and desaturases lead to very long chain fats such as the 24 carbon saturated fat lignoceric acid and the 24 carbon monounsaturated fat nervonic acid. I believe that these very long chain saturated fats are another indicator that your SCD1-PPAR gamma-elovl3-SREBP axis is dys-regulated. Did you see how I snuck “SREBP” in there. We’ll get to it.
If you look at my test results compared to different healthy cultures, you can see that I have a lot more lignoceric (24:0), nervonic (24:1) and behenic (22:0) fatty acids than they do. Judging from those who have sent me test results, a lot of you do as well. Many of us have a dys-regulated SCD1-PPAR gamma-elovl3 axis.
Nor is this necessarily benign. Mental health is beyond the scope of this blog but high levels of circulating nervonic acid are associated with Major Depressive Disorderβ1β and psychosis.β2β
This review paper lays out the metabolism of Very Long Chain Fatty Acids (VLCFA).β3β SCD1 is represented by Delta (triangle) 9 – the green arrows pointing from left to right representing conversion from saturated to monounsaturated. The three key enzyme in lengthening the fats are the elongases: E6 (Elovl6), E3 (Elovl3) and E1 (Elovl1). To make nervonic acid, you need Elovl6 to convert palmitic acid to stearic acid, SCD1 to convert stearic to oleic, Elovl3 to elongate oleic into gondoic AKA Eicosenoic, and then Elovl1 to elongate that into nervonic. In theory you could do it with just Elovl3 and Elovl1 or with Elovl6 and Elovl1. But presumably you’d make the most nervonic acid when all three are elevated.
Evidence is mounting that all of these enzymes – Elovl1, Elovl3, Elovl6 and SCD1 – are coregulated, themselves being upregulated by the transcription factors PPAR gamma and SREBP. PPAR gamma and SREBP are in turn upregulated by the end products of Elovl1, Elovl3, Elovl6 and SCD1.β4β6β I’ve shown how linoleic acid (LA) – omega 6 polyunsaturated fat (PUFA) – can initiate this dys-regulation in mice, but a paperβ6β actually demonstrates direct upregulation of PPAR gamma by LA in normal human skin cells.
VLCFA Correlate Strongly With Advancing Severity of Diabetic Retinopathy
The French study referenced in Membrane Phospholipid Composition of Different Populations shows the fatty acid composition of people who are healthy, diabetic or with increasing severity of diabetic retinopathy (DR). In that post I only presented the healthy controls. Here I’m presenting only the very long chain saturated and monounsaturated fatty acids – longer than 18 carbons – as the French went from healthy to diabetic to increasing degrees of DR as well as my own numbers from last Novemeber.
| Healthy | Diabetic | Mild DR | Medium DR | Severe DR | Me Nov. 2020 | |
| Saturated | ||||||
| 20:0 | 0.15 | 0.18 | 0.21 | 0.26 | 0.32 | 0.26 |
| 22:0 | 0.33 | 0.42 | 0.46 | 0.76 | 0.78 | 0.75 |
| 24:0 | 0.74 | 0.78 | 0.94 | 1.75 | 1.66 | 1.29 |
| MUFA | ||||||
| 20:1 | 0.21 | 0.26 | 0.23 | 0.26 | 0.24 | 0.16 |
| 22:1 | 0.06 | 0.09 | 0.09 | 0.08 | 0.11 | ND |
| 24:1 (nervonic) | 0.69 | 1.15 | 1.31 | 2.16 | 2.00 | 1.35 |
This looks to me like increasing dys-regulation of the elongase-desaturase-PPAR gamma-SREBP axis is strongly correlated with increasing severity of diabetic retinopathy. My numbers are equivalent to a French diabetic with Mild to Medium DR in 2014. It’s not great, but then this blog wouldn’t be very interesting if I wasn’t broken in the same way many of you are!
Many of your numbers – based on those who sent me your tests – are similar to or worse than mine. Check back in over the next couple weeks to see what I did about it and how my numbers have changed.
- 1.Kageyama Y, Kasahara T, Nakamura T, et al. Plasma Nervonic Acid Is a Potential Biomarker for Major Depressive Disorder: A Pilot Study. International Journal of Neuropsychopharmacology. Published online October 6, 2017:207-215. doi:10.1093/ijnp/pyx089
- 2.Alqarni A, Mitchell TW, McGorry PD, et al. Comparison of erythrocyte omega-3 index, fatty acids and molecular phospholipid species in people at ultra-high risk of developing psychosis and healthy people. Schizophrenia Research. Published online December 2020:44-51. doi:10.1016/j.schres.2019.06.020
- 3.Sassa T, Kihara A. Metabolism of Very Long-Chain Fatty Acids: Genes and Pathophysiology. Biomolecules & Therapeutics. Published online March 31, 2014:83-92. doi:10.4062/biomolther.2014.017
- 4.Kobayashi T, Fujimori K. Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPARΞ³ in 3T3-L1 cells. American Journal of Physiology-Endocrinology and Metabolism. Published online June 15, 2012:E1461-E1471. doi:10.1152/ajpendo.00623.2011
- 5.Li Y, Pang Y, Xiang X, Du J, Mai K, Ai Q. Molecular Cloning, Characterization, and Nutritional Regulation of Elovl6 in Large Yellow Croaker (Larimichthys crocea). IJMS. Published online April 11, 2019:1801. doi:10.3390/ijms20071801
- 6.Shirakura Y, Kikuchi K, Matsumura K, Mukai K, Mitsutake S, Igarashi Y. 4,8-Sphingadienine and 4-hydroxy-8-sphingenine activate ceramide production in the skin. Lipids Health Dis. Published online 2012:108. doi:10.1186/1476-511x-11-108
Don’t tease us Brad, tell us what you did! My Nervonic was 1.31% last November, LIgnoceric 2.34%, Behenic 1.42%. All above typical level and indeed outside of the ref. range in two of three.
I took the sterculia oil. It seems like it shuts down the whole cycle of SCD1-PPAR gamma-Elovl3. I just don’t want to shout it too loud yet, since it’s in the very final phases of QC before it can ship! This week or next assuming there’s not some catastrophe.
Brad
good answer!! waiting on my shipment.
were there body comp changes, to boot?
It’s too bad we can’t paste pictures into here.
My 20:0 was 0.23; 22:0 was 1.0; 24:0 was 1.26; 20:1n9 was 0.23; 24:1n9 was 1.0.
Strangely all over the map.
Kobayashi T? Isn’t he a competitive eater?
Brad,
Just a couple of questions:
One, are dietary saturated VLCFAs harmful in and of themselves (since it seems that the references you cited only show that VLCFAs resulting from elongation that happens once in the human body are harmful) or are VLCFAs in the body just merely an associated biomarker for harmful changes (lowered metabolism, metabolic syndrome/metabolic disregulation, pre-diabetes, diabetes, diabetic retinopathy, etc) rather than being harmful agents themselves? Even beef fat (and milk) and mutton fat contain small amounts (circa 0.30% to 0.60% IIRC) of arachidic acid (a C20 saturated fatty acid). Ben oil (morninga oil) contains around 7% C22 behenic acid (while at the same time containing less of a percentage of PUFA overall–and less omega 6 PUFA–than either beef tallow, barley-fed pork lard, or coconut oil; this is very unusual for a plant oil or seed oil)…even macadamia nut oil (another low omega-6 oil and one that is high in the SCD1 inhibitor palmitoleic acid) contains around 1% behenic acid and 3% to 4% arachidic acid.
Two, if dietary VLCFAs are potentially harmful, are the MUFA ones the problem and the saturated ones more benign or is the reverse the case?
Three, why would the body bioaccumulate VLC saturated fatty acids instead of burning them for energy? I’m not referring to the case of someone with ALD, or Refsum, or Zellweger’s; I’m just talking about an average American or Western European circa 2021? If I recall correctly VLCFAs (above 18 or 20 carbon chain length) have to be oxidized in peroxisomes to C8 and/or C10 and (as per what Dr. Dobromylskyj over at Hyperlipid said) the process of doing so wastes a lot of the energy in the fatty acids as heat when compared to normal oxidation of fatty acids from, say, C6 to C18 in chain length; if this is the case, then wouldn’t these fatty acids presumably be less likely to cause weight gain and metabolic disregulation than normal chain length fatty acids? Does their effect on PPAR gamma outweigh this positive effect?
Four, don’t VLC saturated FAs have F:N ratios even “better” (i.e. higher) than those of C18 stearic acid? If I recall correctly (again from a post and/or comments on Hyperlipid) C20 through C24 SFAs have F:N ratios above 0.48 (which is what stearic acid has) and closer to the 0.50 ratio that is as high as a non-branched chain or non-odd chain SFA can get. From what Dr. Dobromylskyj stated it seems the higher the F:N ratio the better. If this is the case then why would VLC SFAs have negative health effects compared to stearic acid or palmitic acid?
1) I doubt it. I think they’re just an indicator that your SCD1/PPAR gamma axis is dys-regulated.
2) I think they both have the same root cause. Most people I’ve seen: if one is high the other is also high.
3) They’re not really “accumulating”. They’re only around 2% at most and this is in red blood cell membranes which is a special case. I think there are a lot less in fat tissue.
4) No. Fats over 18 carbons in length aren’t oxidized in mitochondria, they’re oxidized in peroxisomes. I don’t know that much about fatty acid oxidation in peroxisomes.
Brad
I dont get these newsletter emails. Not sure why
Did you put your email in the “Sign up for the newsletter” box that pops up?
If so, check your spam folder.
Brad
Thanks. No luck on either front.
Iβve ordered the sterculia oil; will you tell us how much/how often you recommend taking?
I am writing up a very detailed post about my experience including dose/effects on my lipid panel/inflammatory markers/etc. It should be out by early next week.
Brad