- 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 Disorder1 and psychosis.2
This review paper lays out the metabolism of Very Long Chain Fatty Acids (VLCFA).3 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 SCD1.4–6 I’ve shown how linoleic acid (LA) – omega 6 polyunsaturated fat (PUFA) – can initiate this dys-regulation in mice, but a paper6 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|
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 PPARγ 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