Gene Expression, Fish Oil, and MTHFR.

Fish oil, which we talked about last week as well, continues to be a big deal for people with the MTHFR mutation. Today, I want to discuss a couple of studies about gene expression, fish oil, and MTHFR, but first I want to make sure everybody understands the basics of gene expression.

When your body makes something out of your genes, it doesn’t just read the DNA and make a protein. There is more to it than that. The process, however, can be broken down into two big chunks – bear in mind that there is far more to it than this as well, but this will help you to understand the research we’re going to talk about..

  1. Transcription -Transcription is the process in which the DNA is opened like a zipper and mRNA is made from one side of the zip, and the resulting mRNA molecule is processed by the body.
  2. Translation – Translation occurs when the mRNA molecule we made above, is used to direct protein synthesis. This is how the MTHFR gene makes the MTHFR enzyme, which is the protein this gene codes for.

mRNA is genetic material just like DNA, but the difference is that while DNA might be the ultimate blueprint, it is also giant, double-stranded, and not easy to work with. RNA of all types, including messenger RNA, is single-stranded and generally transcribed from the master DNA. It is created in small segments and is the signal needed for your body to actually build proteins.

What this means is that mRNA is a good marker, in research, specifically this research about fish oil and MTHFR, for the action of the MTHFR gene and one of the only ways we can measure when the gene is acting.

Gene expression in the homocysteine cycle with Fish Oil and MTHFR

Last week we mentioned that levels of fish oil and homocysteine were linked – the higher the fish oil intake for the person studied, the lower homocysteine levels became. Let’s expand on that.

This study, published in Nutrition Journal, looks at the gene expression, meaning the mRNA levels for different enzymes along the homocysteine pathway. This includes MTHFR, but also other enzymes including MAT, CSE, SAHH, CBS, and MTR. See the diagram to place each enzyme within the pathways for recycling and converting homocysteine.

Human liver cells were treated with either decosahexaenoic acid, DHA, eicosapentaenoic acid, EPA, or alpha-linolenic acid, ALA for 48 hours. A control group with no treatment was also kept for 48 hours and then studied. After that time, mRNA levels were measured from each enzyme in question. It was found that:

  • MTHFR was upregulated by both DHA and ALA.
  • MAT was down regulated by all three treatment groups, but most in the DHA group.
  • CSE expression was increased in the DHA and EPA groups.
  • No significant changes were shown in SAHH, CBS, or MTR.
Omega-3 fatty acids like EPA, DHA, and ALA have an effect on the action of certain gene SNPS and the enzymes they code for.

This study is remarkable because it shows that the action of MTHFR can be influenced with something as simple as fish oil. The next study is even more remarkable.

Pregnancy, Fish Oil, and MTHFR

Methylation is one of the primary drivers of a person’s epigenetic state, and some of the most important methylation happens during gestation, so research involving this period is especially important. This particular study, published in Biomedical Research International, was conducted on rats.

Because previous research has shown that nutritional changes in the mother affect both poly-unsaturated fatty acid metabolism and global methylation in the placenta. This study theorized that the changes are due to some regulation of the maternal enzymes in the methylation cycle by dietary nutrients.

This study divided pregnant rats into six groups.

  • Normal folic acid and B12 (this is the control group)
  • Normal folic acid, B12 deficient
  • Normal folic acid, B12 deficient with omega-3 fatty acids
  • High folic acid, normal B12
  • High folic acid, B12 deficient
  • High folic acid, B12 deficient with omega-3 fatty acids

Placental mRNA levels were tested for MTHFR, MTR, MAT2a, CBS, PEMT, and GAPDH. Placental glutathione and phospholipid analysis were also performed.

In an effort to not bore your pants off, I’ll get to the relevant details about MTHFR.

As expected the mRNA expression of MTHFR was decreased in both B12 deficient groups relative to the normal B12 groups. Interestingly, omega-3 fatty acids were able to return the mRNA to a normal level in the normal folic acid, B12 deficient group but not the high folic acid, B12 deficient group.

This tracks with what we know about folic acid’s double-edged effect on the MTHFR enzyme. A small to normal amount is good (and far better than no folate intake) but too much inhibits the MTHFR enzyme

Placental glutathione levels followed much the same pattern. In the normal folic acid, B12 deficient group the glutathione levels were lower than normal (although not statistically significant). With excess folic acid however, glutathione levels with higher in those rats with normal B12 and significantly lower in the rats with B12 deficiency. Omega-3 fatty acids were able to correct the glutathione level in the normal folic acid, B12 deficient group but not in the excess folic acid group.

My theory about this is that glutathione manufacture is more difficult in the presence of imbalanced folate or B12, but that it increases in the most imbalanced group, which is excess folic acid and deficient B12, in an effort by the body to protect itself with glutathione buffers against increased oxidative stress.

Phospholipid levels tested higher in both B12 deficient groups compared to the control group. In both of those groups omega-3 supplementation reduced them.

This study is so remarkable because we’re looking at the time period when epigenetic is at it’s most potent and when the protective effects of omega-3 fatty acids could potentially alter the course of these pregnancies. While placental levels are being measured, these changes may have an impact for the developing fetus as well. This means that even in the presence of a somewhat unbalanced diet leading to unbalanced methylation, omega-3 fatty acids offer a regulating effect and may mitigate some of the worst of the consequences of the unbalanced diet.

Thus, the metabolisms of folic acid, vitamin B12, and DHA are interdependent on each other possibly through the one-carbon methyl cycle.

Khot V, Kale A, Joshi A, Chavan-Gautam P, Joshi S. Expression of genes encoding enzymes involved in the one carbon cycle in rat placenta is determined by maternal micronutrients (folic acid, vitamin B12) and omega-3 fatty acids. Biomed Res Int. 2014;2014:613078. doi:10.1155/2014/613078

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Fish Oil and MTHFR, What Is The Link?

We’ve all heard about fish oils and omega3 fatty acids for so many incredible reasons. They are strongly anti-inflammatory and perform almost as well as non-steroidal anti-inflammatory tests for pain relief, without side effects. 

They have been most strongly studied for heart disease and show an almost unbelievable array of benefits. Fish oils reduce the risk of sudden death from cardiac arrhythmias, reduce all-cause mortality in patients with known cardiac disease, and help to treat high cholesterol (hyperlipidemia) and high blood pressure (hypertension.) All of this, without significant side effects or drug interactions

Studies have also shown that countries with higher intake of omega-3 fatty acids have lower rates of depression. Fish oils have also shown beneficial effects in both research and clinical practice for diabetes, Alzheimer’s disease, stroke, and autoimmune disease. 

What about Fish Oil and MTHFR?

Most studies aren’t MTHFR-specific.  But, fish oil has benefits for so many of the long-term consequences of unbalanced methylation in MTHFR, that it makes sense that there would be some link.  What reserach has found is some kind of synnergy between fish oil and B vitamins, in which the combination works better than either therapy alone.

Omega-three fatty acids and B vitamins for cognitive decline

A randomized placebo-controlled  trial of people with mild cognitive impairment found that treatment with B vitamins lowered homocysteine and slowed the rate of cognitive decline. Researchers went back and re-analyzed the data from this study to see if baseline levels of omega-three fatty acids interacted wtih the results in any way. The study involved mental testing over the course of two years.They found that for all outcome measures, higher concentrations of DHA significantly enhanced the effects of B vitamins, while the levels of EPA had less of an impact.

Not only that, when omega-3 fatty acid levels are low, B vitamin treatment has no effect on cognitive decline, but when omega threes are in the high-normal range, B vitamin treatment becomes effective. There is some synnergy happening here that needs further investigation to fully understand, but since omega-three fatty acids are good for so many things and truly haven’t shown negative consequences it makes sense to add them in as a no-risk measure for seniors with cognitive decline.

Omega-three fatty acids and homocysteine

The methylation process itself seems to be involved in the metabolism and distribution of these polyunsaturated fats through your body, which means that MTHFR and omega-3s are intimately linked. Also, it has been theorized that omega-three fatty acids actually have expression control on enzymes within the methylation cycle, so effectively MTHFR controls omega-threes, which control MTHFR. There is not a big enough body of research yet to draw firm conclutions, but the evidence is pointing in this direction.  For MTHFR folks, the most important thing to understand is that using fish oils and B vitamins together produces a great reduction in homocysteine levels than using either one alone. 


This research suggests that omega-3 fatty acids (referred to here as PUFA or polyunsaturated fatty acids) actually stimulates the action of the MTHFR enzyme, which activates folate to generate SAMe, the methyl donor. PUFA also stimulates the MAT enzyme which converts methionine to SAM, the CCT enzyme which is involved in the conversion of choline to phosphatidylcholine, and the CGL enzyme which is involved in the conversion of Homocysteine to Glutathione. 

Inflammation, heart disease, cognitive decline, and high homocysteine are all problems that happen more frequently in folks who have MTHFR with unbalanced methylation, and since fish oils effectively address these problems, it almost seems like a gimme.

Next week, we’ll talk about a few bits of research being done regarding fish oil and gene expression for MTHFR folks. The research is new, but it’s starting to get good.

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