“Saturated fats are benign with regard to inflammatory effects, as are the MUFAs [monounsaturated fats]. The meager effect that saturated fats have on serum cholesterol levels when modest but adequate amounts of polyunsaturated oils are included in the diet, and the lack of any clear evidence that saturated fats are promoting any of the conditions that can be attributed to PUFA [polyunsaturated fat] makes one wonder how saturated fats got such a bad reputation in the health literature. The influence of dietary fats on serum cholesterol has been overstated, and a physiological mechanism for saturated fats causing heart disease is still missing.”
Dietary Fats and Health: Dietary Recommendations
in the Context of Scientific Evidence (1)
“In previous generations cardiovascular disease existed largely in isolation. Now two thirds of people admitted to hospital with a diagnosis of acute myocardial infarction really have metabolic syndrome—but 75% of these patients have completely normal total cholesterol concentrations. Maybe this is because total cholesterol isn’t really the problem?”
Aseem Malhotra, interventional cardiology specialist registrar, Croydon University Hospital, London (2)
“Advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for coronary heart disease risk reduction. However, clinical benefits of the most abundant polyunsaturated fatty acid, omega 6 linoleic acid, have not been established. In this cohort, substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These findings could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats.”
Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis (3)
“On the basis of our findings, we can conclude that either omega-6 or omega-3 derived prostanoids PGE2 and PGE3 contribute to the regulation of epithelial barrier function through a similar mechanism. Thus the previously described beneficial effect of EPA [omega 3 eicosapentaenoic acid] on IBD [inflammatory bowel disease] might not be attributed to the reduction in PGE2/PGE3 ratio as both PG has a deleterious effect on epithelial barrier function. [emphasis mine] Therefore, these findings may be taken into account for the future development of new nutritional interventions for IBD.”
Effect of eicosapentaenoic acid-derived prostaglandinE3 on intestinal
epithelial barrier function (4)
“Another way of arguing for the use of fish oil or other omega-3 fats is to show a correlation between disease and a decreased amount of EPA, DHA, or arachidonic acid in the tissues, and to say “these oils are deficient, the disease is caused by a deficiency of essential fatty acids.” Those oils are extremely susceptible to oxidation, so they tend to spontaneously disappear in response to tissue injury, cellular excitation, the increased energy demands of stress, exposure to toxins or ionizing radiation, or even exposure to light. That spontaneous oxidation is what made them useful as varnish or paint medium. But it is what makes them sensitize the tissues to injury. Their “deficiency” in the tissues frequently corresponds to the intensity of oxidative stress and lipid peroxidation; it is usually their presence, rather than their deficiency, that created the disposition for the disease.”
The Great Fish Oil Experiment, Ray Peat (5)
“Jesse! Respect the chemistry!”
Walter White, aka Heisenberg
This is an article I’ve been meaning to get to for a long time, but given time constraints mixed with a healthy dose of neurotic procrastination, I’ve just now gotten around to doing so. I do wish to apologize upfront about its hefty length. Clocking in at just shy of 12,000 words, you could say I got a bit carried away.
I did think of breaking this tome into different posts, but feared that my train of thought might suffer during serialization of such an important topic. And truth be told, I was concerned that the urge to attend to more pleasurable matters during a writing hiatus would cause concluding chapters to be as forthcoming as a blizzard in Miami.
That of course doesn’t mean you need to read this all at one go, dear reader. I’m sure many of you have more pressing and exciting things to attend to than learning the ins and outs of fatty acid chemistry. Plus, there’s a lot of information to digest here, so it may behoove you to return to this post after a break or two.
As you may have gleaned from reading the introductory quotes, I’m not a supporter of the absurd hypothesis that saturated fat, a fat consumed by Homo sapiens for over 100,000 years, is a major contributor to metabolic syndrome, a term that includes under its broad umbrella such disorders as non-alcoholic fatty liver, type 2 diabetes and cardiovascular disease.
Saturated fat, however, is a very convenient whipping boy for certain financially and non-financially motivated groups. And many a health guru and researcher have built a secure, albeit dubious career bashing its supposedly nefarious health effects.
The French paradox (now joined by the Swiss and Spanish paradoxes) of lower heart disease incidence in the face of higher saturated-fat intake than is the case in the U.S., has little to do with the enjoyable consumption of red wine. It is rather a clear refutation of a nutty hypothesis born out of the fevered epidemiological imagination of one Ancel Keys. However, once this belief took hold it was gleefully promoted to profitable effect by the salesmen, stockholders and public relation
whores representatives of the edible oils industry.
Now, this doesn’t mean that I consider saturated fat benign when consumed in excess. Nothing is benign when consumed in excess, including water.
Per gram, fat is more calorically dense than either protein or carbohydrate and will pack on the pounds if consumed in excess of energy need, contrary to the statements of certain diet gurus who will go unmentioned. Nor should anyone read this post as support of very low-carb, ketogenic diets.
I don’t doubt that people lose weight on these eating regimens. Any diet that cuts caloric intake will do so, and certainly for some, these diets prove quite satiating enough to do just that.
However, this blog has never been about dispensing slimming advice to a public craving a return to the waistlines of their misspent youth. Nor will it help the never thin attain some ideal body image conjured up with the “helpful” assistance of images provided by the corporate-owned media.
There are plenty of charlatans out there ready and willing to sell you their “effortless miracle cure” to shed those unwanted pounds. This is not a group I have any desire to join. This is a health blog and as I’ve repeatedly stated, what a person weighs tells us very little about their overall health status.
As far as I’m concerned, the fact that someone can lose weight while on a ketogenic diet proves little about the healthfulness of such an eating style long-term, especially if other health markers fail to improve or actually deteriorate. I’ve received my fair share of emails from low-carbers, both Paleo and not, who have been reduced to eating bone broth and a restricted list of veggies because their GI tracts are so screwed up they can’t stomach much else.
Euthyroid sick syndrome is a common outcome of such diets, and I’ve expressed my reservations about their contribution to small intestinal bacterial overgrowth in my post on thyroid function, so I’ll spare you a rehash of my reasoning. I’ve also stated my concerns in another post about the thinning of glucose-rich mucus layers lining the respiratory and digestive passages in the face of inadequate glucose consumption.
With that out-of-the-way, what finally did motivate me to discuss dietary fat and its relation to gut and overall health? Well, two recent incidents come to mind.
The first was a couple of emails I received from two readers asking about some advice they had been given by their health-care advisers. One suffered from Crohn’s disease, and the other from irritable bowel syndrome. Both were told to begin taking fish oil (fish-oil capsules in one case, cod-liver oil in the other) and asked for my opinion. I can only presume this advice was given because of the anti-inflammatory effect of supplementing with omega 3s.
And yes, omega 3s do have anti-inflammatory effects. However, very few health advisers, whether or not they sport an MD after their name, truly understand the mechanisms behind this effect. I therefore wish to set the record straight with today’s post and explain why I told both readers to ignore this advice.
The second incident that spurred this Tolstoy-esque extravaganza was a recent editorial that appeared in the British Medical Journal (BMJ) titled: Saturated fat is not the major issue. I urge you all to read it. If you register for a 14-day free trial on the BMJ website, you can access the full article free of charge.
I can’t tell you how refreshing it is to see an editorial in a respected medical journal questioning both the saturated fat and cholesterol myths. It’s been a long time coming.
Sadly, it will take many in the medical old guard who have staked their reputations and careers on both hypotheses to retire or die before these ideals are tossed on the scrap-heap of dangerous medical dogma. These are, however, seriously entrenched beliefs that will be vigorously defended by powerful economic interests: think edible oils and statin manufacturers.
However, I do take exception with the statement made in this article that a calorie is not a calorie. Numerous ward studies have long ago debunked the notion that fiddling with macronutrient ratios has any effect on weight loss or gain when calories and energy expenditure are carefully accounted for in a clinical setting. (6)
Nevertheless, the type of calories you consume most definitely can affect health outcomes for better or worse. Anyone who denies this needs to have their head seriously examined.
A diet of excess calories relative to energy expenditure that induces increased intestinal permeability, gut dysbiosis, endotoxemia and resultant inflammation, will increase cortisol secretion and promote the storage of excess calories as visceral fat while inducing insulin resistance. Why? Because those are two of the many negative biological effects of chronically elevated cortisol.
Conversely, a diet of excess calories relative to energy expenditure that does not increase gut leakiness, gut flora imbalances, lipopolysaccharide translocation to the liver and systemic circulation and inflammatory immune responses, will also pack on the pounds, but in a way that is not metabolically harmful. Same weight gain, but vastly different health result.
A recently published study in young identical twins (aged 23 to 36 years) proved this point quite nicely I thought. (7) Sixteen pairs of twins were studied where one twin was obese, and the other lean. In all sixteen pairs, the average weight difference between the lean and obese sibling was 17 kg or about 37 pounds.
In eight of these pairs, the obese twin exhibited liver-fat accumulation, insulin resistance, poor glucose control, high LDL cholesterol, low HDL cholesterol, elevated rates of inflammatory markers and high blood pressure. In other words, these eight people had metabolic syndrome. None of their normal-weight twins suffered with these issues.
In the other eight pairs of identical twins, the obese sibling showed none of these deranged metabolic characteristics. Their glucose, cholesterol and blood pressure regulation was the same as their lean brothers and sisters. They were obese, but metabolically healthy.
These findings should shock none of my long-time readers.
Now, I’m not going to argue that the extra weight carried around by these obese, metabolically healthy twins doesn’t have any downside. It’s no doubt stressful on the joints and spine to lug around excess pounds.
And let’s not forget the issue of discrimination against the overweight that permeates so many cultures. The opprobrium suffered by these folks can be far more deleterious to mental well-being and health than the weight itself.
But none of these considerations take away from the fact that it is far more important to be fit than trim. Trying to starve yourself into a body you were not meant to have is likely injurious to your health, and may very well hasten your exit from this earthly abode.
On the other hand, thinness is not the royal road to glowing health that many make it out to be. It is quite possible to be normal weight and still suffer from metabolic derangement. If the recent diagnosis of Tom Hanks with type-2 diabetes doesn’t convince you of that, then I don’t know what will.
Returning to the BMJ article, the emphasis on reducing saturated fat intake that has been, and continues to be, drilled into the psyche of modern populations everywhere, especially in the English-speaking world, has been in my opinion an unmitigated disaster. But not necessarily because it increased the intake of sugar as claimed by this writer, although I certainly don’t advocate making a habit of consuming boatloads of refined fructose.
No, the real tragedy is substitution of saturated fat with polyunsaturated fat (PUFA). Unlike saturated fat, and to a lesser extent, monounsaturated fat (MUFA), PUFAs are easily damaged by free radicals and produce a witch’s brew of noxious compounds as a result of a process known as lipid peroxidation. I’ll explain what that is in a bit.
There has been, and continues to be, a concerted industry campaign to obscure the negative health effects of consuming excess dietary PUFAs that is eerily reminiscent of the methods used by tobacco interests in the last century to mislead health authorities and the public on the connection between cigarette smoking and lung disease. One glaring example of this was a recently published meta-analysis in the Journal of the Academy of Nutrition and Dietetics that concluded, after reviewing 15 randomized trials, that there was no proof that consuming omega 6 vegetable oils increased inflammation in the body. (8)
For those of you who don’t know what a meta-analysis is, it’s a type of study that reviews previous research to arrive at a consensus view of the subject under scrutiny. How you arrive at your conclusions depends on which studies the authors of said meta-analysis think worthy of inclusion. This method of analysis can be ripe for selection bias by excluding studies, like, oh, I don’t know, the Rose Corn Oil trial (9) or the Sydney Diet Heart study (10), that don’t fit a preconceived narrative.
Which is precisely what this meta-analysis did, because according to the authors of this paper, they wanted to include only trials that studied healthy people. Fair enough, until you realize that the trials reviewed were of very short duration, with the longest lasting a mere forty days. And the most participants any of these studies had to completion was sixty.
Now, if you think the health consequences of consuming PUFAs can be detected within forty days, well have I got a nifty little Chinese-style movie theater I’d like to sell you in sunny Hollywood, California. Also, none of these studies explored what these fats were doing to intestinal cells, gut flora or the liver. They just looked at blood or urinary markers of inflammation.
Sorry, but even tests specifically designed to test for liver abnormalities like alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are often incapable of detecting accumulations of liver fat, and to my knowledge, none of these studies used either test. Nor did there seem to be any awareness that organ inflammation and tissue damage can rage for quite a while before anything shows up in labs.
Further limitations noted by the authors themselves involved the considerable variability in inflammatory markers between people even before commencement of these trials. Also, about half the studies did not explicitly control for the use of anti-inflammatory drugs. Ten of the fifteen studies failed to assess omega 3 levels in the participants. As you’ll read later on, omega 3s have powerful anti-inflammatory effects that can counter inflammation caused by omega 6 PUFA consumption.
To sum up this meta-analysis: garbage in, garbage out.
Now, on the title page of this paper was a trademarked logo that spelled out the words “eat right”. This logo, combined with this paper’s conclusion, made my BS detector squeal like Ned Beatty in Deliverance.
Being the suspicious bloke that I am, I turned to the conflict of interests section and read the following about one of the authors:
“G. H. Johnson is an adjunct associate professor, Department of Food Science and Human Nutrition, The University of Illinois, Urbana-Champaign, and principal, Johnson Nutrition Solutions LLC, Kalamazoo, MI. G. H. Johnson has provided consulting services to the Monsanto Company and Bunge Limited during the past 5 years.”
Further on we read:
“This work was funded through an unrestricted grant from the International Life Sciences Institute North America Technical Committee on Dietary Lipids.”
OK, so what services does Johnson Nutrition Solutions provide? Well, the first bullet point on their website reads: “Assess the scientific literature to support strategic business development and/or claim substantiation.”
In other words, this guy and his firm are hired by clients to trawl scientific papers to counter negative perceptions of said client’s product in the marketplace.
Monsanto, of course, makes a killing selling genetically modified seeds to farmers who in turn grow crops that can be made into vegetable oils. And how exactly does Bunge make its money? Well, according to their website:
“In approximately 40 countries you can find Bunge:
- originating oilseeds and grains from the world’s primary growing regions and transporting them to customers worldwide;
- crushing oilseeds to make meal for the livestock industry and oil for the food processing, food service and biofuel industries;
- producing bottled oils, mayonnaise, margarines and other food products for consumers;
- crushing sugarcane to make sugar, ethanol and electricity;
- milling wheat and corn for food processors, bakeries, brewers and other commercial customers;
- and selling fertilizer to farmers.”
Me thinks the fertilizer is not just being sold to farmers. As to the International Life Sciences Institute, you can read about their “scientific work” for large corporate interests, including the tobacco industry, here.
The demonization of saturated fat serves nicely to augment sales of these industrial seed oils. The medical, dietetic and nutritional associations, along with the active collusion of charitable “non-profits” like the American Heart Association, have taken the bait and industry funding over the last fifty years and run with it.
But chemistry, being part of reality, always asserts itself even if others try their level best to obfuscate the science. Today I’ll be doing my part to bring this chemistry to the forefront.
This one’s for you Mr. White!
Before going any further, it’s important that we all understand the differences in these broad categories of fats, and why they behave as they do when eaten. To keep this as simple as possible, I will spend very little time talking about the various fats that make up each category. For those of you interested in the specifics of fat, I’ll refer you to the book Know Your Fats : The Complete Primer for Understanding the Nutrition of Fats, Oils and Cholesterol.
To indulge my weary fingers and eyes, I’ll be engaging in some copying and pasting from a post done many, many moons ago concerning dietary fat and heart disease. Many of you already understand the chemistry that I’m about to describe, so feel free to skip ahead if you wish.
If, however, you are new to this topic, or consider yourself a Jesse Pinkman type, what follows later will make more sense if you read the next section first.
OK kids, here we go:
Saturated Fat (SAT): These fats do not have any double bonds linking carbon atoms (elements), and all carbon is bound:
Because of this saturation, these fats are extremely stable and are not prone to oxidation when exposed to heat, air, light, pressure or inflammatory immune responses. Because of this stability, they are ideal for cooking, although some medium-chain fatty acids like coconut oil have a much lower smoke point than longer-chain saturated fats like beef tallow.
Because their carbon chain is straight in form, saturated fats pack together readily and are therefore solid or semisolid at room temperature. Saturated fats are found in animal fats, and in tropical oils like palm and coconut.
However, animal fat, just like human adipose tissue, will reflect the type of fat eaten in the diet. In the age of grain-fed, confined-factory farming, this means that a lot of animal fat has experienced an increase in polyunsaturated content thanks to the tireless and highly profitable actions of corporate farming.
Our bodies are quite capable of producing saturated fat. So too our gut flora who produce saturated short-chain fatty acids like butyrate from fermentation of prebiotics.
Monounsaturated Fat (MUFA): These fats have one double bond, which means two carbon atoms in the chain are double-bonded to each other. Because of this, they lack two hydrogen atoms at this juncture:
At the double-bond, these fats form a kink, so they don’t pack as closely together as saturated fat. They are therefore liquid at room temperature, although they will congeal somewhat when refrigerated. While stable, these fats are more prone to oxidation than saturated fat precisely because of these missing hydrogen atoms.
Oleic acid is a common form of monounsaturated fat found in our food, and is the main fatty acid found in olive oil. Almond, pecan, cashews, peanuts and avocados are also rich in monounsaturated fat, as is pork lard. Lard is 44% monounsaturated fat, 42% saturated fat and 10% polyunsaturated fat, although the PUFA content in pigs has gone up partially replacing the other two fats in the modern era for the reasons just cited.
As fats are typically classified by the predominant fatty acid contained in them, lard should be properly classified as a monounsaturated fat, not a saturated one. However, in the overwhelming majority of animal studies that purport to show damaging effects from saturated fat intake, the fat typically used is lard, and it’s commonly mislabeled in these papers as a saturated fat.
Polyunsaturated Fat (PUFA): These types of fats have two or more double bonds between carbon atoms, and therefore lack four or more hydrogen atoms. Like monounsaturated fats, these double bonds are kinked so these fats don’t pack together well, making them liquid even when refrigerated:
PUFAs can be further divided by the position of their first double bond in relation to their omega end, which in this illustration, is found on the left. Polyunsaturated fats are called omega-6 fatty acids when their first double bond is in the sixth position from this end of the carbon chain. This illustration diagrams an omega 6 fat, specifically linoleic acid. Vegetable oils are very high in omega 6s.
Polyunsaturates with their first double bond located at the third position from the omega end, are called omega-3 fatty acids. Flaxseed and fish oils are omega-3s, yet differentiated by the number of carbon atoms and unsaturated double bonds they contain.
Because of their high level of unsaturation, PUFAs are extremely delicate and prone to oxidation when subjected to heat, air, light, pressure, free radicals and inflammatory immune responses. They are not ideal for cooking. Unfortunately, that is exactly what many of these oils are used for. They are routinely used in fast-food chains, restaurants and permeate processed foods everywhere because they are super cheap and profitable to produce.
Most vegetable oils undergo pressure, heat, solvent baths, bleaching, deodorizing and food coloring prior to bottling and sale to food manufacturers and the public. By the time you purchase them, they have long since oxidized. Omega 3s, like flaxseed or fish oil, are even more prone to oxidation, which is why many come in refrigerated opaque bottles.
All fats are combinations of different fatty acids. Canola oil, for example, is 62% monounsaturated fat, 6% saturated fat, and 32% polyunsaturated fat. Butter fat is 56% saturated fat, 29% monounsaturated fat and 3% polyunsaturated fat.
Trans fat are manufactured fats. They are made from polyunsaturated omega 6 vegetable oils after the partial addition of hydrogen atoms to empty spots on their carbon chain. Because hydrogenation straightens these fats, they have similar physical, although by no means biological, characteristics of saturated fat. Olive oil and lard can also be subjected to hydrogenation to extend shelf life. Any lard you see that is not refrigerated is partially hydrogenated.
Soused Rats, Endotoxins, Inflammation and Liver Damage
OK, I now want to highlight some experiments that were conducted in rats to study alcoholic liver disease. Now I’m sure you’re thinking what the hell does this have to do with today’s topic.
Quite a bit actually. I did warn in the last post that animal studies are only ever suggestive until their results are replicated in humans. However, it has been research in rodents that led to the discovery that bacteria translocating to the liver from the gut is a necessary precondition to induce either non-alcoholic or alcoholic fatty liver disease. I discussed that research here and here.
But of equal importance is that cells react to oxidative stress in rats the same as they do in humans. So studying how chronic alcohol feeding affects oxidation in rodents is a very useful model. And sped up in this way, these studies offer us insight into which dietary fats are protective under such circumstances and which aren’t.
I will first report on these findings, and then later explain what caused the discrepancy in effect.
One of the earliest studies of this type was done in 1989. (11) It sought to determine how different dietary fats affect liver disease progression in rodents chronically fed alcohol.
To that end, three groups of rats were fed happy juice for two to six months along with an identical liquid diet that consisted of 25% protein, 25% fat and 50% carbohydrate. All diets were supplemented with vitamins and minerals, including the antioxidant vitamins E and C.
The only difference in diet composition was the type of fat used. One group received corn oil, the other lard and the last group beef tallow. Corn oil is an omega 6 polyunsaturated fat, lard is predominantly a monounsaturated fat and beef tallow is a predominantly saturated fat.
The most severe liver disease assessed by liver biopsy was seen in the rats fed corn oil. On a graph where 7 represents the most liver pathology and zero the least, the corn oil group scored 7. The rats fed lard scored a little over two.
And what of the rats fed beef tallow? They showed no liver damage at all. Zip! Zero! Bupkiss! This after months of chronic alcohol feeding and endotoxemia. Saturated fat had completely prevented the development of alcoholic liver disease in these rodents.
Here we see some photos of what these livers looked like at the end of the experiment:
This is a picture of a rat liver after chronic alcohol ingestion for six months, but with beef fat in the diet. It shows no liver damage, and is identical to a control rat fed no alcohol.
This is the liver of a rat fed alcohol and lard for three months. Note the scarring indicated by the arrow. This is indicative of oxidative stress and tissue damage, not surprising given the chemical reality that the large amounts of monounsaturated fats found in lard are more prone to free-radical damage in the presence of an inflammatory immune response. Even so, the damage was nothing compared to what follows:
This is the liver of the rat fed corn oil and alcohol, but for only three months. You can barely make out a black arrow pointing to a round blob in the lower center section. See it? That’s pointing to a foam cell. You know, the same type of cells that clog arteries leading to the heart.
Here we see another slide of a rat fed corn oil and alcohol, yet this time for six months. Those lines are scar tissue and are indicative of alcoholic liver disease.
These results have been repeatedly replicated, and not just with beef tallow. Saturated coconut and palm oil also protect livers when rats are chronically fed alcohol to induce endotoxemia.
Given that omega 3s are even more unsaturated than omega 6s, is there any indication that these fats also increase oxidative stress in liver cells during chronic alcohol feeding? Glad you asked!
One of the best ways to induce alcoholic liver disease in a rodent model is to feed those animals fish oil with alcohol for six weeks, and in no time you end up with a liver that would be as healthy as the one sported by W.C. Fields. In the next study, that’s exactly what they did. (12) Six weeks of alcohol combined with fish oil was sufficient to cause tissue damage in the liver.
After inducing liver damage, the rats were then divided into three groups, while administration of alcohol was ceased to determine if altering dietary fat type could reverse any of the damage caused by chronic drinking. As the researchers noted, this was important to find out because many alcoholics, even after they cease imbibing alcohol continue to suffer further progression of liver disease, and eventually die as a result.
Group one stayed on a diet where fish oil was the predominant fat. Group two was switched to a palm oil diet. And group three was changed to a coconut oil diet.
In those rats switched to either saturated palm or coconut oil, there was a striking reduction in liver fat and cell death. There was a 10-fold reduction in the number of inflammatory cells in both saturated-fat groups. There was no improvement seen in the rats kept on fish-oil.
Levels of endotoxin went down in all rats after alcohol was stopped, which is to be expected as a result of reduced intestinal permeability. For the rats fed fish oil, these levels declined by about 50%. In contrast, the rats switched to saturated fat experienced an 80% to 85% reduction.
As these researchers noted:
“The current data and work published elsewhere show that it is possible to down-regulate the phenomena activated by exposure to ethanol in a surprisingly simple way, i.e., by manipulating the saturation of dietary fat. Thus, discontinuing ethanol administration and placing rats on a diet enriched in saturated fatty acids reduced indices of inflammation and necrosis and reduced the amounts of fibrous tissue accumulated during the ingestion of ethanol. But whereas diets enriched in saturated fatty acids led to healing of alcohol-induced injury, evidence of injury persisted in the absence of ethanol in rats fed a diet enriched in polyunsaturated fatty acids.”
I could bore you with many, many more studies of this type, but it’s time to explore why these results occurred. What is it about polyunsaturated fats that causes a liver to accumulate fat and leads to tissue damage?
Now, let me just say that I don’t want anyone to get the impression that any amount of dietary PUFA is bad. As the saying goes, the dose makes the poison.
As you’ll see shortly, low intake of PUFAs is likely beneficial, even in spite of the fact that they increase free radical generation and peroxidation. But I’m getting ahead of myself.
Before I go any further, however, I need to cover the structure of the mammalian cell. I’ll try to keep this as painless as possible.
A Brief Overview of the Cell
This illustrates a typical cell in the body, including those that line our intestinal tract and make up our liver. And no, I won’t be explaining what all of these various internal structures or organelles do.
Sitting on my desk is a textbook titled the Molecular Biology of the Cell, 5th edition. At over 1,200 pages, it weighs more than 6 pounds (2.72 kg) and can be considered a lethal weapon in the wrong hands. If you think I can adequately summarize what’s in that book in this post then you have truly overestimated my capabilities my friend.
And for today’s purpose, this isn’t necessary. What I want you to take away from this section is the understanding that many of these structures contain fatty acids, or lipids.
So what exactly is a fatty acid? The technical definition is that they are a collection of biological molecules that are insoluble in water.
In cells, the most important function of these fatty acids is in the construction of cellular membranes. And by cellular membranes I’m not just talking about the membrane that encloses the entire cell, although that envelope is very important.
These membranes also surround the various cellular structures, or organelles, within the cell. For example, see the structures labeled mitochondrion and nucleus? They too are surrounded by membranes partly composed of fatty acids, mainly in the form of phospholipids. In fact, a mitochondrion is actually enclosed by two highly specialized membranes.
Phospholipids are the most pervasive type of lipids found in cellular membranes. Phospholipids are small molecules constructed from fatty acids and glycerol, much like triglycerides. However, in the case of phospholipids, there are two, not three, fatty acid chains attached to a glycerol backbone.
Two fatty layers form these membranes, and they are therefore also referred to as a bilayer. The interior of this membrane repels water (is hydrophobic), while its exterior attracts or is soluble in water (hydrophilic). Here’s a nice illustration of what I’m talking about:
Apart from phospholipids, sphingolipids are also found in cellular membranes. They are saturated fatty acids attached to a serine, rather than a glycerol, molecule.
These structures pack together into what are called lipid rafts that can float freely within cell membranes. These rafts are thick enough to accommodate the largest membrane proteins.
Cell membranes also contain carbohydrates attached to proteins to form glycoproteins, or to fatty acids to form glycolipids. These are found only on the exterior of the cellular membrane and are vital for cell signaling.
Membranes also contain proteins which comprise about 50% of these structures. These proteins are extremely important for the proper functioning of a cell. For example, to express cell receptors, to present antigens to the immune system, to facilitate cell to cell contact and communication and to transport substances across the cell membrane.
Cholesterol is also found in membranes, and is vital for strengthening these structures and modulating membrane fluidity. Lipid rafts are rich in cholesterol and cells are compromised if cholesterol levels run low.
Membranes are extremely important to the life of a cell. The integrity and proper functioning of these structures allows only those extracellular molecules that are supposed to enter a cell to do so, while keeping others out.
This is also true for those intracellular membranes that prevent potentially harmful molecules from reaching the interior of organelle structures. The importance of these membranes is attested to by the fact that about a third of a cell’s genetic DNA codes for them.
The fatty acid composition of these membranes reflects the fatty acids consumed in the diet. The more omega 6s eaten, the more will be incorporated into these structures. Same holds true for omega 3s. Diet, specifically fat intake, has an important influence on cell composition.
Free Radicals and Lipid Peroxidation
The life of a cell is one of constant production of oxidation. Through a process known as cellular respiration, nutrients are converted to energy, specifically adenosine triphosphate (ATP). ATP is the reason you are alive to read this post. No ATP, no life.
This is not the place to list the many steps involved in the production of cellular energy. For now, all you really need to know is that this process occurs in the mitochondrion of the cell and requires oxygen.
Because oxygen is used in cellular respiration, a number of highly reactive free radicals, collectively known as reactive oxygen species (ROS), are released. These free radicals are like bullets ricocheting every which way damaging whatever cell components lie in their path.
These chain reactions can be halted by antioxidants that donate electrons to free radicals, stopping the chain reaction dead in its tracks:
Among these ROS are oxygen itself, superoxide anion, peroxide, hydrogen peroxide, hydroxyl radical and hydroxyl ion. Living is inherently a pro-oxidative process, and this oxidation only stops when you die.
If not neutralized, reactive oxygen species can damage not only the lipid molecules of cells, but so too their protein structures, including the nucleus, site of cellular DNA. And under intense ROS attack, cell death occurs.
Lucky for us, the body has a number of endogenous enzymes that are produced to deal with these free radicals: superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. Other endogenous antioxidants include uric acid and bilirubin, the breakdown product of red blood cells.
Vitamins like vitamin A, C and E also act as antioxidants as do polyphenols from fruits and vegetables, making diets rich in these antioxidants a useful complement to built-in antioxidant defenses. And as I wrote in a previous post, beneficial bacteria also generate antioxidants and are therefore vitally important members of the body’s antioxidant brigade.
Glutathione is the body’s most significant non-enzymatic antioxidant and exists in relatively large amounts, especially in the liver assuming it isn’t depleted by high oxidative stress. Not only does it neutralize free radicals, it preserves the antioxidant status of both vitamins C and E. It is also a necessary part of biological processes responsible for DNA synthesis and repair.
Paradoxically, activities that increase oxidative stress, for example exercise, can actually improve your health by strengthening your cellular antioxidant response. So by no means is increasing oxidative stress always a bad thing, as long as the cellular mechanisms needed to neutralize these effects remain intact.
This is why low amounts of PUFAs derived from whole foods are likely healthy for you. By inducing a compensatory antioxidant response, they actually enhance your health.
The problem, however, comes with overdoing PUFA intake. And neither I nor anyone else has the definitive answer as to when that tipping point is reached, although increasing research suggests it’s much lower than we’ve thought, especially in the presence of chronic immune activation.
Exercise and PUFAs aren’t the only things to increase oxidative stress. You wouldn’t have much of an immune system if various immune cells like neutrophils didn’t produce reactive oxygen species to kill off infected cells. Nor would many cancer treatments work without them.
In fact, it can be quite counterproductive to increase your intake of antioxidants during a cold or flu, for example. The misery you experience during these diseases is not due to the virus itself, but to your immune system’s response to it.
Increasing antioxidant intake during a viral infection may make you feel better in the short-term because it’s neutralizing many of the free radicals your immune system is generating to fight the invader. However, you may also be unnecessarily prolonging the duration of the disease for this very reason.
Antioxidants, like most things in biology, are a double-edged sword. Both too few and too many can result in unintended consequences.
Though we typically want a strong immune response in the face of an acute infection, chronic activation of the immune system is another issue entirely. By continually generating ROS, the risk increases that normal tissue will become irreparably harmed.
Because of their inherent chemical instability, PUFAs incorporated into cellular membranes are especially prone to both sustain and generate free radical reactions. How damaging these reactions become depends upon the antioxidant status of the host.
Free radicals are not the only issue with PUFAs, however. Due to a process known as lipid peroxidation, these same oxidized PUFAs emit a number of very noxious and potentially toxic aldehyde substances.
Aldehydes are highly reactive organic chemical compounds. Some of the best studied are 4-hydroxynonenal (aka 4-hydroxy-2-nonenal), malondialdehyde, 4-hydroxyhexenal and acrolein.
While I could easily spend another 12,000 words detailing the effects of all the many lipid peroxidation products, I just want to concentrate on three: 4-hydroxynonenal, malondialdehyde and 4-hydroxyhexenal.
4-hydroxynonenal and malondialdehyde are derived from the peroxidation of omega 6 fats. 4-hydroxyhexenal is derived from the peroxidation of omega 3s, in particular, highly unsaturated omega 3s found abundantly in oil from cold-water fish.
In the body, these lipid peroxidation products are referred to as “second messengers” of free radicals. They are far more stable and longer lasting than run-of-the-mill free radicals. They easily diffuse to distant regions and are capable of affecting the functions of cells far away from the point of origin.
In low doses, these aldehydes also exhibit hormetic effects: i.e. they enhance health by increasing oxidative stress in cells thus calling forth compensatory antioxidant responses. Unfortunately, at higher concentrations these beneficial effects are replaced by cell damaging and cytotoxic actions.
If the word cytotoxic doesn’t sound good to you, it’s because it isn’t, or at least it isn’t in the vast majority of cases. To be cytotoxic is to be capable of inducing cell death. While it’s a good thing when we’re talking about cancerous or infected cells, it’s certainly nothing to celebrate in normal ones.
Of the three lipid peroxidation products I’m covering today, both 4-hydroxynonenal and malondialdehyde derived from omega 6 fats are the most studied. So let me briefly describe some of the destructive actions of these substances when produced in excess.
This will go a long way in explaining why the rats who were fed both alcohol and omega 6 corn oil experienced liver damage. By the way, what’s true of 4-hydroxynonenal appears to be also true of 4-hydroxyhexenal derived from peroxidation of omega 3s.
4-hydroxynonenal is particularly good at negatively impacting endothelial cells, epithelial cells and tight junction proteins. Recall that these types of cells and proteins not only line the arteries leading to the heart, but also make up the type of cells lining the gastrointestinal tract. 4-hydroxynonenal is therefore quite capable of increasing intestinal permeability.
This no doubt explains the results of two recent studies showing that high omega 6 consumption increased gut dysbiosis and intestinal permeability in rodents. In the first study, female mice were fed three different high-fat diets where the only difference was fatty acid composition. (13)
Diet one consisted of omega-6 rich corn oil. Diet two contained rapeseed or canola oil. Diet three was corn oil supplemented with 1% fish oil.
The diet containing corn oil caused the most gut dysbiosis and intestinal pathogen overgrowth. The canola oil diet didn’t fare much better. The corn oil diet supplemented with fish oil reversed dysbiosis.
Before you get too exited about this effect in the group supplemented with fish oil, be aware that the addition of omega 3s actually increased levels of 4-hydroxynonenal in the small intestine of these mice, attesting to increased oxidation. I’ll explain this paradoxical finding in a bit.
What drove the dysbiosis in rodents fed omega 6 PUFAs was the increase in oxidative stress, lipid peroxidation, cell damage and inflammation in intestinal cells and tight junction proteins of the gut. As I’ve repeatedly said, gut inflammation always predisposes to intestinal pathogen overgrowth.
With increasing inflammation gut flora populations shift to a pro-inflammatory type that are best suited to these conditions, like certain E.coli strains, for example. Because beneficial bacteria do not thrive in the presence of inflammation, their numbers decline, which in turn allows these pathogens even more of a competitive advantage.
That this effect was also noted with canola oil, a current darling of nutritionists because of its high monounsaturated content, should give you pause. I suspect what was behind this effect is the very low-level of saturated fat (6%) in this oil combined with its high (32%) PUFA content.
I know I said that I was not going to bore you with another alcohol-rodent study, but this one specifically dealt with intestinal tight junction proteins. (14) I mentioned this study in my heart-disease series, but thought a re-visit here was justified.
In mice fed alcohol and omega 6 corn oil for eight weeks, significantly increased intestinal permeability was noted along with elevated endotoxin levels emanating from the ileal section of the small intestine. Not only that, but accumulation of liver fat, inflammation and oxidative stress were all higher in the livers of these animals.
Here are the liver slides from our hapless, alcohol-fed mice. The top row is the saturated fat (SF) group both before and after alcohol (EtOH) feeding. These photos display reactive oxygen species accumulation in the liver represented by the lighter areas. Note the relatively low levels of ROS in the saturated-fat-fed mice chronically given alcohol for eight weeks. Do note, however, that this and the corn oil diet contained a small amount of omega 6 soybean oil so that may partly explain some of what is seen in this slide.
Contrast that to the slides on the bottom. Before administration of alcohol, all mice were fed their respective diets for one week. Note the visible accumulation of oxidation in the livers of mice fed corn oil (with added soybean oil) prior to the start of alcohol feeding. The slide on the right shows how oxidation exploded once chronic alcohol intake commenced.
But how specifically do lipid peroxidation substances damage cellular components, including those in the gut and liver?
Well, by actively inhibiting mitochondrial respiration for one. (15) Want to know why consuming vegetable oils consistently lowers cholesterol levels?
This illustrates cholesterol synthesis or the mevalonate pathway in the liver. No, I won’t be explaining these steps to you other than to point your attention to the top left-hand corner. The availability of acetyl-CoA is the rate-limiting step in the entire process.
Acetyl-CoA’s main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be utilized for energy production in the mitochondrion. Recall that mitochondrion are the powerhouse of the cell.
Only a healthy, fully functioning mitochondrion produces acetyl-CoA from either carbohydrates or fats. However, that is not what you will have if you include lots of omega 6 PUFAs in your diet because of damage to these structures caused by free radicals and lipid peroxidation.
Remember that malondialdehyde is another aldehyde produced by omega 6 lipid peroxidation. It is also produced by oxidation of cellular proteins and DNA. It, along with 4-hydroxynonenal, actively impairs mitochondrion function. (16)
By doing so, these peroxidation products inhibit the ability to produce cholesterol because of damage to liver cells. If you are on the advisory committee of the American Heart Association this is cause for great jubilation, because anything that drives down cholesterol levels is blessed by the angels in their eyes. Hence their website recommending inclusion of safflower oil as part of a “heart-healthy” diet.
At 78% linoleic acid, this oil contains more omega 6 PUFA than any other fat. It is therefore absolutely brilliant at pounding down total cholesterol levels via these aldehyde’s suppression of cellular respiration in liver cells! Whoopeeeeee!
Folks, I couldn’t make this crap up even if I tried.
Apart from screwing with the lipid and protein structures of cells, lipid peroxidation products inhibit DNA and RNA synthesis. They are also highly mutagenic, i.e., they can damage the nucleus of cells and DNA, increasing the chance of tumor development.
By reducing cellular respiration, they promote cellular dysoxia. What is cellular dysoxia? The inability of the cell to make full use of oxygen due to mitochondrial derangement.
This is an ideal environment to initiate the Warburg effect. And what, pray tell, is the Warburg effect?
The Warburg effect is named after Otto Heinrich Warburg, an early 20th century German biochemist who won the 1931 Nobel Prize in physiology. In a 1966 lecture delivered when he was director of the Max Planck Institute for Cell Physiology, Warburg described the effect he discovered this way:
“Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar. All normal body cells meet their energy needs by respiration of oxygen, whereas cancer cells meet their energy needs in great part by fermentation. All normal body cells are thus obligate aerobes, whereas all cancer cells are partial anaerobes. From the standpoint of the physics and chemistry of life this difference between normal and cancer cells is so great that one can scarcely picture a greater difference. Oxygen gas, the donor of energy in plants and animals is dethroned in the cancer cells and replaced by an energy yielding reaction of the lowest living forms, namely, a fermentation of glucose.”
In other words, cells that are deprived of oxygen revert to a more ancient form of energy production that predates the formation of the oxygen-rich atmosphere we all take for granted.
4-hydroxynonenal has also shown the ability to form blood clots and lead to thromboxane formation. Thromboxane is a constrictor of blood arteries and a potent initiator of high blood pressure.
Both 4-hydroxynonenal and 4-hydroxyhexenal rapidly deplete levels of glutathione. Recall that glutathione is the body’s master antioxidant, so increases in lipid peroxidation would decrease glutathione reserves. If lipid peroxidation overwhelms the cell’s ability to replenish glutathione, cell death is an inevitable result.
Concentrations of 4-hydroxyalkenals in millimolar ranges are acutely toxic to mammalian cells and will lead to cell death within an hour. Part of this toxic effect appears to be due to the dysregulation of calcium homeostasis within the cell. (17) This, in turn, causes the mitochondrion to release large amounts of reactive oxygen species that ends in cell death.
The role of PUFAs in the development of atherosclerosis and cardiovascular disease is attested to by both the Rose Corn Oil Trial (9) and the Sydney Diet Heart Study (10). A 2005 paper from the University of Bayreuth’s Department of Organic Chemistry entitled The relation of lipid peroxidation processes with atherogenesis: A new theory on atherogenesis arrived at a number of conclusions about these fats and their contribution to heart disease. Allow me to quote some of them for you:
- It is hypothesized that any change in the cell membrane structure, caused by external or internal events, is combined with initiation of LPO [lipid peroxidation] processes
- It seems that a great number of the generated LPO products serve as ligands of proteins which in turn activate gene expression. Thus gene expression is apparently a consequence of LPO. LPO products seem to link events outside and inside the cell with an appropriate cell response.
- All inflammatory diseases are connected with LPO processes. [emphasis mine]
- Atherosclerosis seems to be not a multifactorial disease, but be induced by a sequence of enzymatic and nonenzymatic peroxidation processes. LPO precedes all other reactions, including alteration of proteins.
- Mammalian cholesterol-PUFA ester suffer peroxidation in the PUFA part by storage and heating. These oxidized cholesterol-PUFA esters are apparently incorporated into lipoproteins and transferred by LDL into cells where they induce cell destruction.
- Cell destruction generates LOOHs [lipid hydroperoxide free radicals] and iron ions. These get in contact with neighboring cells and transfer to their membrane phospholipids the LPO reaction. Thus the reaction spreads like an infection from cell to cell.
- Feeding experiments indicate that an LDL oxidation is a direct consequence of PUFA oxidation caused by contact with injured endothelial cells. Increase of PUFA oxidation occurs within 12–16 h. In contrast the cholesterol level remains unchanged, indicating that the increase of cholesterol levels in atherosclerosis is a secondary effect.
- Saturated fatty acids are stable against oxidation. Therefore, they cannot be atherogenic as assumed previously. n-3 [omega 3] PUFAs suffer oxidation like all PUFAs, they seem therefore not to protect against attack of radicals in cardiovascular diseases.
Wow! That doesn’t sound too good, now does it?
Bacterial invasion via compromised gut-barrier function, as I wrote in my heart disease series, is in my humble opinion driving the inflammatory process that results in lipid and protein peroxidation. Ingesting fats that increase translocation of these pathogens to the liver and systemic circulation, while simultaneously hampering cholesterol’s innate ability to bind and neutralize them by actively reducing cholesterol synthesis in the liver as a consequence of oxidation and peroxidation, is no way to keep the cardiovascular system healthy.
Do you think someone should tell this to the American Heart Association? Nah!
Something tells me they already know and would be highly annoyed if you brought it to their attention. After all, admitting that the dietary advice they’ve been dispensing for over 50 years has dispatched millions to an early grave is hard to do, and not likely to win them many friends or charitable donations. Plus, changing dietary recommendations based on proven lipid and protein peroxidation science could seriously imperil a lucrative revenue stream generated by selling all those “Heart-Check marks” to major food manufacturers, and we couldn’t have that now, could we?
OK, it’s now time to switch our attention to omega 3 polyunsaturated fatty acids.
While there is a growing understanding that over ingesting omega 6 vegetable oils is not such a hot idea (unless, of course, your paycheck depends on not understanding these facts), less is known about the dangers related to over-consuming omega 3s.
The belief that supplementing with omega 3s is beneficial in preventing heart disease largely stems from an Italian trial called GISSI-Prevenzione. (18) However, as in many studies showing a dramatic health effect that generated a lot of initial media buzz, subsequent trials have arrived at decidedly undramatic results in regards to omega 3 supplementation and reduction in cardiovascular events.
A 2004 Cochrane Collaboration meta-analysis reviewed the outcomes of 48 randomized controlled clinical trials and 41 cohort studies to determine if omega 3 supplementation was really protective against heart disease. (19) They concluded:
“It is not clear that dietary or supplemental omega 3 fats alter total mortality, combined cardiovascular events or cancers in people with, or at high risk of, cardiovascular disease or in the general population. There is no evidence we should advise people to stop taking rich sources of omega 3 fats, but further high quality trials are needed to confirm suggestions of a protective effect of omega 3 fats on cardiovascular health. There is no clear evidence that omega 3 fats differ in effectiveness according to fish or plant sources, dietary or supplemental sources, dose or presence of placebo.”
A 2012 meta-analysis reviewing the same topic but with more recent data concluded:
“In conclusion, omega-3 PUFAs are not statistically significantly associated with major cardiovascular outcomes across various patient populations. Our findings do not justify the use of omega-3 as a structured intervention in everyday clinical practice or guidelines supporting dietary omega-3 PUFA administration. (20)“
Neither statement is exactly a ringing endorsement for the health claims made by many advocates of omega 3 supplements. This doesn’t mean you shouldn’t eat seafood. These are wonderful foods, and I would certainly miss eating them.
Plus, getting your omega 3s this way has the added benefit of providing you with a trace mineral essential for boosting glutathione levels, i. e. selenium. Selenium is abundant in seafood and would be expected to boost antioxidant status, and thereby help neutralize the free radicals produced by oxidized omega 3s. The seaweed that holds sushi together also contains selenium and is therefore a very clever and healthy culinary innovation.
Omega 3s are the most unsaturated fats of all, and for that reason are even more likely to undergo the lipid peroxidation reactions I’ve already written about. So easily are omega 3s oxidized, that for thousands of years both linseed oil (i.e. flaxseed oil) and fish oil were used as varnishes due to their rapid oxidation when exposed to air.
What sets omega 3s apart from omega 6s, however, is their well-known anti-inflammatory effect. Study after study in both animals and humans has attested to this property of omega 3s.
Now language is a curious beast. You can often use two totally different words or phrases to describe the same phenomenon. If said one way, conferring a warm, positive feeling, yet if said another way, invoking a feeling that is anything but. Loyalty vs. blind obedience, proud vs. narcissistic, cautious vs. cowardly, introvert vs. loner, life of the party vs. drunken boor: the list goes on and on.
When applied to the workings of the immune system, the use of the terms “anti-inflammatory” or “immune-suppressive” work much the same way. Who doesn’t want the benefits of anti-inflammation? Inflammation is such a negative word after all. Yet if you were told that the people experiencing the lowest levels of inflammation alive today have AIDS, would that sound as positive to you?
So, rather than begin this discussion of omega 3s talking about their “anti-inflammatory” effects, I think we would be better served emphasizing their immune suppressive actions for as you will read shortly, that is exactly what excess levels of these PUFAs do to certain arms of the immune system.
Through the years a lot of research has been done to understand how omega 3s tamp down immune responses. However, until fairly recently many of these hypotheses failed to adequately explain a paradox that all of you were introduced to earlier in this post.
Remember the mouse study that found that adding fish oil to the corn oil diet reversed gut dysbiosis and inflammation, yet increased oxidative stress in the small intestine? There are numerous studies in the scientific literature in which oxidative stress in liver cells increases, while inflammatory immune responses in that same organ goes down when animals are fed this class of PUFA. What’s going on here?
Well, perhaps another mouse study can help answer that question. In 2003, a fascinating paper was published showing that when fish oil was fed to rodents, T cell AICD dramatically increased. (21) And what, gentle reader, is AICD? AICD stands for activation-induced cell death.
Yes ladies and germs, it seems that the reason omega 3s are “anti-inflammatory” is because they are very, very efficient at inducing certain types of immune cells to commit “suicide”, thus reducing immune responses.
One type of immune cell they target belongs to the Th1 arm of CD4 T lymphocytes. This effect has also been noted in humans. (22)
It should go without saying that T lymphocytes are very important components of the immune system. There are two main types of T lymphocytes. They are differentiated by the presence of certain molecules on their cell membranes and are thus classified as either CD4 or CD8 T cells.
Those expressing the CD4 molecular signature are recognized as helper T cells (Th), and these cells are the most prolific producers of cytokines. You can think of them as cytokine factories.
Recall that cytokines are signaling proteins that behave like hormones. Their function is to coordinate immune responses.
This CD4 subset can be further subdivided into what are known as Th1, Th2 and Th17 cells. Each one of these cell types produces its own unique set of cytokines to handle different threats.
Activated Th1 cells produce the pro-inflammatory cytokines responsible for destroying intracellular parasites like bacteria or viruses. They are prolific producers of tumor necrosis factor (TNF), interferon-gamma (IFN-y) and interleukin 2 (IL-2). This is the arm of the immune system that is activated when endotoxins reach the liver, for example, or when bacteria enters an open wound.
This is also the arm of the immune system that is responsible for perpetuating autoimmune responses. Obviously, such activation can be quite harmful to the host if left unchecked.
Th2 cells and cytokines tend to suppress Th1 cells. There is also evidence they suppress Th17 cells as well.
The Th2 immune arm is vital in defending against invaders from the digestive tract. Interleukin 4 (IL-4), a Th2 cytokine, encourages B cells to produce IgE antibodies that are especially useful against parasites like hookworm. Interleukin 5 (IL-5) stimulates B cells to produce IgA antibodies that are effective against gut pathogens. Finally, interleukin 13 (IL-13) stimulates the production of intestinal mucus, thereby strengthening gut-barrier function.
These cytokines are all important for preventing gut dysbiosis. However, there’s a wee bit of a problem when overdoing the intake of omega 3s to enhance these immune effects. While these PUFAs do increase the production of cytokines designed to eradicate gut infections, they also increase oxidative stress in intestinal cells.
So like aspirin and other non-steroidal anti-inflammatories, omega 3s dampen certain immune responses, while simultaneously increasing intestinal permeability by elevating oxidative and lipid peroxidation effects in enterocytes and tight junctions lining the gut. Moreover, suppressing immune responses by supplementing with these PUFAs is a very risky strategy as you’re about to see.
This is true of all immune modulators like glucocorticoids or statins. In the case of glucocorticoids, ratcheting down certain immune responses can increase the risk of cancer, and comes with a slew of other unfortunate side effects like deposition of fat in internal organs (visceral fat) and increased risk of developing osteoporosis.
By actively reducing cholesterol synthesis in the liver, statins hamper cholesterol’s ability to bind to and inactivate bacterial endotoxins, an important, yet often overlooked, innate immune function of lipoproteins. (23) This is separate and apart from the negative effect of statins on CoQ10 synthesis, muscle and mental health, exercise endurance and diabetes. (24) (25) (26) (27)
A major concern in using omega 3s to treat gut dysbiosis is the increased risk of unbalancing the immune system away from a Th1 response and towards Th2 dominant activation. One of the common outcomes of doing so is to increase allergic reactions to food, pollen and other environmental inhalants. Many of these allergic immune reactions also underlie various skin diseases like eczema.
Being Th2 dominant will also depress Th1 defenses against bacterial, fungal and viral infections. This can be a dangerous proposition, especially when harmful bacteria enters a break in the skin.
As mentioned, omega 3s also suppress Th17 cells and their cytokine, interleukin 17 (IL-17). (28) (29) In my post on Crohn’s disease, I wrote that IL-17 is usually elevated in this disorder, likely in response to a yeast overgrowth in the intestinal tract.
While omega 3s do decrease the inflammatory response to this type of infection, mainly by inducing death in the immune cells that come to attack and destroy the overgrowth, they would also make it that much harder to eradicate it. If fungal infection is really at the heart of Crohn’s disease, then a strategy of supplementing with omega 3 PUFAs may prove counterproductive. This would also hold true for those trying to overcome a Candida albicans overgrowth.
There is another subset of immune cells that is consistently suppressed by these fatty acids: natural killer cells (NK). NK cells are unique in that like helper T cells they can generate lots of cytokines to destroy infected cells.
However, they also have another very important function. They are surveillance cells responsible for the early detection and destruction of tumor cells.
The ability of omega 3s to depress natural killer cell activity is a cause of concern. A study done in humans found that a moderate amount of eicosapentaenoic acid (EPA), an omega 3 found in fish oil, decreased natural killer cell activity in healthy adults over the age of 55. (30) Whether this translates to greater cancer risk is yet to be determined.
One meta-analysis found that there is no proof that omega 3s increase the risk of prostate cancer in males. (31) However, these results are in contrast to two other studies showing elevated levels of serum omega 3 in men being strongly associated with aggressive prostate cancer. (32) (33) Given the powerful immune-modulating effects of these PUFAs, I would caution anyone from getting their omega 3s anywhere other than from whole foods rich in glutathione precursors or antioxidants.
Of course, this possible cancer connection has raised howls of protest from sellers of omega 3 supplements. Dr. Mercola, a long-time purveyor of his own line of omega 3 krill oil, called the results of these studies absurd, going so far as to quote a Dr. Roundtree who claimed:
“Considering the extensive body of literature that supports the anti-inflammatory effects of omega-3 fatty acids, there is no credible biological mechanism, nor is one suggested in the article, that would explain why these essential fatty acids might increase tumorigenesis.”
It appears that both Dr. Mercola and Dr. Roundtree are enamored with the positive connotation of the word anti-inflammatory. That neither doctor is capable of finding the “credible biological mechanism” that I just outlined speaks volumes about their research skills, scientific thinking and perhaps most importantly of all, monetary self-interest. But boy what I wouldn’t give for a slice of the multi-million dollar flaxseed and fish oil business!
So while many researchers, doctors, naturopaths and supplement manufacturers see only good in these “anti-inflammatory” effects, I’m far more cautious (or cowardly;). Yes, omega 3s are powerful anti-inflammatories. However, these effects come with a cost, and neither I nor anyone else for that matter knows for sure what that cost really is.
It is for this reason that Ray Peat, a Ph.D. biologist, felt compelled to write his article The Great Fish Oil Experiment. I highly recommend reading it. That post will also introduce you to another omega 3 peroxidation product called acrolein, which has been shown to have extremely toxic effects on brain cells. (34) (35) (36) (37)
Nevertheless, let me just say that suppression of immune function was not the only reason I advised my two readers to forgo taking fish oil to treat their digestive problems. Rather, it was the recent findings of two in vitro studies, one out of Spain and the other out of Japan, concerning intestinal-barrier function and omega 3 PUFAs. (38) (39)
In the Spanish study, prostaglandin E3, derived from EPA, was found to increase intestinal permeability to the same extent as omega 6 derived prostaglandin E2. So again, this study corroborates the finding that like all PUFAs, omega 3s result in enough oxidative stress at the gut wall to increase leakiness.
The Japanese study came to similar conclusions, noting that the peroxidation of these highly unsaturated lipids activated receptors (toll-like receptor 4 or TLR4) that are primed to detect lipopolysaccharides (LPSs) from gram-negative bacteria. The authors of this study concluded:
“…peroxidation of fatty acids having unsaturated bond(s) is essential for inducing their acute action on TLR4, which follows the same pathway as LPS. This would suggest that lipotoxicity on vascular function requires fatty acids having unsaturated bond(s) and an oxidative microenvironment. Additionally, use of PUFAs as an anti-inflammatory agent may cause opposite effects in patients with inflammatory disorders involving TLR4 signaling.”
There is now increasing recognition within the scientific community that omega 3s have very serious side effects. In a review paper just published on October 31st the abstract reads:
“Recent studies of bacterial, viral, and fungal infections in animal models of infectious disease demonstrate that LCω-3PUFA [long-chain omega 3 polyunsaturated fatty acid] intake dampens immunity and alters pathogen clearance and can result in reduced survival. The same physiological properties of EPA/DHA [eicosapentaenoic/docosahexaenoic acid] that are responsible for the amelioration of inflammation associated with chronic cardiovascular pathology or autoimmune states, may impair pathogen clearance during acute infections by decreasing host resistance or interfere with tumor surveillance resulting in adverse health outcomes. Recent observations that high serum LCω-3PUFA levels are associated with higher risk of prostate cancer and atrial fibrillation raise concern for adverse outcomes.” (40)
To those health-care advisers reading this post, my counsel to you is to not recommend supplementing omega 3s to your patients suffering from intestinal diseases. And if, as Ray Peat warns, omega 3 lipid peroxidation reaches levels that are cytotoxic to brain cells in free-living humans supplementing with these PUFAs, you may be trading your patient’s temporary improvement in GI symptoms for long-term mental impairment. I don’t believe this is a very wise tradeoff.
Final Words (It’s about bloody time!)
It should be clear from this post that when it comes to dietary fat and gut health, saturated and monounsaturated fats are your safest options. And when it comes to monounsaturated oils, olive oil is far safer than canola oil because of its lower PUFA and higher saturated fat content.
To maintain both gut and liver health, I highly recommend you limit PUFA intake to what you would naturally get from eating whole foods, and excluding, of course, added vegetable oils and omega 3 supplements. Sadly, the food supply is permeated with these fats. And a push is on to increase omega 3 content in processed foods for their supposedly “heart-healthy” effects.
On its website, Bunge Inc. proudly crows about its customers in the restaurant, foodservice and food manufacturing industries located across the globe. And they are not alone. According to Hoovers.com:
“The US edible oils manufacturing industry includes about 200 companies with combined annual revenue of about $55 billion. Major companies include Archer Daniels Midland, Bunge, Cargill Foods, and CHS. The industry is highly concentrated: the eight largest companies account for about 80 percent of industry revenue.”
If you think anything is going to change regarding the availability of these fats in the food supply, then you are truly smoking some serious ganja my friend. This is a lucrative domestic and export market that the U.S. government has no intention of messing with. Any change will have to come from the consumer.
The key to correcting an omega 6 and omega 3 imbalance in your diet is not to increase omega 3 consumption, but by cutting omega 6 intake.
If you don’t eat home-prepared meals, this can be very difficult to achieve in a country like the United States or Canada. I’m not trying to dissuade you from eating out. I do so twice a week. I’m just saying it’s harder to control your intake of PUFAs if most meals are eaten outside of the home.
Including saturated fat in your diet can go a long way in mitigating the effects of oxidation and lipid peroxidation caused by dietary PUFAs. In the rat studies I cited at the beginning of this post, no increase in liver damage was detected in rats if 85% of the fat eaten was composed of saturated fatty acids, even though 15% of fat was derived from PUFAs.
And much oxidative damage can be mitigated by including plenty of nutrient-dense foods rich in antioxidants and glutathione precursors to help neutralize the effects of these highly unstable fats. Selenium, and sulfur amino acids like cysteine and methionine, boost glutathione levels.
As noted, beneficial gut flora improve antioxidant status. As such, supplementing with both probiotics and prebiotics would be expected to have a positive effect against rampant oxidation, not to mention correct some of the gut flora dysbiosis caused by excess PUFA intake.
However, antioxidants can only go so far. While they do neutralize free radicals, they can only do so much in regards to cellular lipid and protein damage caused by peroxidation products. The emphasis should be on preventing these reactions, not reversing them after the fact.
I started this post with a quote from the paper Dietary Fats and Health. I’d like to end it with another quote from the same paper:
“Various aldehydes produced in the oxidation of PUFAs, as well as sugars, are known to initiate or augment several diseases, such as cancer, inflammation, asthma, type 2 diabetes, atherosclerosis, and endothelial dysfunction. Saturated fats per se may not be responsible for many of the adverse health effects with which they have been associated; instead, oxidation of PUFAs in those foods may be the cause of any associations that have been found. Consequently, the dietary recommendations to restrict saturated fats in the diet should be revised… It is time to reevaluate the dietary recommendations that focus on lowering serum cholesterol and to use a more holistic approach to dietary policy.”
I couldn’t agree more.
OK Mr. White, my work is done.
It’s time to rest in peace.