Ketogenic diet – is it safe? (lipid peroxidation, prostaglandins, inflammation)

Two aspects might be of concern when eating a ketogenic diet…

Increase ROS due to more saturated fat consumption and more lipid peroxidation due to more unsaturated fat ingestion.


Let’s start with the increase in ROS

1 glucose molecule produces 10 NADH and 2 FADH2 through glycolysis and the TCA cycle. During beta-oxidation, for each two carbons it removes from the fatty acid chain, it produces 1 NADH and 1 FADH2. Each double carbon is converted to 2 acetyl-CoA where it enters the TCA cycle and produces another 6 NADH and 2 FADH2. However, a monounsaturated and polyunsaturated fat doesn’t produce a FADH2 and NADH when the double bond is cleaved during beta-oxidation. So the more unsaturated the fatty acid, the less FADH2 and NADH is produced.

So glucose give a NADH:FADH2 ratio of 5:1. And a fully saturated fatty acid such as palmatic or stearic acid give a ratio of 3:1.

So what does this matter?

Well, NADH donates its electron at complex I in the electron transport chain, where the electron then flows through complex II and III to IV and V.

FADH2 donates its electrons at complex II (succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR)) in the electron transport chain. This acts as a blockage for electrons flowing from complex I. This causes electrons to reverse flow through complex I and produce free radicals, ROS (reactive oxygen species). The more unsaturated the fatty acid is, the less FADH2 is being produced, less reverse electron flow is happening and the less ROS is produced.

Does this mean PUFAs are prefered over saturated fats?

Absolutely not! Here are three reasons:

1) The ROS produced during the oxidation of saturated fat stimulate mitochondrial biogenesis so that you can produce brand new mitochondrias. New, perfect mitochondiras mean better energy production and less waste production and nutrient wastage/loss.

2) The more ROS are producted the more insulin resistance you’ll become. SFAs = insulin resistance, PUFAs = insulin sensitivity. During “starvation” such as during a ketogenic diet, you don’t want all the tissue to be insulin sensitive and to take up glucose. There will be a very limited amount of glucose around, of which you want to be used by the tissue that need it, such as the brain. This is a very effective survival mechanism and is very much needed. And when your tissue are insulin resistant, those tissue (such as the adipose tissue) can’t take up nutrients and become fat. It helps you to stay/become lean. SFA will lead to much better blood glucose homeostasis.

3) The ROS that is produced can react with unsaturated fats and cause lipid peroxidation and severe mitochondrial damage, lipofuscin formation, etc… Basically bad stuff. This brings us to our next point, lipid peroxidation.


Lipid peroxidation

Increased ingestion of linoleic and arachidonic acid increases prostaglandins. Linoleic is converted to arachondonic, which is the precursor to prostaglandins. Arachidonic acid is found in cell membranes (phospholipids) and is cleaved by phospholipase A2, from the sn-2 position. Arachidonic acid is then converted via COX to the eicasanoids, which is then converted to a variety of prostaglandins. Estrogen, inflammation (IL-6, IFN-a, γ-interferon, etc) and 5-HT2 receptor activation increase phospholipase A2 and COX, resulting in an increase sythesis of PGs. Arachidonic acid creates PGE2, F2a, D2 etc, where are EPA (fish oil) creates PGE3, which is about a 1/4 as strong as E2, which is much less damaging than omega 6, hence the “anti-inflammatory” properties of omega 3. However, fish oils leads to CVD, inhibit androgens receptors, etc, but that is for another post.


So, does the increase in SFA and PUFAs affect you negatively or positively during a ketogenic diet?

When carbohydrates are very low, you start generating ketones. This increase in ketones 1) increase the NAD/NADH ratio (which is one of the best indicator of general health), 2) enhances mitochondrial respiration in neocortical neurons (this mechanism may, in part, contribute to the neuroprotective activity of ketones by restoring normal bioenergetic function in the face of oxidative stress. (1)), 3) enhances mitochondrial antioxidant status, (2) by increasing GSH biosynthesis, through its inhibitory action on histone deacetylases and activation of the Nrf2 pathway (3) (GSH is a major mitochondrial antioxidant that protects mitochondrial DNA (mtDNA) against oxidative damage), glutathione peroxidase (GPx) (a peroxidase found in erythrocytes that prevents lipid peroxidation), catalase,  NAD(P)H dehydrogenase quinone 1 (NQO1) and superoxide dismutase (SOD1/2). (4)

Further ketones reduces levels of reactive oxygen species and increases ATP availability. This reduction in ROS is due to increase uncoupling. Only fats are able to increase uncoupling proteins. UCP1 is expressed in brown adipose tissue and UCP3 is expressed in the muscle. Long chain fatty acids increase those proteins, whereas medium chain triglycerides (MCT) don’t. Uncoupling (proton leak) leads to less reactive oxygen species (ROS) production, as protons are now “leaking” into the mitochondria and is not used to produce ATP, but heat instead. Although this “mild” uncoupling may incur a small reduction in ATP generated through oxidative phosphorylation, its overall net effect is to enhance respiration and ATP levels through a reduction in reactive oxygen species formation

During ketosis, there is a decrease in malondialdehyde (MDA), which is a marker of lipid peroxidation and oxidative stress, although there is a significant increase in MDA during non-ketosis. (5) Also, there is a significant decrease in inflammatory markers despite a marked increase in plasma arachidonic acid during a low carb diet (6). The metabolic intermediates in the production of arachidonic acid are decreased suggesting that synthesis is not increased. According to the study, this effect is rather that the increase was due to better preservation of arachidonic and that there is a significant inverse correlation between changes in urine 8-iso PGF (which is a marker of oxidative stress) and phospholipid arachidonic acid. (7) (Side note: PGF is necessary for muscle regeneration of adaption.) Ketogenic diets reduce lipid peroxidation and oxidative stress, despite the fact of significant increases in arachidonic acid in cell membranes.

Fatty acids only increase peroxisome proliferator activated receptors (PPAR) which are anti-inflammatory. Circulating free fatty acids, (longer chains, 16-20 carbons, with a double bond or two), increase PPARα. PPARα has analgesic properties and reduces iNOS and inflammation, and also COX. PPARα reduces pain and inflammation and further inhibits the release of several pro-inflammatory and pro-angiogenic enzymes (e.g., iNOS, chymase, and metalloproteinase MMP-9), and mediators (e.g., NO and TNF-α).(8, 9) So PPARα helps to prevent lipid peroxidation, by lowering COX and inflammation.

Another prostaglandin ,15d-PGJ2 (Arachidonic acid → PGG2 → PGH2 → PGD2 → PGJ2), have anti-inflammatory properties, as 15d-PGJ2 is recognized as the endogenous ligand for the intranuclear receptor PPARγ (this property is responsible for many of the 15d-PGJ2 anti-inflammatory functions) (10) and inhibition of nuclear factor-kappaB (NF-kappaB).

Classic inhibitors of PG synthesis such as nonselective and cyclooxygenase-2 (COX-2) selective inhibitors (nonsteroidal anti-inflammatory drugs) may actually prolong inflammation when administered during the resolution phase. These effects may regulate not only tissue inflammation but also vascular disease (11)

Ketones, such as HMB, inhibits the NLRP3 inflammasome in a manner that is independent of starvation-induced mechanisms such as AMPK, autophagy, or glycolytic inhibition. The NLRP3 inflammasome is responsible for the cleavage of procaspase-1 into caspase-1 and the activation of the cytokines IL-1β and IL-18. Its inhibition prevents IL-1β and IL-18 generation and their downstream effects (12).


It’s also a great idea to combine ketogenic diet with high intensity training (HIT, such as sprints, weight training) as HIT causes a decrease of ω6/ω3 in phospholipids. This reduces exercise-induces inflammatory responses. This also leads to an increase in stearic acid insertion for membrane lipid regeneration. The more saturated your cell membranes, the more stable and rigid your cells are, which makes them more resistant to harm, less lipid peroxidation, more resistant to water soluble steroids (such as estrogen) and a greater affinity to lipophilic steroids (such as testosterone and DHT) (13)


Taken together

A ketogenic diet results in less ROS production, more ATP, uncoupling, reduces inflammation and reduced lipid peroxidation and above all creates new mitochondrias. Remember, without or with broken mitochondrias, you’ll have insufficient energy production and disease follows after that.

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