Inflammation is a biological mechanism our bodies use to deal with internal and external events, such as combatting infections, repairing tissues or mitigating the immediate consequences of a fractured bone.
However, it often carries a negative connotation since many diseases provoke symptoms through the process of inflammation.
So although it is absolutely necessary for keeping the human body functioning properly, like so many things in biology, too much or too little is the problem. Inflammation can be managed with and without drugs.
We will focus on ketogenesis and ketones with regards to treating inflammation.
What is ketogenesis?
Ketogenesis is a series of biochemical reactions that builds ketones from parts of other ones (like 2 acetyl-CoA molecules).
How ketone bodies are formed?
The liver is where fat is used as the raw material to produce the ketone D- β –hydroxybutyrate.
Once you’ve produced enough ketones by upregulating** ketogenesis, you eventually move into a metabolic state called ketosis. People are in ketosis when they are on a ketogenic diet or fasting.
** Upregulating: increasing responsiveness by increasing the number of receptors on the cells.
Ketogenesis
Consuming very few calories or carbohydrates releases the main metabolic break that was stopping your body from producing ketones unnecessarily. The decision to make ketones or not happens at the metabolic ‘roundabout’ in our body.
Please see the image of the traffic roundabout.
This roundabout is called the Krebs cycle, or the TCA cycle (tricarboxylic acid cycle). The TCA cycle acts more like a traffic circle on a busy highway in which the flow of cars into the circle must be balanced by the flow out.
Keeping with this analogy, ketogenesis results from changes in the balance of cars entering and exiting the roundabout. Specifically, when the ratio of Oxaloacetate to Acetyl-CoA drops below 1, more and more fats get turned into ketones.
How are ketones metabolized?
Your body builds ketones in the liver (ketogenesis), uses them up in other tissues (ketolysis). Ketolysis is the process where ketones are broken down into smaller molecular units that get consumed.
Ketones are fully metabolized by a series of enzymes that break them down into acetyl-CoA molecules, which produce the energy currency of your cells, ATP.
What does ketosis do to the body?
Ketosis is a metabolic state that helps to handle long fasts and carbohydrate restriction. Ketogenesis is an important adaptation our ancestors evolved to help them get through ice ages. Humans developed the ability to store lots of energy as body fat that turned into energy-efficient molecules [6,7].
Please see the image Table 23-5 Available Metabolic Fuels in a Normal-Weight 70 kg Man and in an Obese 140 kg Man at the Beginning of a Fast.
Please notice each of the men would survive without food in this table. [8]
Ketones are also signaling molecules. They play a role in how the nervous system manages energy use during periods of fasting [9].
Ketones also affect inflammatory processes and structures. One structure is the NLRP3 inflammasome.
What’s the NLRP3 inflammasome?
It is part of theinnate immune system, the defence system we have to react quickly and non-specifically to biological threats, such as a sudden infection from a wound.
It mediates the release of cytokines by the NLRP3 inflammasome. It can also give the go-ahead for cells to activate caspase-1, a major switch used by the cell to decide whether or not to commit suicide.
The NLRP3 inflammasome senses threats, which may be toxins such as too much glucose. It may be mitigated somewhat by stimulating ketogenesis to help dampen the activity of this inflammasome. Ketogenesis can be engaged by eating a high-fat diet low in carbohydrates and by fasting (intermittently) or for longer periods of time.
How does ketogenesis or ketones modulate the NLRP3 inflammasome?
The ketone body β-hydroxybutyrate, (BhB) sticks to the NLRP3 inflammasome and stops it from firing the cytokines that are causing inflammation. It also stops the inflammasome from activating the caspase-1 switch [11].
What diseases or conditions could benefit from dampening NLRP3-mediated inflammation?
Obesity – The fat tissue of people with severe obesity is highly inflamed due mainly to the activity of the NLRP3 inflammasome [13].
The figure below depicts imbalances in the elements listed on the left-hand side leading to insulin resistance via NLRP3 inflammasome activation, and resulting in the diseases and symptoms listed on the right-hand side [15].
Please see the image of the Nlrp3 Inflammasome and Insulin Balance below.
Rheumatoid arthritis – Rheumatoid arthritis is a condition where joints like the knees and wrists are swollen, stiff and painful. It has a major inflammatory component to it. The cytokine bullet fired by the NLRP3 inflammasome, destroys cartilage in rheumatoid arthritis.
Epilepsy (or other CNS disorders)– Epilepsy can present in many ways but generally it can be described as a strong sensory disturbance leading to convulsions and loss of consciousness. It is thought to be due to electrical disturbances in the brain since this feature very strongly correlates with seizure activity.
- There is evidence suggesting that brain cells with dysregulated production of reactive oxygen species (ROS) or inappropriate K+ efflux activate the NLRP3 inflammasome and trigger epilepsy [17].
- The human brain is particularly well suited to using ketone bodies as a major source of energy, which makes its therapeutic use for epilepsy all the more intriguing.
- Fasting or a combination of these interventions could be useful to control NLRP3-mediated inflammation
What kind of ketone-based metabolic therapy should I use?
It’s not always clear which aspect of a ketogenic diet used to reverse obesity is actually doing the work. Is it the appetite suppressing effects? Is the lowered inflammation in fat tissue normalizing local insulin signaling? Or is it a combination of both and more? And in epilepsy, is a ketone-based metabolism improving seizure control through normalized ROS signaling? Or is it due to dampened inflammation deriving from NLRP3 inflammasome activity? Whatever the case may be, there are different ketone-based approaches that are available and worth considering.
For a drug-centric approach, exogenous ketones are available, such as ketone esters and ketone salts. One advantage with exogenous ketones is it is easier and quicker to get a desired level of ketones circulating in the bloodstream than it is through dietary manipulation.
Please see my blog, Ketone Supplements: The Pros and Cons https://2healthyhabits.wordpress.com/2019/06/07/ketone-supplements-the-pros-and-cons/
For drug-free approaches, ketogenic diets or some form of fasting can generate levels of ketones that have therapeutic effects on inflammation. Fasting or intermittent-fasting is a time-tested intervention in obesity as well as epilepsy.
It is free and human physiology is well adapted to it. But it cannot be bottled and sold for profit so, it is discouraged by the food industry and medical establishment.
Ketogenic diets are cheaper than medications for epilepsy or immune therapies for rheumatoid arthritis. It is recommended that you consult dietitians or doctors that can help you implement a well-formulated ketogenic diets.
Conclusion
- Inflammation is a life-maintaining biological process. However, it needs to be kept in check and not activated chronically above a certain level or it can lead to symptoms or disease.
- It can be controlled with exogenous ketones or by being in ketosis. Their use should preferably be discussed with medical professionals beforehand, especially when suffering from a medical condition and taking medications.
This Post has been condensed from https://breaknutrition.com/how-ketogenesis-and-ketones-treat-inflammation/
Please see the original for the Footnotes and Citations for the scientific studies.
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