Ketogenesis & Ketolysis

The buzz, every now and again, surrounds the latest diet fads. In this article, we will not cover the ketogenic diet, but rather, the physiological and bioenergetic state the diet leads to in humans. If you would like to know the physiology of the inter-organ play, as well as the enzymatic reactions of the ketogenic state, you have found the right article.

What is Ketogenesis?

Ketogenesis is a point at which the body uses fatty acids from the blood stream to synthesize energy containing molecules called ketones.

Why does it occur?

It occurs when serum glucose levels are not being maintained by nutrition, leading the liver to produce an alternative form of energy for, primarily, the brain [2].

Understanding the Physiology

Although one could argue it, it is appreciated that the brain is the most important organ of the body and all efforts should be made to maintain its existence. So, as humans are not continuously consuming carbohydrates, or a person is not always eating, period, there must be another source of energy the body can use for energy; that form of energy is fat. However, while most cells can use fatty acids as energy, and the brain can as well, the brain does not use fatty acids readily, because of a variety of reasons, but a few of the plausible ones being the higher demand for oxygen when metabolizing fat, severe oxidative stress from fat metabolism (in the lack of a strong antioxidant defense, as seen in neurons), and ATP production is slower than that seen with glucose due to, presumably, having to undergo B-oxidation and having to cross the blood-brain barrier [3][4][15]. So, the brain needs another form of fatty acid called ketones.

Ketones are formed in a fasted state, this we know, but how?

As the fasted state extends and energy demands from the system remain constant, the adipocytes (fat cells) are stimulated to lipolyze triglycerides via the action of glucagon (note: other hormones - like epinephrine and cortisol - can also play a role), although most of these hormones are trumped by the action of insulin (glucagon to insulin ratio must be high, that is) [4][5]. So, with high circulating glucagon from the islet pancreatic cells and predictably low levels of circulating insulin, triglycerides are lipolyzed to fatty acids, glycerol from adipocytes by the action of glucagon primarily, and glycerol is also released from muscle through epinephrine, but not glucagon as muscle does not have glucagon receptors [4][6][7][8][9][10]. Fatty acids can then be used in heart, skeletal muscle, kidneys, and liver to be used as energy, while glycerol is shuttled to the liver and kidneys to undergo gluconeogenesis [6][11].

So, the focus is on the fatty acids that are de-esterified (aka, “released”) from the adipocytes, because as they make their way to the liver (primarily), kidney, intestines, and astrocytes of the nervous system, the cells take in fatty acids by CD36 and other Fatty Acid Transporters [12]. Once in the cell, they enter the mitochondria, largely by the carnitine palmitoylransforase-1 (CPT-1) transport protein, where they undergo B-oxidation in the mitochondria, just as any other fatty acid might, to eventually end up as acetyl CoA of the mitochondria to be, potentially, fed into the tricarboxylic acid cycle (TCA) [4]. This is where the determination of fatty acids being spun through the TCA for energy production via oxidative phosphorylation or the production of ketones is made. If the liver needs to maintain its own energetic state, it will run acetyl CoA through oxidative phosphorylation for ATP production. If the liver (or any other ketogenic capable tissue) needs to release ketones into circulation, it undergoes ketogenesis, described next.



In the mitochondria, acetoacetyl-CoA thiolase (ACAT), the first enzyme in ketogenesis, takes two acetyl CoA molecules and forms acetoacetyl-CoA, which is then transformed to 3-hydroxy-3-methylglytaryl-CoA (HMG CoA) via the further attachment of an acetyl CoA by the enzyme mitochondrial HMG-CoA synthetase [2][4]. HMG CoA then loses an acetyl CoA and the molecule is slightly restructured to yield the removed acetyl CoA to be recycled in TCA or in ketogenesis and an acetoacetate via the HMG CoA lyase enzyme; this acetoacetate is the first ketone body [2][4]. The majority of acetoacetate is then reduced to B-hydroxybutyrate, using an NADH, by B-hydroxybutyrate dehydrogenase, and a small amount is used to produce the ketone, acetone [2][4][13]. B-hydroxybutyrate is the third and most abundant ketone as it is the ketone that is shuttled out of the liver and undergoes ketolysis in ketone accepting tissues [2][4]. The production of acetone, of which carbon dioxide is a product, occurs spontaneously, and there is currently no known metabolic function of acetone in the body, but is exhaled via the lungs; this is a valuable marker of rampant ketone body production.


As one might assume, ketolysis is the process by which tissues that use ketones (brain, skeletal muscle, etc.) for energy. So, once ketones are exported from the ketogenic tissues, via monocarboxylate transporters (MCTs), ketones circulate in the blood stream and are then reabsorbed by tissues that need energy, and especially the brain as the brain does not process fatty acids well [2][4][14]. So, once it crosses the cell membrane of these various tissues, again using MCTs, and enters the mitochondria of the cells, ketolysis begins.

As B-hydroxybutyrate is then reconverted to acetoacetate by B-hydroxybutyrate dehydrogenase, unless the ketone leaves the ketogenic tissue as acetoacetate, it is converted to acetoacetyl-CoA by succinyl-CoA-dependent transferase (SCOT) [4]. Interestingly, the liver has very low levels of this enzyme, which leads it to not be able to metabolize its own ketones, meaning the liver produces, but never consumes [4]. Finally, acetoacetyl-CoA is cleaved into two acetyl CoA molecules by acetoacetyl-CoA thiolase (ACAT), and these two acetyl CoA molecules enter the tricarboxylic acid cycle for ATP production [4].


Writer: Nicolas Verhoeven

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