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I am studying biochemistry right now and I am having a little trouble as to understanding ketone body metabolism. I have understood the steps and all but just cannot seem to link it with Fatty Acid Metabolism and thus, fail to understand the following concept::

Why do we need Ketone Bodies in the first Place? Aren't they just Fatty acids being used to make Ketone bodies which later become Acetyl CoA in the tissues? Isn't that what beta-oxidation does? Produce Acetyl CoA? Why can't tissues simply oxidize Fatty Acids to generate the Acetyl CoA?

As far as I have understood, I believe that the Fatty Acids from the adipose tissues, cannot directly go to other tissues, hence they need to be converted into Ketone bodies (which can only be done by the liver). Is this at all correct? Am I missing a big link like the location of enzymes or the absence of certain processes in some cells? Please clarify this, it has been driving me insane.

P.S: I have already gone through Lippincott Biochem and Kaplan Step 1 biochem lectures. Thanks :)

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Why do we need ketone bodies?

The main role of ketone bodies is to serve as a fuel (mainly for the brain) when there are not enough dietary carbohydrates available (during a low-carbohydrate diet or fasting) to produce glucose, which is otherwise the main fuel in the human body. Additionally, ketones can be used as a fuel in untreated diabetes mellitus type 1, in which glucose is available but can't enter the cells, but ketones can.

During fasting, your liver and kidneys (but not other organs) can produce some glucose by gluconeogenesis from glucogenic amino acids (from your body protein), glycerol (from your body fat), lactate (from glycolysis in muscles) and from pyruvate. The amount of glucose produced by gluconeogenesis is sufficient to meet the demands of organs that can use glucose as the only fuel (the testes, renal medulla and erythrocytes), but not the brain (which needs ~120 g glucose/day). The brain can use ketones, but not fatty acids,

...because they are bound to albumin in plasma and so do not traverse the blood-brain barrier (Biochemistry, J.M. Berg, 2002).

Fatty acids can go from adipose to other tissues.

After triglyceride breakdown (lipolysis) in the adipose (or other) tissue, fatty acids can leave the cells and can be delivered to other tissues (but not the brain) and can be used as a fuel:

...lipolysis occurs in essentially all tissues and cell types, it is most abundant, however, in white and brown adipose tissue...Upon increased energy demand, TAG stores are mobilized by their hydrolytic cleavage and the resulting NEFAs are delivered via the circulation to peripheral tissues for β-oxidation and ATP production. (TAG = triglycerides, NEFA = non-esterified fatty acids; Progression in Lipid Research)

The major fuels for muscle are glucose, fatty acids, and ketone bodies (Biochemistry, J.M. Berg, 2002).

Normal fatty acid metabolism

In short, the catabolic part of fatty acid metabolism consists of beta oxidation of fatty acids, which yields acetyl-CoA...

The acetyl-CoA produced by beta oxidation enters the citric acid cycle in the mitochondrion by combining with oxaloacetate to form citrate. This results in the complete combustion of the acetyl-CoA to CO2 and water...This is the fate of acetyl-CoA wherever beta oxidation of fatty acids occurs, except under certain circumstances in the liver...

During fasting, fatty acids breakdown after beta oxidation is diverted from citric cycle toward ketogenesis.

...In the liver oxaloacetate can be wholly or partially diverted into the gluconeogenic pathway during fasting, starvation, a low carbohydrate diet, prolonged strenuous exercise, and in uncontrolled type 1 diabetes mellitus. Under these circumstances oxaloacetate is hydrogenated to malate which is then removed from the mitochondria of the liver cells to be converted into glucose in the cytoplasm of the liver cells, from where it is released into the blood. In the liver, therefore, oxaloacetate is unavailable for condensation with acetyl-CoA when significant gluconeogenesis has been stimulated by low (or absent) insulin and high glucagon concentrations in the blood. Under these circumstances acetyl-CoA is diverted to the formation of acetoacetate and beta-hydroxybutyrate...and their spontaneous breakdown product, acetone, known as ketone bodies. The ketones are released by the liver into the blood. All cells with mitochondria can take ketones up from the blood and reconvert them into acetyl-CoA, which can then be used as fuel in their citric acid cycles, as no other tissue can divert its oxaloacetate into the gluconeogenic pathway in the way that this can occur in the liver. Unlike free fatty acids, ketones can cross the blood-brain barrier and are therefore available as fuel for the cells of the central nervous system, acting as a substitute for glucose, on which these cells normally survive.

  • omg thanks a ton. you saved my sanity – abacus143 Nov 26 '19 at 11:10

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