Skip to main content
Biology LibreTexts

9.6: Ketone body production and acidosis

  • Page ID
  • \( \newcommand{\vecs}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}} } \) \( \newcommand{\vecd}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash {#1}}} \)\(\newcommand{\id}{\mathrm{id}}\) \( \newcommand{\Span}{\mathrm{span}}\) \( \newcommand{\kernel}{\mathrm{null}\,}\) \( \newcommand{\range}{\mathrm{range}\,}\) \( \newcommand{\RealPart}{\mathrm{Re}}\) \( \newcommand{\ImaginaryPart}{\mathrm{Im}}\) \( \newcommand{\Argument}{\mathrm{Arg}}\) \( \newcommand{\norm}[1]{\| #1 \|}\) \( \newcommand{\inner}[2]{\langle #1, #2 \rangle}\) \( \newcommand{\Span}{\mathrm{span}}\) \(\newcommand{\id}{\mathrm{id}}\) \( \newcommand{\Span}{\mathrm{span}}\) \( \newcommand{\kernel}{\mathrm{null}\,}\) \( \newcommand{\range}{\mathrm{range}\,}\) \( \newcommand{\RealPart}{\mathrm{Re}}\) \( \newcommand{\ImaginaryPart}{\mathrm{Im}}\) \( \newcommand{\Argument}{\mathrm{Arg}}\) \( \newcommand{\norm}[1]{\| #1 \|}\) \( \newcommand{\inner}[2]{\langle #1, #2 \rangle}\) \( \newcommand{\Span}{\mathrm{span}}\)

    Source: BiochemFFA_6_2.pdf. The entire textbook is available for free from the authors at

    Ketone body metabolism

    Ketone bodies are molecules made when the blood levels of glucose fall very low. Ketone bodies can be converted to acetyl-CoA by reversing the reaction of the pathway that makes them (Figure 6.78). Acetyl CoA, of course, can be used for ATP synthesis via the citric acid cycle. People who are very hypoglycemic (including some diabetics) will produce ketone bodies (Figure 6.79) and these are often first detected by the smell of acetone on their breath.

    Figure 6.78 Ketone body metabolism. Image by Pehr Jacobson
    Figure 6.79 - Three ketone bodies - acetone (top), acetoacetic acid (middle), and β-hydroxybutyrate (bottom)

    Overlapping pathways

    The pathways for ketone body synthesis and cholesterol biosynthesis (Figure 6.80 and see HERE) overlap at the beginning. Each of these starts by combining two acetyl-CoAs together to make acetoacetyl-CoA. Not coincidentally, that is the next to last product of β-oxidation of fatty acids with even numbers of carbons (see HERE for fatty acid oxidation). In fact, the enzyme that catalyzes the joining is the same as the one that catalyzes its breakage in fatty acid oxidation – thiolase. Thus, these pathways start by reversing the last step of the last round of fatty acid oxidation.

    Figure 6.80 - Diverging biosynthetic pathways for ketone bodies (left) and cholesterol biosynthesis (right). Image by Penelope Irving

    HMG-CoA formation

    Both pathways also include addition of two more carbons to acetoacetyl-CoA from a third acetyl-CoA to form hydroxy-methyl-glutaryl-CoA, or HMG-CoA, as it is more commonly known. It is at this point that the two pathways diverge. HMG-CoA is a branch point between the two pathway and can either go on to become cholesterol or ketone bodies. In the latter pathway, HMG-CoA is broken down into acetyl-CoA and acetoacetate.

    Acetoacetate is itself a ketone body and can be reduced to form another one, D-β-hydroxybutyrate (not actually a ketone, though). Alternatively, acetoacetate can be converted into acetone. This latter reaction can occur either spontaneously or via catalysis by acetoacetate decarboxylase. Acetone can be converted into pyruvate and pyruvate can be made into glucose.

    D-β-hydroxybutyrate travels readily in the blood and crosses the blood-brain barrier. It can be oxidized back to acetoacetate, converted to acetoacetyl-CoA, and then broken down to two molecules of acetyl-CoA for oxidation in the citric acid cycle.


    When a body is producing ketone bodies for its energy, this state in the body is known as ketosis. Formation of ketone bodies in the liver is critical. Normally glucose is the body’s primary energy source. It comes from the diet, from the breakdown of storage carbohydrates, such as glycogen, or from glucose synthesis (gluconeogenesis). Since the primary stores of glycogen are in muscles and liver and since gluconeogenesis occurs only in liver, kidney, and gametes, when the supply of glucose is interrupted for any reason, the liver must supply an alternate energy source.

    From fatty acid breakdown

    In contrast to glucose, ketone bodies can be made in animals from the breakdown of fat/fatty acids. Most cells of the body can use ketone bodies as energy sources. Ketosis may arise from fasting, a very low carbohydrate diet or, in some cases, diabetes.


    The term acidosis refers to conditions in the body where the pH of arterial blood drops below 7.35. It is the opposite of the condition of alkalosis, where the pH of the arterial blood rises above 7.45. Normally, the pH of the blood stays in this narrow pH range. pH values of the blood lower than 6.8 or higher than 7.8 can cause irreversible damage and may be fatal. Acidosis may have roots in metabolism (metabolic acidosis) or in respiration (respiratory acidosis).

    There are several causes of acidosis. In metabolic acidosis, production of excess lactic acid or failure of the kidneys to excrete acid can cause blood pH to drop. Lactic acid is produced in the body when oxygen is limiting, so anything that interferes with oxygen delivery may create conditions favoring production of excess lactic acid. These may include restrictions in the movement of blood to target tissues, resulting in hypoxia (low oxygen conditions) or decreases in blood volume. Issues with blood movement can result from heart problems, low blood pressure, or hemorrhaging.

    Strenuous exercise can also result in production of lactic acid due to the inability of the blood supply to deliver oxygen as fast as tissues require it (hypovolemic shock). At the end of the exercise, though, the oxygen supply via the blood system quickly catches up.

    Respiratory acidosis arises from accumulation of carbon dioxide in the blood. Causes include hypoventilation, pulmonary problems, emphysema, asthma, and severe pneumonia.


    Figure 6.81 - Symptoms of acidosis

    9.6: Ketone body production and acidosis is shared under a CC BY-NC-SA license and was authored, remixed, and/or curated by Kevin Ahern, Indira Rajagopal, & Taralyn Tan.