Lipid Metabolism › Fatty Acids

Ketone Bodies

Notes

Ketone Bodies

Sections

KETOGENESIS

  • Ketone bodies synthesized in liver only (mitochondrial matrix)
  • Occurs under 2 clinical conditions: prolonged starvation & uncontrolled diabetes
  • Substrate: excess acetyl CoA (derived from fatty acid oxidation)
  • Normal, healthy adult: excess acetyl CoA shunts to citric acid cycle or cholesterol biosynthesis

KETONE BODIES

  1. Acetoacetate
  2. Acetone
  • Volatile
  • Breathed out unused
  1. Beta-hydroxybutyrate

KETOGENIC PATHWAY

  • Fasting conditions (starvation or uncontrolled diabetes)
  1. Oxaloacetate shunts into gluconeogenesis: slows down citric acid cycle
  2. Acetyl CoA builds up and shunts into ketogenesis
  3. 2 Acetyl CoA --> Acetoacetyl CoA (acetoacetyl CoA thiolase, reversible)
  4. 1 Acetyl CoA + Acetoacetyl CoA --> HMG CoA (HMG CoA synthase)
  • Thiolase & HMG CoA synthase also in cholesterol biosynthesis (ketogenic isozymes in matrix not cytosol)
  1. HMG CoA --> Acetyl CoA + Acetoacetate (HMG CoA lyase)
  2. Acetoacetate + NAD+ --> beta-hydroxybutyrate + NADH (beta-hydroxybutyrate dehydrogenase, reversible)

KETOSIS

  • Spontaneous when [acetoacetate] is high
  • Acetoacetate --> Acetone + CO2

RATE LIMITING STEP

  • HMG CoA synthase: enzyme localized in liver
  • Activated by: fasting, increased cAMP and increased lipolysis
  • Inhibited by: feeding & insulin

TARGET CELL KETONE BODY USE

  • Cells that can use ketone bodies
  • Include: cardiac/skeletal muscle, renal cortex, intestinal mucosa, brain cells in starvation
  • Ketone bodies can cross blood brain barrier: do NOT bind albumin (fatty acids do)
  • Mobilized in matrix

Enzyme beta-ketoacyl CoA transferase

  • NOT in liver (liver cannot mobilize ketone bodies)
  • Acetoacetate + succinyl CoA --> acetoacetyl CoA + succinate (reversible)
  • Remaining reactions are the reverse of ketogenesis

CLINICAL CORRELATION

Untreated diabetics

  • Have fruity breath due to exhalation of acetone (ketosis)
  • Decreased cellular glucose and CAC intermediates leads to inc. FA mobilization & acetyl CoA
  • Excess acetyl CoA shunts into ketogenesis

Full-Length Text

  • Here we will learn about ketone bodies, which function as an alternative source of fuel when blood glucose levels are low.
  • To begin, start a table to learn some key features of ketone bodies.
  • Denote that they are synthesized in the liver, and at the cellular level, the mitochondrial matrix.
  • Two common clinical causes of ketogenesis are prolonged starvation uncontrolled diabetes.
  • The substrate is excess acetyl CoA.
  • It's derived from fatty acid oxidation.
  • Most of the acetyl CoA released from fatty acid oxidation enters the citric acid cycle or cholesterol biosynthesis.

Now, let's learn the ketogenic pathway.

  • First draw a portion of a mitochondrion within a liver cell and label the matrix.
  • Now, within the matrix, draw a circle of arrows to represent the citric acid cycle and include the intermediate oxaloacetate.

Next, let's see what happens in conditions that promote ketogenesis, such as: periods of starvation or uncontrolled diabetes.

  • Show that oxaloacetate shunts into gluconeogenesis, thus slowing the citric acid cycle.
  • In these conditions gluconeogenesis is favored over glucose breakdown, so the citric acid cycle slows down.
  • Show that acetyl CoA builds up in the cell and shunts into ketogenesis.

Let's illustrate ketogenesis, now.

  • First, draw the Lewis structure for acetyl CoA.
  • Show that 2 acetyl CoA molecules reversibly combine to form acetoacetyl CoA.
  • Again, draw the Lewis structure.
  • Indicate that acetoacetyl CoA thiolase (often referred to as just "thiolase") catalyzes this reaction.
  • Next, show that a third acetyl CoA combines with acetoacetyl CoA to form 3-hydroxy-3-methylglutaryl (HMG) CoA.
  • Indicate that HMG CoA synthase catalyzes this second reaction.
  • Now, highlight the first two enzymes and indicate that they are also the first two enzymes in cholesterol biosynthesis.
  • However, write that these isozymes are localized in the matrix as opposed to the cytosol.
    • Cholesterol biosynthesis and ketone body synthesis share early intermediates and enzymes, but are separated within the cell.
  • Now, write that mitochondrial HMG CoA synthase is only found in the liver.
    • Thus, only the liver can synthesize ketone bodies.
  • Now, for the third step, indicate that HMG CoA lyase cleaves HMG CoA to produce acetyl CoA and acetoacetate.
  • Circle it to indicate that acetoacetate is the first ketone body.
  • Finally, show that beta-hydroxybutyrate dehydrogenase reversibly reduces acetoacetate to produce beta-hydroxybutyrate.
  • Circle this product; it is our second ketone body.
  • Show that NADH is the reducing power.
  • Finally, indicate that when the acetoacetate concentration is high, it spontaneously decarboxylates to form acetone, the last ketone body.
    • Label this spontaneous reaction "ketosis."
  • Write that acetone is very volatile and not used for energy like the other ketone bodies; it is breathed out through the lungs, instead.
  • As a clinical correlation, write that ketosis occurs in untreated diabetic patients, and that the increased acetone production produces a sweet, fruity odor on the patient's breath. We will learn more about this shortly.

Finally, let's illustrate how and when ketone bodies are used.

We'll start with the when.

  • Indicate that HMG CoA synthase is the rate-limiting step in ketone body synthesis.
  • Show that the following conditions increase the rate of its transcription, and thus upregulate ketogenesis:
    • Fasting.
    • A rise in cAMP, which is a marker of low blood glucose.
    • Increased lipolysis, which produces the ketogenic substrate acetyl CoA.
  • Show that feeding and insulin decrease HMG CoA synthase transcription.

Let's take a closer look at this concept.

  • As a clinical correlation, write that untreated diabetics have low cellular glucose because they lack insulin (or insulin sensitivity). As a result, citric acid cycle intermediates are not replenished.
    • Simultaneously, the absence of insulin upregulates fatty acid mobilization.
    • However, without citric acid cycle intermediates, acetyl CoA accumulates in the cell and is shunted into ketone body synthesis.
    • This explains why ketosis is a telltale symptom in untreated diabetics.

Now, let's illustrate how ketone bodies are used.

  • Draw a vessel and show that it leads to a target cell mitochondrion.
  • Now, return to our table to list some cells that can use ketone bodies for energy.
  • Denote that the target cell may be cardiac or skeletal muscle, the renal cortex, or intestinal mucosa.
  • Denote that it may also be a brain cell during starvation.
  • Now, draw beta-hydroxybutyrate (a ketone body).
  • Show that beta-hydroxybutyrate dehydrogenase reversibly converts it to acetoacetate, the second ketone body.
    • This reaction proceeds in the opposite direction in ketogenesis.
  • Indicate that this time, one NADH is produced.
  • For the next step, draw a circle of arrows to represent the citric acid cycle, and this time include the intermediate succinyl CoA.
  • Show that acetoacetate reversibly converts to acetoacetyl CoA.
  • Now, show that succinyl CoA donates its coenzyme to become succinate.
  • Indicate that the enzyme beta-ketoacyl CoA transferase catalyzes this reaction.
    • This enzyme is often called CoA transferase.
  • Importantly, write that this enzyme does not occur in the liver.
    • Thus, the liver is the only organ that can synthesize ketone bodies, but it cannot use them for energy, itself!
  • Finally, illustrate that thiolase reversibly converts acetoacetyl CoA to two acetyl CoA molecules.
    • Again, the reverse reaction occurs in ketogenesis.

Now, you might be wondering how the brain can use ketone bodies for energy, when it can't use fatty acids.

  • Write that fatty acids bind to albumin in circulation, and cannot cross the blood-brain barrier. Ketone bodies, however, can.