Unit 3- Ketone Bodies

How is OAA made in the cell (i.e what are precursor molecules → OAA)

1. Glucose→ pyruvate (glycolysis)

2. glycerol→ DHAP → pyruvate

3. Odd chain FA→ propionyl → succinyl coA→ OAA at the top through TCA cycle

4. fermentation where lactate→ pyruvate

5. glycogenic aas (can be converted to glucose)→ TCA cycle

Under fasting/starvation conditions what occurs

• TAGs broken down → glycerol + FAs

• These products (via albumin) are transported by blood→ other tissues where they can be catabolized for fuel

• BUT under starvation glycogen stores only provide day’s worth of energy

  • liver must make glucose to supply rest of body

In the liver what process occurs that converts glycerol to glucose?

• GNG (gluconeogenesis) under starvation conditions or decrease [blood sugar]

  • Glycerol→ DHAP→ glucose

In the liver (fasting/starvation condtns) FAs will undergo

• B-oxidation → acetyl coAs

• BUT only a small amount of these acetyl coAs will enter the citric acid cycle in LIVER

Why do most of acetyl coAs gen in liver (under starv/fasting condtns) not enter the citric acid cycle (CAC)

• under starvation/fasting (↓ [blood glucose]) there’s a lack of OAA in liver cells (bc its getting diverted and depleted to make glucose via GNG) so acetyl coA doesn’t enter TCA cycle in large amounts

  • since acetyl coA binds with OAA→ citrate

• So we make KBs bc we have lots of acetyl coA

In liver cells what happens with OAA during starvation/untreated diabetes (why is there no net gain of OAA)

• OAA removed from TCA cycle and used to make glucose via GNG

Can acetyl coA alone be used to make glucose?

• NO

• acetyl coA cannot be used to make a net gain of OAA or glucose

GNG in liver brief overview

• Pyruvate→ PEP→ DHAP→Glucose

• OAA feed back in → PEP→ DHAP→ glucose

• Glycerol phosphorylated + oxidized → DHAP→ glucose

Where are ketone bodies produced and exported

• produced in liver (from acetyl coA)( in MT matrix)

• exported into bloodstream to other tissues that use KBs for fuel like

  • heart

  • renal cortex

  • brain

  • skeletal muscle

The ketone bodies that are formed are (know structures and names)

1. Acetone

• Produced in smaller amounts and exhaled

1. Acetoacetate

2. D-B-hydroxybutyrate

• both are transported to tissues other than the liver like skeletal and heart muscle, renal cortex, and brain

these are blood friendly versions of acetyl coA

Why can’t brain use free FAs for energy?

• need to send KBs to brain if low on glucose (what we usually send) bc FAs too large to pass through BB barrier

Ketone body synthesis (liver)

What molecules combine to form acetoacetyl coA

• 2 acetyl coA combine→ acetoacetyl coA

  • this is reverse rxn of last step of B-ox (thiolysis)

• Enzyme- thiolase

Ketone body synthesis (liver)

• Acetoacetyl coA then ….

• condenses w/ another acetyl coA→ HMG-coA

  • a coA produced in this step

• Enzyme= HGM-CoA synthase

Ketone body synthesis (liver)

• HMG-CoA is cleaved to form

• The K.B acetoacetate

• Acetyl coA also produced

• enzyme= HMG-CoA lysase

Ketone Body Synthesis (liver)

• the other 2 kbs (acetone and D-B-hydroxybutyrate) are produced from ..

• Acetone: acetoacetate through decarboxylation

• D-B-Hydroxybutyrate: using 1 NADH reducing equiv

• Then ketone bodies exported→ extrahepatic tissues as fuel sources

Why is it important to regen coA in liver when KBs being made?

• Need CoA to continue B-oxidation of FAs in liver

• bc CoA needed in last step of B-oxidation (thiolysis)

What determines whether acetoacetate or D-B-hydroxybutyrate is made from HMG-CoA?

• Ratio of NADH: NAD+ in cell (le chateliers principle)

• if have high NADH then favors D-B-hydroybutyrate

• if have high NAD+ then favors acetoacetate

Which KB is more oxidized, acetoacetate or D-B-hydroxybutyrate?

• Acetoacetate more oxidized

  • has double bond to O

So summary of during sever starvation or untreated diabetes

• liver performs GNG→ supply extrahepatic tissue w/ glucose

• Liver also oxidized FAs(B-ox)→ acetyl coA→ Ketone bodies

all being stimulated by glucagon (lipolysis, B-ox of the FAs, then KB synthesis, and GNG)

When the ketone body D β-hydroxybutyrate arrives at extrahepatic tissue (tissue outside liver) it is

• oxidized (+1 NADH reducing equiv made) to form acetoacetate

If acetoacetate arrives at the extrahepatic tissue then it

• doesnt need to be oxidized

Then after 2 enzymatic steps acetoacetate made into

• 2 acetyl coA molecules

• the acetyl coA can enter CAC of extrahepatic tissues

Why do liver cells express very low levels of B-ketoacyl-coA transferase?

• To prevent futile cycle in liver bc we dont wanna be synthesizing AND using ketone bodies at the same time

• this enzyme is breaking down KBs for energy in extrahepatic tissues

Where do extrahepatic tissues get OAA during severe starvation?

• extrahepatic tissues get enough glucose from liver (oprah)

• convert glucose→ OAA therefore acetyl coA made from KBs can enter TCA cycle in extrahepatic tissues ONLY

Ketogenesis needs what in diet

1. Lots FAs, proteins

2. Low glucose, starch diet

pushes body into ketone body synthesis

Which of the following conditions/states would NOT promote ketogenesis (the production of ketone bodies)?

A. An individual performing a marathon run.

B. An individual consuming a high carbohydrate/low fat diet.

C. An individual consuming a low carbohydrate/high fat diet.

D. An individual who is fasting for more than 24 hours.

E. An individual suffering from untreated diabetes.

B→ have lots of stores then

Why do rats fed odd-chain fatty acids (heptanoic acid, C7:0) remain healthy and gain weight, while those fed even-chain fatty acids (octanoic acid, C8:0) lose muscle mass and weaken when used as their sole carbon source?

• odd-Chain Fatty Acid (C7:0)→ propionyl-CoA during B-oxidation, which → to succinyl-CoA and yields net oxaloacetate for gluconeogenesis

  • The rats stay healthy because they can synthesize glucose from their diet.

• Even-Chain Fatty Acid (C8:0)→ only acetyl-CoA, whose carbons are lost as Co2 in the citric acid cycle.

  • Mammals cannot convert acetyl-CoA into glucose.

  • Because brain and blood cells require glucose, the C8:0 group must break down muscle proteins for gluconeogenic amino acids, leading to severe muscle loss and weakness.

What’s ketoacidosis

• if prolonged starvation or untrated diabetes continues acetyl coA will continue to accumulate (bc cant be oxidized in CAC as OAA being used for GNG)

• this results in increased conc of KBs in blood which are acidic decreasing blood pH→ coma or death