Sirtuins

Question 1

What do sirtuins sense?

Answer 1

Cellular NAD+ fluctuation

Question 2

Briefly describe what sirtuins are

Answer 2

• A family of histone/protein deacetylase - removes acetyl groups from proteins
• Use NAD+ as a cofactor (so can sense intracellular energy change)
• 7 members of Sirtuins in mammals; Sirt1 is most studied

Question 3

What are Sirtuins’ main function?

Answer 3

To remove acetyl group from proteins (deacetylation) to regulate protein function
- post-translational modification of a protein’s function

Question 4

Give the general reaction catalyzed by Sirt1 using NAD+ as a cofactor

Answer 4

Sirt1 removes an acetyl group from target protein and modifies their function; NAD+ is a physiological activator of Sirt1

Question 5

Name some environmental changes/changes in nutrient availability that would result in NAD+ levels rising (activating Sirt1)

Answer 5

• Fasting
• Calorie restriction
• Exercise
• Chemical activators

Question 6

How does fasting or calorie restriction activate Sirt1?

Answer 6

During these times cellular NAD+ concentration is elevated due to inactive glycolysis pathway

Question 7

What effect does Sirt1 activation have on metabolism in the liver? Muscle? Adipose tissue?

Answer 7

Liver:
• Promotes gluconeogenesis
• Regulates lipid metabolism

Muscle:
• Promotes fatty acid oxidation

Adipose:
• Less well studied - induces browning, promotes fat mobilization

Question 8

Describe how Sirt1 activation promotes gluconeogenesis in the liver during prolonged fasting

Answer 8

• Sirt 1 mediates CRTC2 deacetylation, targeting it for destruction and blocking CREB (short-term fasting transcription factor; *same thing AMPK does)
• Then it de-acetylates (activating) a coactivator for FOX01, promoting gluconeogenesis

Question 9

How does Sirt1 activation regulate lipid metabolism in the liver during fasting?

Answer 9

• Sirt1 deacetylates SREBP1 (lipogenesis master regulator) and targets the protein for destruction —> suppressed fatty acid and cholesterol synthesis
• Promotes reverse cholesterol transport by increasing gene expression of ATP-binding cassette transporter 1 (ABCA1)
• Enhances fatty acid oxidation by inducing mitochondrial biogenesis

Question 10

How does Sirt1 activation promote fatty acid oxidation in muscles? Explain the link to AMPK.

Answer 10

• In skeletal muscle, fasting and exercise induce a switch from CHO –> lipid use (NAD+ rises, as does AMP levels)
• Sirt1 is activated and deacetylates (activates) PGC-1a, inducing mitochondrial biogenesis and FA oxidation
• AMPK is also activated, activating PGC-1a
• These two activations increases mitochondrial biogenesis and FA oxidation in muscle
• Sirt1 and AMPK amplify each other - AMPK can increase NAD+ levels and Sirt1 can AMPK through deacetylation

Question 11

How does Sirt1 affect metabolic regulation in adipose tissue?

Answer 11

• Not very studied
• Increases adiponectin expression and secretion
• Promotes fat mobilization
• Induces browning

Question 12

Describe Sirtuin activation’s link to calorie restriction results

Answer 12

• Sirt1 knockout mice do not live longer on a CR diet
• Sirt1 activators, such as RESVERATROL, exert effects similar to those of CR
• Aging assoc with declined intracellular NAD+ levels