Cholesterol Biosynthesis and Keton Bodies

Question 1

What are the precursors to cholesterol?

Answer 1

Cholesterol is synthesized from acetyl-CoA.

Question 2

Why is cholesterol clinically significant?

Answer 2

High levels of cholesterol in the blood correlate strongly with cardiovascular disease.

Cholesterol is a crucial component of cellular membranes and a precursor to steroid hormones and bile acids.

Question 3

How many carbons are present in cholesterol, and from which molecule are they derived?

Answer 3

Cholesterol has 27 carbons, all derived from acetyl-CoA.

Question 4

What are the four stages of cholesterol biosynthesis?

Answer 4

Condensation of three acetate units to form mevalonate (6 carbons).

Conversion of mevalonate to activated isoprene (5 carbons).

Polymerization of six isoprene units to form squalene (30 carbons).

Cyclization of squalene to form the four rings of the steroid nucleus in cholesterol.

Question 5

What enzyme reduces HMG-CoA to mevalonate in Stage 1 of cholesterol synthesis?

Answer 5

HMG-CoA reductase.

Question 6

Why does Stage 2 of cholesterol synthesis require ATP?

Answer 6

Three phosphate groups are transferred to mevalonate, requiring three ATP molecules to produce activated isoprene.

Question 7

What is the product of condensing two activated isoprenes in Stage 3?

Answer 7

Geranyl pyrophosphate (10 carbons).

Question 8

How is squalene formed in Stage 3?

Answer 8

Farnesyl pyrophosphate (15 carbons) is formed from geranyl pyrophosphate and an additional isoprene unit. Two farnesyl pyrophosphate molecules then condense to form squalene (30 carbons).

Question 9

What catalyzes the cyclization of squalene in Stage 4?

Answer 9

Squalene monooxygenase adds one oxygen atom to squalene, forming an epoxide. Cyclization results in lanosterol, which is then converted to cholesterol.

Question 10

What are the metabolic fates of cholesterol?

Answer 10

Bile acids: Emulsify dietary fat.

Cholesterol esters: Transport and storage forms of cholesterol.

Steroid hormones: Examples include testosterone and estradiol.

Question 11

How is cholesterol synthesis regulated?

Answer 11

Insulin: Activates HMG-CoA reductase.

Glucagon: Inactivates HMG-CoA reductase.

AMPK: Inactivates HMG-CoA reductase under low ATP conditions.

High cholesterol esters: Activate ACAT, promoting ester formation.

Oxysterols: Downregulate HMG-CoA reductase and LDL receptor activity.

Question 12

What are statins, and how do they lower cholesterol levels?

Answer 12

Statins are competitive inhibitors of HMG-CoA reductase, resembling mevalonate, and reduce serum cholesterol levels.

Question 13

What are ketone bodies, and why are they significant?

Answer 13

Ketone bodies (acetoacetate, D-\u03b2-hydroxybutyrate, and acetone) are produced in the liver as an alternative fate for acetyl-CoA. They serve as a vital energy source, particularly for the brain during low glucose availability.

Question 14

What are the 5 steps of ketone body synthesis?

Answer 14

Two acetyl-CoA molecules condense to form acetoacetyl-CoA.

Acetoacetyl-CoA condenses with another acetyl-CoA to form HMG-CoA.

HMG-CoA is cleaved to form acetoacetate and acetyl-CoA.

Acetoacetate is reduced to D-\u03b2-hydroxybutyrate.

Acetoacetate is decarboxylated to acetone (exhaled as waste).

Question 15

Where does ketone body synthesis occur?

Answer 15

In the mitochondrial matrix of hepatocytes.

Question 16

How are ketone bodies broken down in extrahepatic tissues?

Answer 16

D-b-hydroxybutyrate is oxidized to acetoacetate.

Acetoacetate is metabolized to acetoacetyl-CoA.

Acetoacetyl-CoA is cleaved into two acetyl-CoA molecules, which enter the Citric Acid Cycle.

Question 17

Why does ketone body production increase during starvation?

Answer 17

Gluconeogenesis depletes Citric Acid Cycle intermediates, slowing the cycle. Acetyl-CoA is diverted to ketone body formation.

Question 18

What is ketoacidosis, and when does it occur?

Answer 18

Ketoacidosis occurs when ketone body levels become excessively high, acidifying the blood. It is commonly associated with prolonged starvation or diabetes.

Question 19

What benefits do ketone bodies provide?

Answer 19

They allow the liver to export fuel from D-b-oxidation without depleting Citric Acid Cycle intermediates or hepatic CoA pools.

Question 20

How is ketone body production linked to diabetes?

Answer 20

Insufficient insulin prevents glucose uptake, stimulating D-b-oxidation and gluconeogenesis. This depletes Citric Acid Cycle intermediates, leading to increased ketone body formation.

Question 21

How do ketone bodies serve as fuel for the brain?

Answer 21

Ketone bodies cross the blood-brain barrier and are converted back to acetyl-CoA for use in the Citric Acid Cycle during low glucose conditions.

Question 22

What triggers the mobilization of triglycerides for ketone body production?

Answer 22

Low blood glucose levels promote the breakdown of triglycerides in adipose tissue, releasing fatty acids and glycerol. Fatty acids are metabolized to acetyl-CoA in the liver, driving ketone body synthesis.