Complex Lipids & Cholesterol Biochemistry

Question 1

Sources of cholesterol

Answer 1

• Diet: consume ~300-600 mg/day
  
  • Half is absorbed
• De novo synthesis: ~1gm/day
  
  • Mostly in liver (highly regulated process)

Question 2

General steps of de novo cholesterol synthesis

Answer 2

In hepatocyte cytoplasm:

Acetyl CoA (thiolase & HMG CoA synthase) –> HMG CoA (HMG CoA reductase*) + NADPH –> NADPH –> mevalonate –> lots of complicated steps resulting in key intermediates geranyl pyrophosphate and farnesyl pyrophosphate –> cholesterol

*key regulated step, rate limiting

Question 3

Key regulated step in cholesterol synthesis

Answer 3

HMG CoA (HMG CoA reductase*) + NADPH –> mevalonate

Primary means for controlling intracellular cholesterol levels

Question 4

4 levels of HMG CoA reductase regulation

Answer 4

• Transcriptional regulation
• Translational regulation
• Regulation of degradation
• Regulation of phosphorylation

Question 5

Key features of glycerophospholipids, sphingomyelin, glycosphingolipids (general)

Answer 5

• All lipids begin with glycerol or ceramide (sphingosine) backbone
• Polar head group:
  
  • Phosphate linked to alcohol: glycerophospholipid
  • Phosphate linked to choline: sphingomyelin
  • Sugar moiety: glycosphingolipids

**Sphingolipids have no glycerol backbone - instead sphingosine with nitrogen in it

Question 6

Synthesis of different glycerophospholipids

Answer 6

• Backbone comes from phosphatidic acid (precursor in triglyceride biosynthesis)
• Head group added:
  
  • Phosphatidylserine (PS)
  • Phosphatidylethanolamine (PE)
    
    • Head group formed de novo or from diet, activated by CDP then attached to backbone
  • Phosphatidylcholine (PC)
    
    • Head group formed de novo or from diet, activated by CDP then attached to backbone
• Another synthesis pathway: “base exchange”
  
  • Head groups exchanged onto previously synthesized phospholipids

Question 7

Important functions of sphingomyelin

Answer 7

• Major structural lipid in nerve tissue

Question 8

Important functions of phosphatidylinositol

Answer 8

• Important in signal transduction
• Reservoir for arachidonic acid
• Important in membrane protein anchoring

Question 9

Important functions of phosphatidylcholine

Answer 9

• Lung surfactant
• Reservoir of choline
• Present in bile
• Most abundant phospholipid in body

Question 10

Synthesis of arachidonic acid

Answer 10

Made from dietary linoleic acid

Question 11

Synthesis of prostaglandins

Answer 11

Synthesized from arachidonic acid by COX

Question 12

Fates of cholesterol

Answer 12

• Steroid hormones
• Bile acids
  
  • Secrete 300-600mg of cholesterol in bile salts/day
• Component of membranes
• Vitamin D

Question 13

Transcriptional regulation of HMG-CoA reductase

Answer 13

• Cholesterol present in excess –> HMG CoA reductase gene transcribed 20x less
• Insulin/glucagon regulate via transcription
  
  • Insulin increases expression of enzyme (high in fed state when NADPH is high)
  • Glucagon decreases expression

Question 14

Translational regulation of HMG-CoA reductase

Answer 14

• Cholesterol present in excess –> translation rate of coding mRNA 5x less than in absence of cholesterol
• mRNA half-life decreases with excess cholesterol

Question 15

Regulation of degradation of HMG-CoA reductase

Answer 15

• In excess cholesterol –> half-life of HMG-CoA reductase decreases from 11 hours to 2 hours

Question 16

Regulation of phosphorylation of HMG-CoA reductase

Answer 16

• AMP kinase phosphorylates HMG-CoA reductase –> inactivates
• Protein phosphatase removes phosphate –> activates