Cholesterol Metabolism

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Cholesterol Metabolism
Southwestern Medical School Dallas, Texas
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Familial Hypercholesterolemia

• 1 in a million homozygous HO (both alleles)
• 1 in 500 heterozygous HT (one defective allele)
• HO serum cholesterol 650-1000 mg/100 ml
• HT serum cholesterol 250-500 mg/100 ml
• HO develop atherosclerosis, die before 20 yrs
• HO death due to heart disease
• HT enjoy normal life span but are at risk

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Whats Wrong in FH?
HMG-CoA Reductase

• Suppressed by cholesterol
• 50-100 fold more active without cholesterol
• FH have high activity all the time
• Purified HMG-CoA reductase is inhibited
• Cholesterol not entering cell to suppress
• Receptor for cholesterol not present
• FH must lack a means of taking up the cholesterol
  from the plasma

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What did Goldstein and Brown Accomplish?

• LDL has a specific membrane surface receptor
• LDL receptors are needed to take up cholesterol
• The binding of LDL to a receptor initiates
  endocytosis, which brings LDL and its receptor
  inside the cell within an endosome
• The endosome fuses with a lysosome
• LDL receptor escapes degradation
• Cholesterol is free inside the cell
• Receptor recycles to the cell surface

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See p. 261
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HDL
CM
LDL
HDL
HDL
HDL
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Cholesterol Uptake from LDL
See p 263
Golgi
Coated vesicle
ACAT
Endosome
Coated Pit
Lysosome
LDL with apoB100
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Membrane-like coat
ApoB100
LDL (180-260) Angstroms
Core of cholesterol esters
LDL Particles
Cholesterol-rich, triglyceride-poor lipoprotein
particles
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Clathrin Coat surrounding coated pits
Coated Pits shown with actin filaments
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Lipoprotein Metabolism I

• Liver and intestine are primary source of
  circulating lipids
• Chylomicrons carry triacylglycerols and
  cholesterol esters from intestine to tissues
• VLDL carry same from liver
• Lipoprotein lipases hydrolyze triacylglycerols
• VLDL ? IDL ? LDL
• LDL with apoB100 enters tissues

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Lipoprotein Metabolism II

• HDL smallest LP
• Made in liver, released with no cholesterol
• Life span 5-6 days (longest LP)
• Receives cholesterol esters from LCAT
• Cholesterol ester transfer protein transfers
  ester to LDL and VLDL
• Most cholesterol esters are returned to liver

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STATINS
(Competitive inhibitors of HMG-CoA Reductase)
R H X H Compactin
R CH3 X H Lovastatin (MevacorTM)
R OH X H Pravastatin (PravacholTM)
R CH3 X CH3 Simvastatin (ZocorTM)
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Summary

• LDL is required for cholesterol absorption
• LDL arises from VLDL by TG removal
• Lipoprotein lipase required to form LDL
• LDL has apoB100 to recognize receptor
• Receptor-mediated endocytosis
• HDL takes cholesterol from LDLvia LCAT
• HDL cholesterol goes back to the liver for
  oxidation, not deposition