Cholesterol Metabolism
Southwestern Medical School Dallas, Texas
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
What’s Wrong in FH?
• 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
HMG-CoA Reductase
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
See p. 261
Liver LiverIntestine
Plasma
HDL
CMLDLHDLHDL
HDL
Cholesterol Uptake from LDL
Golgi
Endosome
Lysosome
Coated vesicleACAT
Coated Pit
LDL withapoB100
See p 263
LDL Particles
ApoB100
Cholesterol-rich, triglyceride-poor lipoprotein particles
LDL(180-260) Angstroms
Core of cholesterolesters
Membrane-like coat
Coated Pits shown with actin filaments
Clathrin Coat surroundingcoated pits
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
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
HDL
C
OH
HOCOO-
H3C
Mevalonate
R = H X = H CompactinR = CH3 X = H Lovastatin (MevacorTM)R = OH X = H Pravastatin (PravacholTM)
CH3
O
O
CH3
C COO-
OH
HO
R
X
R = CH3 X = CH3 Simvastatin (ZocorTM)
STATINS (Competitive inhibitors of HMG-CoA Reductase)
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