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

HO

COO-

H3C

Mevalonate

R = H X = H Compactin

R = 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