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Lipid Transport. Lipoprotein Structure, Function, and Metabolism. Clinical Case. 8 y.o. girl Admitted for heart/lung transplantation Medical history Xanthomas at 2 yo MI symptoms at 7 yo TC=1240mg/dl TG=350mg/dl Diet & statin & cholestyramine Mother TC= 355, father TC=310

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lipid transport

Lipid Transport

Lipoprotein Structure, Function, and Metabolism

clinical case
Clinical Case
  • 8 y.o. girl
    • Admitted for heart/lung transplantation
  • Medical history
    • Xanthomas at 2 yo
    • MI symptoms at 7 yo
      • TC=1240mg/dl
      • TG=350mg/dl
      • Diet & statin & cholestyramine
      • Mother TC= 355, father TC=310
    • Coronary artery bypass at 7 yo
    • 8 yo severe angina, second bypass
      • TC = 1000mg/dl
  • Transplantation successful
    • TC=260mg/dl, xanthomas regressing
plasma lipoproteins structure figure 19 1
Plasma LipoproteinsStructurefigure 19-1
  • LP core
    • Triglycerides
    • Cholesterol esters
  • LP surface
    • Phospholipids
    • Proteins
    • cholesterol
plasma lipoproteins classes functions
Plasma LipoproteinsClasses & Functions
  • Chylomicrons
    • Synthesized in small intestine
    • Transport dietary lipids
    • 98% lipid, large sized, lowest density
    • Apo B-48
      • Receptor binding
    • Apo C-II
      • Lipoprotein lipase activator
    • Apo E
      • Remnant receptor binding
chylomicron metabolism figure 19 3
Chylomicron Metabolismfigure 19-3
  • Nascent chylomicron (B-48)
  • Mature chylomicron (+apo C & apo E)
  • Lipoprotein lipase
  • Chylomicron remnant
    • Apo C removed
    • Removed in liver
plasma lipoproteins classes functions6
Plasma LipoproteinsClasses & Functions
  • Very Low Density Lipoprotein (VLDL)
    • Synthesized in liver
    • Transport endogenous triglycerides
    • 90% lipid, 10% protein
    • Apo B-100
      • Receptor binding
    • Apo C-II
      • LPL activator
    • Apo E
      • Remnant receptor binding
plasma lipoproteins classes functions7
Plasma LipoproteinsClasses & Functions
  • Intermediate Density Lipoprotein (IDL)
    • Synthesized from VLDL during VLDL degradation
    • Triglyceride transport and precurser to LDL
    • Apo B-100
      • Receptor binding
    • Apo C-II
      • LPL activator
    • Apo E
      • Receptor binding
plasma lipoproteins classes functions8
Plasma LipoproteinsClasses & Functions
  • Low Density Lipoprotein (LDL)
    • Synthesized from IDL
    • Cholesterol transport
    • 78% lipid, 58% cholesterol & CE
    • Apo B-100
      • Receptor binding
vldl metabolism figure 19 4
VLDL Metabolismfigure 19-4
  • Nascent VLDL (B-100) + HDL (apo C & E) = VLDL
  • LPL hydrolyzes TG forming IDL
    • IDL loses apo C-II (reduces affinity for LPL)
  • 75% of IDL removed by liver
    • Apo E and Apo B mediated receptors
  • 25% of IDL converted to LDL by hepatic lipase
    • Loses apo E to HDL
plasma lipoproteins classes functions10
Plasma LipoproteinsClasses & Functions
  • High Density Lipoprotein (HDL)
    • Synthesized in liver and intestine
    • Reservoir of apoproteins
    • Reverse cholesterol transport
    • 52% protein, 48% lipid, 35% C & CE
    • Apo A
      • Activates lecithin-cholesterol acyltransferase (LCAT)
    • Apo C
      • Activates LPL
    • Apo E
      • Remnant receptor binding
ldl metabolism
LDL Metabolism
  • LDL receptor-mediated endocytosis
    • LDL receptors on ‘coated pits’
      • Clathrin: a protein polymer that stabilizes pit
    • Endocytosis
      • Loss of clathrin coating
      • uncoupling of receptor, returns to surface
    • Fusing of endosome with lysosome
      • Frees cholesterol & amino acids
coordinate control of cholesterol uptake and synthesis
Coordinate Control of Cholesterol Uptake and Synthesis
  • Increased uptake of LDL-cholesterol results in:
  • inhibition of HMG-CoA reductase
    • reduced cholesterol synthesis
  • stimulation of acyl CoA:cholesterol acyl transferase (ACAT)
    • increased cholesterol storage
    • TG + C -> DG + CE
  • decreased synthesis of LDL-receptors
    • “down-regulation”
    • decreased LDL uptake
heterogeneity of ldl particles
Heterogeneity of LDL-particles
  • Not all LDL-particles the same
    • Small dense LDL (diameter <256A)
    • Large buoyant LDL (diameter >256 A)
    • Lamarche B, St-Pierre AC, Ruel IL, et al. A prospective, population-based study of low density lipoprotein particle size as a risk factor for  Can J Cardiol 2001;17:859-65.
      • 2057 men with hi LDL, 5 year follow-up
      • Those with elevated small dense LDL had RR of 2.2 for IHD compared to men with elevated large buoyant LDL
    • Detection expensive
    • Treatment for lowering small dense LDL similar to lowering all LDL (diet, exercise, drugs)
      • Some drugs (niacin, fibrates) may be more effective at lowering small dense LDL.
ldl particle size and apolipoprotein b predict ischemic heart disease quebec cardiovascular study
LDL Particle Size andApolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study

6.2

(p<0.001)

Apo B

2.0

>120 mg/dl

1.0

1.0

<120 mg/dl

>25.64

<25.64

LDL Peak Particle Diameter (nm)

Lamarche B et al. Circulation 1997;95:69-75.

hdl metabolism functions
HDL Metabolism: Functions
  • Apoprotein exchange
    • provides apo C and apo E to/from VLDL and chylomicrons
  • Reverse cholesterol transport
reverse cholesterol transport figure 19 6
Reverse cholesterol transportfigure 19-6
  • Uptake of cholesterol from peripheral tissues (binding by apo-A-I)
  • Esterification of HDL-C by LCAT
    • LCAT activated by apoA1
  • Transfer of CE to lipoprotein remnants (IDL and CR) by CETP
  • removal of CE-rich remnants by liver, converted to bile acids and excreted
resolution of clinical case
Resolution of Clinical Case
  • Familial hypercholesterolemia (FH)
    • Family history
    • Early xanthomas and very high TC
    • Absence of LDL-receptors
      • Homozygous FH
  • Parent TC consistent with heterozygous FH
    • 1/500 Americans with heterozygous FH, treatable with diet/drugs
    • 1/106 with homozygous FH
  • Diet and drugs relatively ineffective
  • Liver has ~70% of LDL-receptors
    • Combined liver/heart recommended because of advance CHD
exam 2 monday july 18
Exam 2Monday, July 18
  • Lipid Transport
    • Chapter 19
    • MAAG chapter 54
      • Type 2 Diabetes and Insulin Resistance in Adipose
        • Effect on LPL causing hyperlipidemia
        • Signaling fault resulting in inappropriate lipolysis
  • Cholesterol Metabolism
    • Chapter 21
    • MAAG chapter 32
  • Format
    • Multiple choice questions
    • Short essay questions
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