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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 l.jpg

Lipid Transport

Lipoprotein Structure, Function, and Metabolism


Clinical case l.jpg
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 l.jpg
Plasma LipoproteinsStructurefigure 19-1

  • LP core

    • Triglycerides

    • Cholesterol esters

  • LP surface

    • Phospholipids

    • Proteins

    • cholesterol


Plasma lipoproteins classes functions l.jpg
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


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Chylomicron Metabolismfigure 19-3

  • Nascent chylomicron (B-48)

  • Mature chylomicron (+apo C & apo E)

  • Lipoprotein lipase

  • Chylomicron remnant

    • Apo C removed

    • Removed in liver


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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


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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


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Plasma LipoproteinsClasses & Functions

  • Low Density Lipoprotein (LDL)

    • Synthesized from IDL

    • Cholesterol transport

    • 78% lipid, 58% cholesterol & CE

    • Apo B-100

      • Receptor binding


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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


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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


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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


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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


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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 l.jpg
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.


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HDL Metabolism: Functions

  • Apoprotein exchange

    • provides apo C and apo E to/from VLDL and chylomicrons

  • Reverse cholesterol transport


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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


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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


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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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