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Dyslipidemias . SCHEME FOR LIPID TRANSPORT. Production / Catabolism = Number.  Over- production Very common (? Cause).  Decreased Catabolism Defective Receptor in FH (RARE). Cell receptors. Endogenous transport. Lipoprotein lipase. Hepatic lipase. LDL receptor. VLDL.

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Dyslipidemias

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Dyslipidemias


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SCHEME FOR LIPID TRANSPORT

Production / Catabolism

= Number

Over-

production

Very

common

(? Cause)

Decreased

Catabolism

Defective

Receptor

in FH

(RARE)

Cell receptors

Endogenous

transport

Lipoprotein

lipase

Hepatic

lipase

LDL

receptor

VLDL

IDL

LDL

Lipoprotein lipase

Exogenous

transport

chylomicrons

remnants

gut

Remnant

receptor

Free cholesterol + phospholipids + C-apolipoproteins

Nascent HDL

Mature HDL

Lecithin: cholesterol

acyltransferase

 [circulating LDL]

 risk for atherosclerosis


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GENETIC

DYSLIPIDEMIAS

I ApoB:

II HDL

III Lipoprotein Modifying Enzymes


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GENETIC/METABOLIC CLASSIFICATION

OF PRIMARY HYPERLIPIDAEMIAS


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GENETIC/METABOLIC CAUSES

OF PRIMARY HYPERLIPIDAEMIAS


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Chylo

↑ ↓ ↓


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Familial Lipoprotein Lipase Deficiency

APO C-II

DEFICIENCY

LIPOPROTEIN LIPASE

DEFICIENCY

NORMAL

CHYLOMICRON

CHYLOMICRON

CHYLOMICRON

APO C-II

APO C-II

LIPOPROTEIN

LIPASE

LIPOPROTEIN

LIPASE

FFA

FFA


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Xanthomas


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CLINICAL FINDINGS IN

Familial Lipoprotein

Lipase Deficiency

RECURRENT ACUTE PANCREATITIS

ERUPTIVE XANTHOMAS

RETINAL LIPEMIA

HEPATOSPLENOMEGALY

AUTOSOMAL RECESSIVE INHERITANCE

(CONSANGUINITY COMMON)


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↑↑


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DISORDERS OF LDL

RECEPTORS: RARE

  • Familial hypercholesterolemia

    • (defective receptor)

  • Familial defective B100

    • (defective ligand)


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FH

BTg

B

Tg

VLDL

B

B

B

B

B

B

B

B

B

B

B

B

CE

CE

CE

CE

CE

CE

CE

CE

CE

CE

CE

CE

LDL

LDL

Clearance


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IDL

IDL

Free Cholesterol

Free Cholesterol

HTGL

Lysis

Lysis

B-100

Receptor

LDL

LDL

B-100

Receptor

PERIPHERAL

CELLS

LIVER


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                                                                     <>


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Collagen Rich Plaque


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→ →

↑ ↑ ↑


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Familial

Combined

Hyperlipidemia/

HyperapoB


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PRODUCTION

BREAKDOWN


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Features of HyperapoB

  • Increased LDL particle number due

  • primarily to increased secretion of

  • hepatic B100 lipoprotein particles.

  • Often, but not always, many of the

  • LDL particles are smaller and denser

  • than normal.


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HETEROGENEITY OF LDL

B

CE

NORMAL

FC

CE

Tg

FC

Tg

PL

B

FC

B

CE

FC

CE

Tg

FH

Tg

PL

B

B

CE

CE

FC

Tg

HYPERAPO B

Tg

FC

PL

PL


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CII

FH

CI

CIII

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

CE

CE

CE

CE

CE

CE

CE

CE

CE

CE

E

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

CE

CE

CE

CE

CE

CE

CE

CE

CE


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HyperapoB

CII

CII

CI

CI

CIII

CIII

Tg

Tg

Tg

Tg

Tg

Tg

CE

CE

CE

CE

CE

CE

E

E

E

E

Tg

CE

Tg

CE

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

CE

CE

CE

CE

CE

CE

CE

CE

CE


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Interaction of apoB and LDL size as

Determinants of CAD Risk

6.2

(p < 0.001)

apoB

Odds ratios for IHD

2.0

1.0

1.0

LDL peak particle diameter


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  • HYPERAPO B IS

  • ASSOCIATED WITH:

  • SMOKING

  • MALE SEX

  • ABDOMINAL OBESITY

  • HYPERINSULINEMIA

  • OFFSPRING OF PARENTS WITH CAD


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Principle I:

VLDL synthesis and secretion

is substrate

driven.


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Effect of Fatty Acid on

Liver Cholesterol Synthesis

4HR

pmol/min/mg


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Direct Correlation between Cholesterol Synthesis and

Hepatic Secretion of apoB 100 in Normolipidemic Subjects

15

10

5

Hepatic secretion ratio to

VLDL apoB (mg/kg/day)

0 2 4 6 8 10

Plasma mevalonate concentration (ng/ml)


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Principle II:

What comes out

depends on what went in.

FA

CHO


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HDL ←

↑ ↑


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COMMON GENETIC CAUSES

OF HDL DEFICIENCY

SECONDARY:

1. Familial Hypertriglyceridemia with

Hypoalphalipoproteinemia (low apo A1)

2. Familial Combined Hyperlipidemia

(Hyperapo B) with Hypoalphalipoproteinemia

PRIMARY:

Familial Hypoalphalipoproteinemia


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FUNCTIONS OF HDL

CHOLESTEROL

ESTERS

LCAT

LCAT

CHOLESTEROL

LIVER

PERIPHERAL

CELLS

NASCENT

VLDL

VLDL

NASCENT

CHYLOMICRON

CHYLOMICRON

HDL

VLDL

HDL

CHYLOMICRON


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RARE GENETIC CAUSES

OF HDL DEFICIENCY

NamePremature CAD

Tangier disease+

Apo A1, Clll, AlV deficiency++

Apo A1, Cll deficiency+++

Apo A1 deficiencyUK

Apo A1 variantsUK

LCAT deficiency+


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SECONDARY CAUSES OF

DECREASED HDL

  • Hypertriglyceridemia

  • Obesity

  • Diabetes Mellitus

  • Cigarette smoking

  • Beta blockers

  • Liver cirrhosis


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SECONDARY

DYSLIPIDEMIAS

AND

DRUG EFFECTS

ON LIPIDS


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DISEASES CAUSING

SECONDARY HYPERLIPIDAEMIA


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LIPID ABNORMALITIES

IN LIVER DISEASE


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LIPID ABNORMALITIES

IN RENAL DISEASE


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DRUGS THAT CAN CAUSE

SECONDARY HYPERLIPIDAEMIA

DIURETICS

BETA BLOCKERS

ESTROGENS

PROGESTERONE

RETINOIDS

CORTICOSTEROIDS

MICROSOMAL ENZYME INDUCERS

egPHENYTOIN


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