LIPIDS 101LIPIDS 101

Ulrich K. SchubartUlrich K. Schubart

JMCJMC

AECOMAECOM

•Physiology of Lipids and Lipoproteins

• Lipoprotein Disorders

Chylomicrons VLDL LDL HDL

COMPOSITION OF PLASMA LIPOPROTEINS

Densityg/ml

0.93 0.93-1.006 1.019-1.063 1.063-1.25

Size (nM) 75-1200 30-60 18-25 9-12

Cholesterol/cholesteryl estersProteinTriglyceridePhospholipid

Bilheimer. Textbook of Internal Medicine. 1989:2139-44

Chylomicrons VLDL LDL HDL

86 55 6

5

57

50

196

1822

2240

33

22

2

Apo E Apo E

Exogenous Pathway (Chylomicron metabolism)Exogenous Pathway (Chylomicron metabolism)

B48CE

Chylomicron Remnant Liver

Intestines

CEB48

CETG

LPL

C-II

Fatty acids

TG

Remnant Receptor

Endogenous Pathway (VLDL metabolism)

Apo E Apo E

B100

CE

VLDL Remnant LDL (VLDL/IDL)

Liver

CEB100

CETG

RemnantReceptor LPL

C-II

Fatty acids

TG

B100

CE

Basic Pathways in LDL Regulation

apo B-100

apo C

apo E

VLDL

VLDLRemnant

LDL

Liver

VLDLPRODUCTION

LDL CLEARANCE

LIPOLYSIS

CONVERSION

Other sites

SHUNT PATHWAY

Rader et al JCI 2003

Nabel E NEJM 2003

Familial Hypercholesterolemia

• Autosomal Dominant Inheritance

• LDL Receptor Deficiency:

- Heterozygous (1/500)

- Homozygous (1/1,000,000)

• LDL Cholesterol Increased

- Heterozygous 2 times (>250 mg/dl)

- Homozygous 4-6 times elevated

• Familial Defective apoB is an exact phenocopy

(note this is NOT Familial Combined HLD)

Familial Hypercholesterolemia

Apo E Apo E

apoBCE

ChyloVLDL Remnants LDL

Liver

CEapoB

CETG

LPL

C-II

Fatty acids

TG

B100LDL-R

Familial Hypercholesterolemia: Clinical Manifestations

• Severe Hypercholesterolemia (LDL>250 mg/dl)

- Atherosclerotic vascular disease

• Premature CHD

• Xanthelasma/ Corneal Arcus as young adults

• Tendon Xanthomas

• Arthritic type pains in joints

• Family History of premature CHD

Familial Hypercholesterolemia: Ligand Defective ApoB

B100LDL-R

Apo E Apo E

apoBCE

ChyloVLDL Remnants LDL

Liver

CEapoB

CETG

LPL

C-II

Fatty acids

TG

Familial Combined HyperlipidemiaFamilial Combined Hyperlipidemia

Common (1/100)Common (1/100)

Autosomal dominant pattern of inheritanceAutosomal dominant pattern of inheritance

Variable lipoprotein pattern in individual and familyVariable lipoprotein pattern in individual and family

Multiple Phenotypes (IIa, IIb, IV, V)Multiple Phenotypes (IIa, IIb, IV, V)

Pathophysiology: overproduction of apoB-100 Pathophysiology: overproduction of apoB-100

particlesparticles

CHD risk is increasedCHD risk is increased

Familial Combined Hyperlipidemia (HyperapoB)

Liver

CE

Apo E

B100CETG

LPL

C-II

Fatty acids

Apo E

B100CE

TG

B100

VLDL Remnant LDL (VLDL/IDL)

LDL-RCE

Familial (Type I) Hyperlipoproteinemia/Chylomicronemia

• Rare (1/1,000,000)

• Recessive inheritance

• Triglycerides > 1000 mg/dl with usual diet

• Presents in childhood, especially puberty in girls

• Pathophysiology: absence of lipoprotein lipase or

apo C-II

• Complications: pancreatitis, xanthomatosis,

hepatosplenomegaly

Familial (Type I) Hyperlipoproteinemia/Chylomicronemia

Apo E Apo E

apoB

Chylo/VLDL Remnants LDL (VLDL/IDL)

Liver

CEapoB

CE

TG

LPL

C-II

Fatty acids

CE

TG

B100LDL-RCE

Remnant Removal Disease

• Synonyms: Familial Dysbetalipoproteinemia, Type III hyperlipoproteinemia, Broad beta disease

• Uncommon: 1/1000 – 1/5000

• Requires apo E2/E2 (1/100) + second defect for clinical expression

• Pathophysiology: impaired clearance of apoB/E remnant particles by the remnant receptor

• Chylomicron and VLDL (-VLDL) remnants accumulate

• Diagnosis: VLDL-C/TG >0.3; broad -band on EP

• CHD and peripheral vascular disease

• Palmar and tuberoeruptive xanthomata

_

Remnant Removal Disease (Type III Hyperlipidemia)

B100LDL-R

Apo E Apo E2/E2

apoBCE

ChyloVLDL Remnants LDL

Liver

CEapoB

CETG

LPL

C-II

Fatty acids

TG

Nabel E NEJM 2003

Primary Hypercholesterolemia: Clinical Classification

• Elevated LDL cholesterol (>160 mg/dl; 1/4 of all

American Adults)

- Familial Hypercholesterolemia (1/500)

- Familial Combined Hyperlipidemia (1/100)

- Polygenic Hypercholesterolemia (1/4)

Dietary HyperlipidemiaDietary Hyperlipidemia

VLDL

LDL

Apo E

Apo C

apoB-100

LDL

VLDLremnants

Increased conversionto LDL

XX

Overproduction ofVLDL TG

Other sites

Reduced activityof LDL receptors

( Saturated fat and cholesterol In the diet)

Caloric intake

HDLHDL

Reverse cholesterol transportReverse cholesterol transport

A-I

Liver

CECE

FCLCAT

FC

Bile

A-I

ABCA1

Macrophage

Mature HDL

Nascent HDL

FCCE

Reverse cholesterol transport : Reverse cholesterol transport : Role of CETP in HDL MetabolismRole of CETP in HDL Metabolism

CETP = cholesteryl ester transfer protein

A-I

Liver

CECE

FCFCLCAT

FC

Bile

SR-BI

A-I

ABCA1

Macrophage

CE B

LDLR

VLDL/LDL

CETP

Mature HDL

Nascent HDL

CE

SRA

OxidationCETG

Rader D JCI Dec 06

Rader D JCI Dec 06

Rader D JCI Dec 06

Secondary Causes of Low HDL-CSecondary Causes of Low HDL-CSmokingSmoking

Obesity (visceral fat)Obesity (visceral fat)

Sedentary LifestyleSedentary Lifestyle

High carbohydrate or very-low-fat dietHigh carbohydrate or very-low-fat diet

Hypertriglyceridemia (from any cause)Hypertriglyceridemia (from any cause)

DrugsDrugs– Beta-blockers Beta-blockers – Androgenic steroidsAndrogenic steroids– Androgenic progestinsAndrogenic progestins

Cholesterol disorders associated with premature CAD

Familial Hypercholesterolemia Low HDLNephrotic SyndromeLp(a) [ not ApoA].

Triglyceride Disorders associated with premature CAD

(+) premature CAD (-) premature CAD

Familial Combined HLD Familial HTGRemnant Removal Dz Familial ChylomicronemiaCentral Obesity (metabolic syndrome) EstrogenDiabetes AlcoholNephrotic syndrome/Uremia/dialysis Bile Acid ResinsHypothyroidism High Carbohydrate dietCushing’s syndrome

New Concepts in Atherosclerosis New Concepts in Atherosclerosis Risk: Risk:

Triglycerides, Small Dense LDL Triglycerides, Small Dense LDL and the Metabolic Syndromeand the Metabolic Syndrome

MetabolicSyndrome

HDLAtherogenicDyslipidemia

Insulin Resistance ProcoagulantState

BP

Atherosclerosis

HDL VLDL IDL

TG

LDL

CigaretteSmoking

HypertensionDiabetes

Pro CoagulantState

Thrombosis

CHD

HYPERTRIGLYCERIDEMIA

Small, dense LDL

HDL IDL

VLDLremnants

Chylomicronremnants

Metabolic Consequences of Hypertriglyceridemia

Insulin Resistance and Insulin Resistance and DyslipidemiaDyslipidemia

(lipoprotein or

hepatic lipase)

Fat Cells

Insulin

IR

FFA

Liver

(CETP)

CE

TG Apo A-I(CETP)CE TG

VLDL HDL

SDLDLLDL

TGApo BVLDL

Kidney

v

Feingold KR et al. Arterioscler Thromb. 1992;12:1496-1502.Lamarche B et al. Circulation. 1997;95:69-75.

Significance of Small, Dense LDLSignificance of Small, Dense LDL

Low cholesterol content of LDL particlesLow cholesterol content of LDL particles particle number for given LDL-C levelparticle number for given LDL-C level

Associated with Associated with levels of TG variable LDL-C, and levels of TG variable LDL-C, and levels of HDL levels of HDL22

Marker for common genetic trait associated with Marker for common genetic trait associated with risk of coronary disease (LDL subclass pattern B) risk of coronary disease (LDL subclass pattern B)

Possible mechanisms of Possible mechanisms of atherogenicity atherogenicity– greater arterial uptakegreater arterial uptake uptake by macrophagesuptake by macrophages oxidation susceptibilityoxidation susceptibility

Atherogenic Particles

B B B

E E

C

Small VLDLRemnant

IDL LDL

Atherogenic CholesterolAtherogenic Cholesterol

VLDL + IDL + LDL

= Total Cholesterol - HDL

= non HDL cholesterol

Calculating LDL CholesterolCalculating LDL Cholesterol

• LDL-C = TC – HDLC – TG/5

• Invalid when TG > 400 mg/dl

• Underestimates “atherogenic cholesterol”

when TG >200 mg/dl

• nonHDL-C = TC - HDLC

Non-HDL CholesterolNon-HDL Cholesterol

Predictive of CV Events Rates in ProspectivePredictive of CV Events Rates in Prospective

Clinical TrialsClinical Trials

Useful when triglycerides > 200 mg/dlUseful when triglycerides > 200 mg/dl

Allows use of NCEP LDL guidelines Allows use of NCEP LDL guidelines

(+ 30 mg/dl)(+ 30 mg/dl)

Flexible - Allows use of non fasting samplesFlexible - Allows use of non fasting samples

to assess lipid treatment goalsto assess lipid treatment goals

ATP III: The Metabolic Syndrome*ATP III: The Metabolic Syndrome*

*Diagnosis is established when 3 of these risk factors are present.†Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. ‡Some men develop metabolic risk factors when circumference is only marginally increased.

Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

Risk Factor Defining LevelAbdominal obesity† (Waist circumference‡)MenWomen

>102 cm (>40 in)>88 cm (>35 in)

TG 150 mg/dLHDL-C

MenWomen

<40 mg/dL<50 mg/dL

Blood pressure 130/85 mm HgFasting glucose 110 mg/dL

ATP III: New Features of Guidelines—ATP III: New Features of Guidelines—Focus on Multiple Risk FactorsFocus on Multiple Risk Factors

Persons with diabetes without CHD raised to level of Persons with diabetes without CHD raised to level of CHD risk equivalentCHD risk equivalent

Framingham 10-year absolute CHD risk projections Framingham 10-year absolute CHD risk projections used to identify certain patients with used to identify certain patients with 2 risk factors for 2 risk factors for more intensive treatmentmore intensive treatment

Persons with multiple metabolic risk factors (the Persons with multiple metabolic risk factors (the metabolic syndrome) identified as candidates for metabolic syndrome) identified as candidates for intensified therapeutic lifestyle changes (TLC)intensified therapeutic lifestyle changes (TLC)

Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

“It’s 11 PM….do you know what your Cholesterol is?