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Lipids and Lipoproteins
Roger L. Bertholf, Ph.D.
Associate Professor of Pathology
Director of Clinical Chemistry & Toxicology
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Classification of lipids
• Fatty acids (palmitic, linoleic, etc.)
• Glycerol esters (triglycerides)
• Sterols (cholesterol, hormones, vitamin D)
• Terpenes (vitamins A, E, K)
• Sphingosine derivatives (sphingomyelin)
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Fatty acids
• Even-numbered fatty acids predominate• The most common saturated fatty acids are palmitic
(16:0) and stearic (18:0), but unsaturated fatty acids are more common in nature
OH
O
Lauric acid (C12, 12:0, n-dodecanoic acid)
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Unsaturated fatty acids
• Double bonds in fatty acids are nearly always cis
OH
O
Palmitoleic acid (16:19, 9-hexadecanoic acid)
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Essential fatty acids
• Mammals can synthesize saturated and mono-unsaturated fatty acids.
• Linoleic (18:2) and linolenic (18:3) fatty acids cannot be synthesized, and therefore must be obtained from the diet (plants).– Both are required for the biosynthesis of
prostaglandins
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Clinical importance of fatty acids• Fecal fatty acids are sometimes measured to
detect malabsorptive and pancreatic disorders—the test is mostly considered obsolete
• Serum free fatty acids help distinguish between hyperinsulinemic hypoglycemia (FFA normal) and disorders of fatty acid oxidation (FFA elevated and negative ketones)
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Glycerol esters (acylglycerols)
• Triglycerides are the most abundant family of lipids in plant and animal cells, and are major components of the the human diet
H
CH OH
C
C
H OH
H
H OH
Glycerol
H
CH O
C
C
H O
H
H O
CO
CO
CO (CH2)n
(CH2)n
(CH2)n
CH3
CH3
CH3
Triglyceride
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Measuring triglycerides (reference method)
• Triglycerides are extracted into chloroform prior to analysis
Triglycerides
KOHfatty acids + glycerol
Periodateformic acid + formaldehyde
chromotropic acidchromogen=570 nm
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Measuring triglycerides (enzymatic method)
Triglycerides
Glycerol + FFAsLipase
Glycerophosphate + ADPGlycerokinase
ATP
Dihydroxyacetone + H2O2
Glycerophasphateoxidase
PeroxidaseQuinoneimine dye
max 500 nm
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Sterols (cholesterol)
• Sterols are steroid backbones that have a hydroxyl group at position 3 and a branched aliphatic chain of 8 or more carbons at position 17
HO
12
34
56
7
89
1112
10
13
14 1516
17
A B
C D
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Cholesterol biosynthesis
• About 2% (approximately 1 g) of total body cholesterol is replenished each day– Dietary sources account for less than half– Cholesterol is synthesized from Acetyl CoA– 90% of in vivo synthesis occurs in the intestine
and liver (although all cells have the capability)
• Absorption of dietary cholesterol appears to have a maximum of approximately 1 g/day
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Cholesterol biosynthesis
Acetyl-CoA 3-Hydroxy-3-methylglutaryl-CoA
Mevalonate
HMG-CoA reductase
Squalene
Cholesterol + Lecithin Cholesterol esterLCAT
“Statin” drugs inhibit this enzyme
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Measuring cholesterol by L-B
• The Liebermann-Burchard method is used by the CDC to establish reference materials
• Cholesterol esters are hydrolyzed and extracted into hexane prior to the L-B reaction
HO
H2SO4/HOAc
HOO2S
Cholesterol Cholestahexaene sulfonic acid
max = 620 nm
L-B reagent
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Enzymatic cholesterol methods
• Enzymatic methods are most commonly adapted to automated chemistry analyzers
• The reaction is not entirely specific for cholesterol, but interferences in serum are minimal
Cholesterol esters
Cholesterol
Cholesterylester
hydroxylase
Choles-4-en-3-one + H2O2
Cholesteroloxidase
Quinoneimine dye (max500 nm)
Phenol4-aminoantipyrinePeroxidase
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Lipoproteins• In order to be transported in blood, lipids must
combine with water-soluble compounds, such as phospholipids and proteins.
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Lipoprotein classes%TG %Chol LPE
Chylomicrons 86 3 Origin
VLDL 55 12 Pre-
IDL 23 29 Pre-/
LDL 6 42
HDL 3 15
Lp(a) (LDL) (LDL) Pre-
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Appearance of hyperlipidemia
• Standing Plasma Test for chylomicrons– Plasma is placed in refrigerator (4°C) overnight– Chylomicrons accumulate as floating “cream”
layer– Chylomicrons in fasting plasma are abnormal
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Lipoprotein electrophoresis
• LEP is no longer a common laboratory test– Standing plasma test for chylomicrons– Total cholesterol, TG, HDL, and LDL can be
measured directly
Pre-
- +
Chylomicrons LDL VLDLLp(a)
HDL
Migration
IDL
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Fredrickson classificationType Refrig. LPE LPs
I Pos, clear Normal TG (chylos)
IIa Neg, clear band LDL
IIb Neg, cloudy , pre- LDL, VLDL
III Occ., cloudy pre- Chol, TG, VLDL
IV Neg, cloudy -2 VLDL
V Pos, cloudy -2 VLDL Chylos
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Measuring HDL cholesterol• Ultracentrifugation is the most accurate method
– HDL has density 1.063 – 1.21 g/mL
• Routine methods precipitate apolipoprotein B with a polyanion/divalent cation– Includes VLDL, IDL, Lp(a), LDL, and chylomicrons
HDL, IDL, LDL, VLDL HDL + (IDL, LDL, VLDL)Dextran sulfate
Mg++
• Newer automated methods use a modified form of cholesterol esterase, which selectively reacts with HDL cholesterol
• Newer automated methods use a modified form of cholesterol esterase, which selectively reacts with HDL cholesterol
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Indirect LDL cholesterol
• Friedewald formula assumes that all cholesterol is VLDL, LDL, and HDL lipoproteins– Chylomicrons are usually low in normal,
fasting subjects, and IDL and Lp(a) are usually insignificant contributors to total cholesterol
• Since VLDL is 55% TG and 12% Chol:[LDL Chol] = [Tot Chol] – [HDL Chol] – [TG]/5
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Direct LDL cholesterol
• Older direct methods for LDL involved precipitation with heparin or polyvinyl sulfate
• Newer methods involve precipitation of VLDL, IDL, and HDL with polyvalent antibodies to Apo A and Apo E– LDL is almost exclusively Apo B-100
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Direct vs. Indirect LDL
• The Friedewald equation assumes that chylomicrons, IDL, and Lp(a) are not significant– Non-fasting specimens can have chylomicrons– TG > 400 mg/dL indicates the presence of
chylomicrons (or remnants)
• Type III hyperlipidemia is characterized by high -VLDL, which has a 3:1 TG:C ratio
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Apolipoproteins
• The protein composition differs from one lipoprotein class to another, and the protein constituents are called Apolipoproteins
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Functions of apolipoproteins
• Activate enzymes involved in lipid metabolism (LCAT, LPL)
• Maintain structural integrity of lipid/protein complex
• Delivery of lipids to cells via recognition of cell surface receptors
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Apolipoprotein content of LPs
Lipoprotein Apolipoprotein(s)
Chylomicron AI, B-48, CI, CII, CIII
VLDL B-100, CI, CII, CIII, E
IDL B-100, E
LDL B-100
HDL AI, AII
Lp(a) (a), B-100
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Cholesterol metabolism (exogeneous)Dietary cholesterol,
triglycerides
C,TG
B
A
Chylomicron
Apo-C, E from HDL
Endotheliu
m
LPLC,TG
B
A
CE
C,TG
BE
Chylomicronremnant
Hepatocyte B/E receptors
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Cholesterol metabolism (endogeneous)
C,TG
B
VLDL
Endotheliu
m
LPL
C,TG
BE
IDLLDL
EC
C
B
Hepatocyte B-100receptors
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Dyslipoproteinemias
• Causes can be primary or secondary– Secondary causes include starvation, liver disease,
renal failure, diabetes, hypothyroidism, lipodystrophies, drugs
• Primary causes of hyperlipidemia:– Increased production
– Defective processing
– Defective cellular uptake
– Inadequate removal
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Dyslipoproteinemias
• Hyperchylomicronemia– LPL deficiency– Apo C-II deficiency
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HyperchylomicronemiaDietary cholesterol,
triglycerides
C,TG
B
A
Chylomicron
Apo-C, E from HDL
Endotheliu
m
LPLC,TG
B
A
CE
C,TG
BE
Chylomicronremnant
Hepatocyte B/E receptors
ChylomicronsTriglyceridesHDLLDL
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Dyslipoproteinemias
• Hyperchylomicronemia– LPL deficiency
– Apo C-II deficiency
• Hyperbetalipoproteinemia– Overproduction of VLDL
– Enhanced conversion of VLDL to LDL
– LDL enriched with cholesteryl esters
– Defective LDL structure
– Decreased LDL receptors
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Hyperbetalipoproteinemia
C,TG
B
VLDL
Endotheliu
m
LPL
C,TG
BE
IDLLDL
EC
C
B
Hepatocyte B-100receptors
LDLNormal TG
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Dyslipoproteinemias
• Combined hyperlipoproteinemia– Normal LDL receptors– Overproduction of VLDL and Apo B-100
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Combined hyperlipoproteinemia
C,TG
B
VLDL
Endotheliu
m
LPL
C,TG
BE
IDLLDL
EC
C
B
Hepatocyte B-100receptors
LDLNormal TG
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Dyslipoproteinemias
• Combined hyperlipoproteinemia– Normal LDL receptors– Overproduction of VLDL and Apo B-100
• Dysbetalipoproteinemia– Both cholesterol and triglyceride elevated– Mutant form of Apo E
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DysbetalipoproteinemiaDietary cholesterol,
triglycerides
C,TG
B
A
Chylomicron
Apo-C, E from HDL
Endotheliu
m
LPLC,TG
B
A
CE
C,TG
BE
Chylomicronremnant
Hepatocyte B/E receptors
CholesterolTG
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Dyslipoproteinemias
• Familial hypercholesterolemia– Defect in LDL receptor
• Absent
• Defective
– Incidence = 1:500
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Familial hypercholesterolemia
C,TG
B
VLDL
Endotheliu
m
LPL
C,TG
BE
IDLLDL
EC
C
B
Hepatocyte B-100receptors
LDLor n TGHDL
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Dyslipoproteinemias
• Familial hypercholesterolemia– Defect in LDL receptor
• Absent
• Defective
– Incidence = 1:500
• Familial defective Apolipoprotein B-100
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Familial hypercholesterolemia
C,TG
B
VLDL
Endotheliu
m
LPL
C,TG
BE
IDLLDL
EC
C
B
Hepatocyte B-100receptors
or n LDL
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High cholesterol, high LDL
• Diet/Lifestyle• 2° to hypothyroidism or nephrotic syndrome
(disruption of Apo-B metabolism)• Polygenic: (means we don’t know)• Familial hypercholesterolemia• Familial defective Apo-B• Rare disorders
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High TG, normal cholesterol
• Diet/Lifestyle• 2° to diabetes, thiazide diuretics, Cs, beta-
blockers, CRF/Nephrotic syndrome• Familial hypertriglyceridemia (etiology
unknown)• ApoC-III excess (interferes with LPL)• LPL deficiency• ApoC-II deficiency
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High cholesterol, TG
• Obesity
• 2° to steroids, Cs, hypothyroidism, CRF
• Familial combined hyperlipidemia (multifactorial)
• Peroxisome proliferator-activator receptor
• Dysbetalipoproteinemia (Type III)
• Hepatic lipase deficiency (rare)
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Low cholesterol, low/normal HDL
• Abetalipoproteinemia (ApoB degraded after synthesis causes fat malabsorption)
• Hypobetalipoproteinemia (genetically defective ApoB)
• Chylomicron retention disease (unknown cause)
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Low HDL
• Lifestyle
• 2° to steroids, beta-blockers, progestogens
• Familial hypoalphalipoproteinemia (ApoA-I, C-III, or A-IV defects)
• ApoA-I variants
• Tangier disease (enhanced HDL degredation)
• LCAT deficiency
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High HDL
• Lifestyle (ethanol)
• 2° to phenytoin, phenobarbitol, rifampicin (p-450 inducers) and estrogens
• Cholesteryl Ester Transfer Protein defects