Lipoproteins
Overview of lipoproteins
Lipoproteins (in order of
descending density)
Composition
Function
Apolipoproteins
High-density
lipoprotein (HDL)
Mostly proteins and
phospholipids
Some cholesterol
Few triglycerides
Secreted by intestinal epithelium and liver
Transport cholesterol from peripheral tissues (e.g., atherosclerotic arteries) to
the liver (reverse cholesterol transport), where it is excreted (e.g., via bile)
Stores apolipoproteins essential VLDL and chylomicron metabolization (C, E)
HDL synthesis is stimulated by alcohol
Often referred to as “good cholesterol.”
A-I (65%), A-II (30%),
C-II, E
Low-density
lipoprotein (LDL)
Mostly cholesterol
Some phospholipids and proteins
Few triglycerides
Arise from IDL that is modified by hepatic lipases in peripheral tissue and the liver
Transport cholesterol from the liver to peripheral tissues and arteries
Target cells absorb LDL through receptor-mediated endocytosis
Often referred to as “bad cholesterol”
B-100
Intermediate-density
lipoprotein (IDL)
Triglycerides, cholesterol,
eins, and phospholipids
(quite equal proportions)
Degradation of VLDL into IDL
Transport triglycerides and cholesterol to the liver
B-100, E
Very low-density
lipoprotein (VLDL)
Mostly triglycerides
Some cholesterol and
phospholipids
Few proteins
Secreted by the liver
Transport hepatic triglycerides from the liver to peripheral tissues
B-100, C-II, E
Chylomicron
Mostly triglycerides
Some proteins
Very little cholesterol and
phospholipids
Secreted by the intestinal epithelial cells into lymphatics
Transport dietary triglycerides from the intestine to peripheral tissues
Transport cholesterol to the liver in the form of triglyceride-depleted chylomicron remnants
B-48, C-II, E
prot
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Apolipoproteins
Apolipoproteins are a specialized group of proteins that associate with lipids
and mediate several steps in lipid metabolism.
Functions:
§
Structural proteins for lipid particles
§
Enzyme cofactors: Apolipoproteins regulate the activities of
enzymes (LPL, HL, LCAT, CETP), and can transfer between different
lipoprotein classes.
§
Ligands for cell surface receptors: Apolipoproteins control cellular
uptake of lipoproteins through binding to membrane lipoprotein
receptors.
o apoB100 and apo E bind to the apoB/E (LDL) receptor;
apoE also binds to the LDL receptor related protein (LRP).
o Apo A bind to the scavenger receptor B1
Types: A, B, C, D, E, H (also F and G, but they play a smaller role)
Apolipoprotein
Apo E
Function
Component of
Mediates remnant uptake by the liver; binding to LDL and remnant receptors
All except for LDL
Apo A-I
Activates LCAT
HDL
Apo C-II
Cofactor for LPL (lipoprotein lipase), which participates in the cleavage of the substrates of the enzymes
Insulin increases regulation of C-II
Chylomicron
VLDL
HDL
Apo B-48
Mediates the secretion of chylomicron particles that originate from the intestine into the lymphatics
Chylomicron
Chylomicron remnant
Apo B-100
Mediates endocytosis of LDL by binding to LDL receptors on hepatic and extrahepatic tissues
Particles originating from the liver
LDL
IDL
VLDL
Clinical Utility of apo A1, apo B-100, and Lp(a)
https://www.aacc.org/science-and-research/scientific-shorts/2020/what-is-the-clinical-utility-of-measuring-apolipoprotein-b-in-addition-to-the-standard-lipid-profile
1) Apo B100
One molecule of apolipoprotein B (apo B) is present in all atherogenic lipoproteins, including chylomicrons, VLDL, IDL, LDL, and Lp(a).
Measurement of apo B is available through automated and standardized immunoassays and provides an efficient and inexpensive method to reflect the number of
atherogenic particles
§
apoB as the most accurate marker representing atherogenic lipoproteins for predicting cardiovascular risk (2020 European Society of Cardiology)
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§
§
§
§
apo B is typically highly correlated with metrics in the standard lipid profile (LDL-C and non-HDL-C) with few exceptions (e.g. DM, metabolic syndrome)
apo B measurement to assess ASCVD risk is especially important in modern society with the burden of overweight and obesity, metabolic syndrome and
diabetes. Current evidence supports screening of apo B in addition to standard lipid profile at early ages to reduce lifetime ASCVD risk, and to monitor
apo B following lipid-lowering treatment.
Apo B is included in current 2021 CCS dyslipidemia guidelines: apoB can be used for initiating statin therapy or as a goal of therapy
Useful in differentiating familial hypertriglyceridemia (no risk of CAD) from combined familial hyperlipidemia (high risk of CAD).
2) Apo A1
§
Apo A1 is major structural protein of HDL
§
Decreased levels have been associated with higher risk of premature CAD, but not measured routinely (not included in CCS guidelines.
§
several studies support the apoB/apoA-I ratio to be a better predictor of CVD risk when compared to individual parameters of standard lipid tests, but
without added benefit in comparison to cholesterol and HDL
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The exogenous pathway:
(The process of ingestion and absorption of dietary lipids - predominately triglycerides (TG) and cholesterol (2040% of daily cholesterol requirements))
§ TGs are solubilized by bile acids and digested by pancreatic lipase into free fatty acids and monoglycerides +
free glycerol and diacylglycerides. These are absorbed by enterocytes and repackaged into chylomicrons
together with Apo B48 (Apo B48 does not interact with LDL receptor) and a little esterified cholesterol.
§ Chylomicrons enter mesenteric lymph and pass into blood circulation through the thoracic duct.
§ Circulating HDL transfers Apo C-II and Apo E to the chylomicron. Apo C-II interacts with LPL produced by
muscle and adipose tissue and bound to luminal side of capillaries.
§ LPL hydrolyses and cleaves TG from chylomicrons into monoglycerides + free glycerol and diacylglycerides to
be taken up by adipose tissue (resynthesized into TGs for storage) and muscle (used for energy). Chylomicrons
are now chylomicron remnants.
§ Apo C-II is then transferred to HDL and remnants are taken up by liver from circulation via interaction of
hepatic LRP1 and LDL receptors with Apo E on chylomicron remnants.
Endogenous pathway: (Synthesis of lipoproteins and delivery of lipids from liver to tissues)
§
VLDL is synthesized in liver (TG + cholesterol + cholesterol esters + Apo C-II + Apo E + 1 molecule of Apo B100) and released into circulation
§
LPL on capillaries hydrolyse VLDL TGs to release free fatty acids and monoglycerides for energy and storage by
muscle and adipose tissue. Apo C-II is an essential cofactor for LPL, while apo C-III is a potent inhibitor of LPL.
§
VLDL also sheds Apo C-II to HDL to become IDL.
§
If IDL sheds TG with further hepatic lipase (HL) hydrolysis and transfer of Apo E to HDL it will become LDL. LDL
can then be removed from circulation by liver with interaction of LDL receptor and Apo B-100 (weak
interaction) or Apo E (strong interaction) [from white book].
§
HDL can transfer cholesterol to lipoproteins in exchange for TG via cholesterol ester transport protein (CETP).
Reverse cholesterol transport: (Returning excess cholesterol from tissue to the liver)
§
liver and small intestine produce nascent HDL
§
intracellular maturation of proapolipoprotein AI (apoA-I) into apoA-I
§
early acquisition of phospholipids (PL) and free cholesterol (FC) of apoA-I through ATP-binding cassette transporter A1 (ABCA1) activity, which results in the production of
pre-β-HDL at the cellular membrane
§
nascent HDL matures through the acquisition of cholesteryl ester (CE) that are generated by lecithin:cholesterol acyltransferase (LCAT). The enrichment of the core of HDL
with CE causes HDL to become spherical and less dense (generating the HDL3 and HDL2 subspecies)
§
Cholesteryl ester transfer protein (CETP) facilitates transfer of CE from HDL to triglyceride-rich lipoprotein (TRL) in exchange for triglycerides (TG)
§
actions of both hepatic lipase (HL) and endothelial lipase break down HDL-TG and PL, respectively, enhance the dissociation of lipid-free or lipid-poor apoA-I from larger
HDL, making HDL prone to renal catabolism via LDL–related protein 2 (LRP2) and cubilin (CUBN)
§
lipoprotein lipase (LPL)–mediated lipolysis of TG in triglyceride-rich lipoproteins (TRL), which include activators/modulators (apo C-II), and inhibitors (apo C-III) frees
constituents (apolipoproteins, PL, and FC) for the pool of HDL particles.
§
SR-BI (scavenger receptor class B, type I), the main HDL receptor, can mediate the uptake of CE in the liver and in adrenal gland, testes, ovaries via apo A-I binding. Mature
HDL can also gain apoE, which enables additional hepatic clearance by LDL receptor.
§
Once HDL is removed from circulation, the cholesterol it contained can be converted into hormones, repackaged as VLDL cholesterol, or excreted into the gastrointestinal
tract as bile acids.
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Enzyme
Hepatic lipase (HL)
Site
Released by the liver and activated in the bloodstream
Function
Hydrolyze triacylglycerides remaining in IDL particles (also called hepatic triglyceride lipase)
Hormone-sensitive lipase
Intracellular
Hydrolyzes triglycerides and diglycerides stored in adipocytes into monoglycerides (lipolysis)
Lecithin-cholesterol
acyltransferase (LCAT)
Found on the surface of HDL (synthesized by the liver)
Lipoprotein lipase (LPL)
Secreted in vascular endothelial surface of extrahepatic
tissues (esp. adipose tissue, heart, and skeletal muscle)
Cholesteryl ester transfer
protein (CETP)
Synthesized by the liver, secreted into the blood stream
Catalyzes esterification of plasma cholesterol (converts approx. ⅔ free cholesterol into cholesteryl
ester)
Nascent HDL → mature HDL
Activated by Apo A-I
Hydrolyzes triglycerides circulating in chylomicrons and VLDLs into fatty acids and glycerine, which can
be taken up by cells
Upregulated by insulin
Transport protein
Promotes the transfer of cholesteryl esters from HDL to apoB containing lipoproteins (chylomicrons,
VLDL, IDL, LDL) in exchange for TG à HDL cholesterol decreases, and cholesterol content in VLDL
increases
PCSK9
A protease that mediates the degradation of LDL receptors
Binding of PCSK9 to LDL receptors → internalization and breakdown of LDL receptors → inability of LDL
receptors to bind LDL → ↑ in serum LDL
Inhibition of PCSK9 → ↑ recycling of LDL receptors → ↓ serum LDL
Pathway
Exogenous
Enzyme/transport protein
Receptor
MTP (packages TG, PL, FFA to form CM) | Abetalipoproteinemia
LDLR (apo E) |Type 2a,b
LPL (hydrolyzes TG) |apo E, C-II activate; C-III inhibits | Type 1
hepatic LRP1
Endogenous MTP (secretes VLDL) | Abetalipoproteinemia
LDLR (apo E strong, apo B-100 weak)
LPL (hydrolyzes TG) |apo E, C-II activate; C-III inhibits | Type 1
remnant receptor (apo E)
hepatic lipase | no cofactors, insulin regulated
CETP (exchange of cholesterol in HDL for TG in TRP)
PCSK9 (degrades LDL receptors) | hypobetalipoproteinemia
Reverse
ABCA1 (production of nascent HDL) | Tangier’s disease, hypoalphalipoproteinemia
SR-B1 (apo A-I)
LCAT (maturation of HDL, activated by apo A-I) | hypoalphalipoproteinemia
LDLR (if HDL gains apo E)
CETP (exchange of cholesterol in HDL for TG in TRP)
hepatic lipase (HL)
renal catabolism LDLrp2 or cubilin (post HL degradation)
LDLR, LDL receptor; LPL, lipoprotein lipase; MTP, mitochondrial transport protein; CETP, cholesteryl ester transfer protein; SR-B1, scavenger receptor class B type 1; TRP,
triglyceride rich particles (i.e. chylomicrons, VLDL, IDL, LDL)
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Secondary Dyslipidemia
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I
Frederickson classification of inherited hyperlipoproteinemias
IIb
III
Familial
Familial combined
Familial
hypercholesterolemia
hyperlipidemia
dysbetalipoproteinemia
(or remnant
hyperlipoproteinemia)
Heterozygous: 1:500
1:50–1:200
1:1000–1:5000
Homozygous: very rare
(approx, 1:1,000,000)
IIa
IV
Familial
hypertriglyceridemia
V
Mixed hyperlipidemia
1:50–1:100
Very rare
Autosomal recessive
Autosomal dominant
Autosomal recessive
Defective ApoE
Hepatic overproduction
of VLDL or defective Apo
A-5
Defective Apo A-5
Premature atherosclerosis
Palmar and Tuberoeruptive
xanthomas
Premature atherosclerosis
Tuberoeruptive xanthomas
Acute pancreatitis
(if TG> 900 mg/dL)
Features of hyperglycemia
(due to abnormal glucose
tolerance and insulin
resistance)
No ↑risk of atherosclerosis
Eruptive xanthomas
Features of hyperglycemia
Abdominal pain
VLDL
Chylomicrons and VLDL
Massively ↑
Remnants
of VLDL and chylomicrons
↑
Normal to mildly ↑
↑
LDL
LDL
VLDL
Chylomicrons
VLDL
VLDL
Chylomicrons
VLDL
Massively ↑
Can be > 2,000 mg/dL
Normal
↑
↑
Massively ↑
Massively ↑
Creamy top layer
Clear
Clear
Turbid
Turbid
Creamy top and turbid
bottom layer
Condition
Familial
hyperchylomicronemia
Frequency
Rare
Inheritance
Autosomal recessive
Autosomal dominant
Pathogenesis
Deficiency
of lipoprotein lipase
(LPL) or Apo C-II
Defective LDL receptors or ApoB100, missing LDL receptors
Clinical
manifestations
No increased risk
of atherosclerosis
Eruptive xanthomas
Hepatosplenomegaly
Recurrent episodes
of acute
pancreatitis and/or
abdominal pain
Lipemia retinalis
Bile duct stenosis
Premature atherosclerosis, may lead to myocardial
infarction at a very young age (< 20 years)
Arcus lipoides corneae
Tuberous/tendon xanthomas (especially
the Achilles tendon) in type IIa
Xanthelasma in type IIb
Lipoprotein
defect
Total cholesterol
Chylomicrons
LDL
LDL and VLDL
Normal to mildly ↑
Homozygotes: > 600
mg/dL
Heterozygotes: > 250
mg/dL
Elevated
serum lipoprotei
ns
TG
Chylomicrons
Overnight
plasma
(apo E genotyping test)
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