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Lukasz Materek
Endocrinology Rounds
August 10, 2011
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Review cholesterol transport
LDL receptor
Understand genetic lipid disorders
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LDL receptor is synthesized in the rough
endoplasmic reticulum and processed in the
golgi apparatus before insertion into the cell
membrane within clathrin-coated pits
LDL receptors bind cholesterol-rich LDL
particles through the interaction of apoprotein
B100 and the LDL receptor
Receptor-bound LDL is then carried into the
cell via endocytosis. LDL dissociates from the
receptor, which is either recycled to the cell
surface or degraded
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Cholesteryl esters are hydrolyzed within
intracellular lysosomes
cholesterol molecules can then be utilized as
substrate in various biosynthetic pathways
cholesterol produced from hydrolysis of LDL
particles exerts a negative feedback effect on de
novo cholesterol synthesis by mevalonate
pathway, as well on the synthesis of new LDL
receptors
Intracellular cholesterol also stimulates activation
of the enzyme acetyl-coenzyme A (CoA)
cholesteryl acyltransferase (ACAT), which helps to
re-esterify cholesterol for intracellular storage
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de novo synthesis of cholesterol occurs via a series of
biochemical reactions
synthesis of mevalonate from acetyl-CoA and
acetoacetyl-CoA by the enzymes 3-hydroxy-3methylglutaryl (HMG)-CoA synthase and
HMG-CoA reductase.
Endogenous intracellular cholesterol, obtained from
plasma LDL, inhibits both of these enzymes, thus
regulating de novo cholesterol synthesis.
Low levels of mevalonate continue to be produced,
however, to maintain a supply of the non-sterol
isoprenoids.
In the presence of LDL cholesterol and excess
mevalonate, this pathway is shut off entirely
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The mechanism of action of the statin drugs is
the inhibition of the enzyme HMG-CoA
reductase, the rate-limiting step in this process.
In response to inhibition of HMG-CoA
reductase, hepatocytes increase expression of
LDL receptors.
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Proprotein convertase subtilisin kexin type 9
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PCSK9 is a protease expressed in the liver
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When LDL cholesterol binds to the LDL
receptor, they are both internalized into the cell
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If the cholesterol-bound LDL receptor is also
bound to PCSK9, the LDL receptor is redirected
for lysosomal degradation and prevented from
recycling to the cell surface.
If an internalized LDL receptor is not bound to
PCSK9, the receptor is recycled to the cell
surface, where it continues to remove LDL
cholesterol from circulation.
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permits efficient transport of dietary lipids
Dietary triglycerides are hydrolyzed by lipases within
the intestinal lumen and emulsified with bile acids to
form micelles
Dietary cholesterol, fatty acids, and fat-soluble
vitamins are absorbed in the proximal small intestine.
Cholesterol and retinol are esterified (by the addition
of a fatty acid) in the enterocyte to form cholesteryl
esters and retinyl esters, respectively.
Longer-chain fatty acids (>12 carbons) are incorporated
into triglycerides and packaged with apoB-48,
cholesteryl esters, retinyl esters, phospholipids and
cholesterol to form chylomicrons.
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chylomicrons are secreted into the intestinal lymph and delivered
via the thoracic duct directly to the systemic circulation
particles encounter lipoprotein lipase (LPL), which is anchored to
proteoglycans on the capillary endothelial surfaces of adipose
tissue, heart and skeletal muscle
triglycerides of chylomicrons are hydrolyzed by LPL, and free
fatty acids are released.
ApoC-II, which is transferred to circulating chylomicrons from
HDL, acts as a cofactor for LPL in this reaction.
the released free fatty acids are taken up by adjacent myocytes or
adipocytes and either oxidized to generate energy or reesterified
and stored as triglyceride.
some of the released free fatty acids bind albumin before entering
cells and are transported to other tissues, especially the liver.
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The chylomicron particle progressively shrinks in
size as the hydrophobic core is hydrolyzed
hydrophilic lipids (cholesterol and phospholipids)
and apolipoproteins on the particle surface are
transferred to HDL, creating chylomicron
remnants.
Chylomicron remnants are rapidly removed from
the circulation by the liver through a process that
requires apoE as a ligand for receptors in the liver.
Consequently, few, chylomicrons or chylomicron
remnants are present in the blood after a 12-h fast
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hepatic secretion of apoB-containing lipoproteins and
their metabolism
VLDL particles resemble chylomicrons in protein
composition but contain apoB-100 rather than apoB-48
and have a higher ratio of cholesterol to triglyceride
The triglycerides of VLDL are derived predominantly
from the esterification of long-chain fatty acids in the
liver.
The packaging of hepatic triglycerides with the other
major components of the nascent VLDL particle (apoB100, cholesteryl esters, phospholipids, and vitamin E)
requires the action of the enzyme microsomal
triglyceride transfer protein (MTP)
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After secretion into the plasma, VLDL acquires
multiple copies of apoE and apolipoproteins of
the C series by transfer from HDL.
As with chylomicrons, the triglycerides of
VLDL are hydrolyzed by LPL, especially in
muscle and adipose tissue.
After the VLDL remnants dissociate from LPL,
they are referred to as IDLs, which contain
roughly similar amounts of cholesterol and
triglyceride.
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The liver removes approximately 40–60% of
IDL by LDL receptor–mediated endocytosis via
binding to apoE.
The remainder of IDL is remodeled by hepatic
lipase (HL) to form LDL.
During this process, most of the triglyceride in
the particle is hydrolyzed, and all
apolipoproteins except apoB-100 are
transferred to other lipoproteins.
The cholesterol in LDL accounts for over half of
the plasma cholesterol in most individuals
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Approximately 70% of circulating LDL is
cleared by LDL receptor–mediated endocytosis
in the liver.
Lipoprotein(a) [Lp(a)] is a lipoprotein similar
to LDL in lipid and protein composition, but it
contains an additional protein called
apolipoprotein(a) [apo(a)].
Apo(a) is synthesized in the liver and attached
to apoB-100 by a disulfide linkage. The major
site of clearance of Lp(a) is the liver, but the
uptake pathway is not known.
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Pathway transports excess cholesterol from the
periphery back to the liver for excretion in the bile.
The liver and the intestine produce nascent HDLs.
Free cholesterol is acquired from macrophages and
other peripheral cells and esterified by LCAT,
forming mature HDLs.
HDL cholesterol can be selectively taken up by the
liver via SR-BI (scavenger receptor class BI).
Alternatively, HDL cholesteryl ester can be
transferred by CETP from HDLs to VLDLs and
chylomicrons, which can then be taken up by the
liver.
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All nucleated cells synthesize cholesterol, but
only hepatocytes and enterocytes can
effectively excrete cholesterol from the body,
into either the bile or the gut lumen. In the
liver, cholesterol is excreted into the bile, either
directly or after conversion to bile acids.
Cholesterol in peripheral cells is transported
from the plasma membranes of peripheral cells
to the liver and intestine by a process termed
"reverse cholesterol transport" that is facilitated
by HDL
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Transporter - major regulator of cellular
cholesterol and phospholipid homeostasis
ABCA1 mediates the efflux of cholesterol and
phospholipids to lipid-poor apolipoproteins (apo-A1
and apoE), which then form nascent high-density
lipoproteins (HDL)
It also mediates the transport of lipids between Golgi
and cell membrane
Mutations in this gene have been associated with
Tangier disease / familial high-density lipoprotein
deficiency
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Lipoprotein lipase deficiency
Gene Defect: LPL (LPL)
Increased Chylomicrons
Eruptive xanthomas, hepatosplenomegaly,
pancreatitis
AR
1/1,000,000
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Familial apolipoprotein C-II deficiency
Gene Defect ApoC-II (APOC2)
Increased Chylomicrons
Eruptive xanthomas, hepatosplenomegaly,
pancreatitis
AR
<1/1,000,000
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ApoA-V deficiency
Gene defect ApoA-V (APOAV)
Increased Chylomicrons, VLDL
Eruptive xanthomas, hepatosplenomegaly,
pancreatitis
AD
<1/1,000,000
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Familial hepatic lipase deficiency
Gene defect Hepatic lipase (LIPC)
Increased VLDL remnants
Premature atherosclerosis, pancreatitis
AR
<1/1,000,000
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Familial dysbetalipoproteinemia
Gene defect apoE (APOE)
Increased Chylomicron and VLDL remnants
Palmar and tuberoeruptive xanthomas, CAD,
PVD
AR/AD
1/10,000
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Familial hypercholesterolemia
Gene Defect LDL receptor (LDLR)
Increased LDL
Tendon xanthomas, CAD
AD
1/500
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Familial defective apoB-100
Gene Defect apoB-100 (APOB)
Increased LDL
Tendon xanthomas, CAD
AD
<1/1000
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Autosomal dominant hypercholesterolemia
Gene defect PCSK9 (PCSK9)
Increased LDL
Tendon xanthomas, CAD
AD
<1/1,000,000
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Autosomal recessive hypercholesterolemia
Gene defect ARH (ARH)
Increased LDL
Tendon xanthomas, CAD
AR
<1/1,000,000
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Sitosterolemia
Gene defect ABCG5 or ABCG8
Increased LDL
Tendon xanthomas, CAD
AR
<1/1,000,000
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Familial Hypercholesterolemia (FH)
Familial Defective ApoB-100 (FDB)
Autosomal Recessive Hypercholesterolemia
(ARH)
Autosomal Dominant Hypercholesterolemia
(ADH)
Sitosterolemia
Polygenic Hypercholesterolemia
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Familial Chylomicronemia Syndrome (Type I
Hyperlipoproteinemia; Lipoprotein Lipase and
ApoC-II Deficiency)
ApoA-V Deficiency
Hepatic Lipase Deficiency
Familial Dysbetalipoproteinemia (Type III
Hyperlipoproteinemia)
Familial Hypertriglyceridemia (FHTG)
Familial Combined Hyperlipidemia