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Slide 1

Lipoprotein Metabolism

Steen E. Pedersen
spedersen@rossu.edu

Reading Assignment:
Meisenberg and Simmons, 4th edition, Chapter 27.

Pedersen 2019 January 8 1

Appointments by email.
Office hours will be announced once we get a system in place.
Slide 2

Lipoprotein Metabolism
Objectives
• Discuss the composition and functions of the different lipoproteins and importance
of lipoprotein lipase
• Explain the reverse cholesterol transport pathway and its importance in other
lipoprotein metabolic pathways
• Outline the mechanisms and regulation of intracellular cholesterol and its importance
in disease states
• Describe the hyperlipidemias and their importance in disease states with emphasis on
ischemic heart disease
• Discuss the relationship between hypercholesterolemia and CHD
• Know Fredricksons classification of hyperlipidemias
• Explain cholesterol synthesis; describe its regulation, rate-limiting step and drugs that
target it.

Pedersen 2019 January 8 2


Slide 3

Lipoprotein Metabolism
Coverage
• Clinical problems related to lipoproteins
• Lipoprotein particles, properties and composition
• Metabolism of the various lipoproteins:
– Chylomicrons
– VLDL
– LDL
– HDL
• Regulation of Cholesterol and its synthesis
• Abnormalities in lipoprotein metabolism
– Atherosclerosis
– Hyperlipidemias

Pedersen 2019 January 8 3


Slide 4

Lipoprotein Metabolism
Introduction
• Lipids:
– Generally water insoluble
– Can form small vesicles or
micelles
• Lipid Plasma Transport
– Requires carrier method to
make soluble
– Formation of particles
• Lipoproteins Ferry Lipids

Pedersen 2019 January 8 4

Lipoprotein Particle General structure

Lipoproteins are mixtures of lipids and proteins.


Their purpose is to traffic lipids through the body

Lipoproteins: mixtures of protein, phospholipids, triglycerides, cholesterol, and


cholesterol esters.
Apolipoproteins: are the proteins that constitute part of the lipoprotein particle
- Structure
- Identification
- receptor uptake ligand
- Interaction with enzymes

Lipoprotein structure:
A shell that is a monolayer of phospholipids and cholesterol (looks like ½ of a
lipid bilayer)
Apolipoproteins embedded in the shell.
A hydrophobic core
Slide 5

Lipoprotein Metabolism
Related Clinical problems
Worldwide
• Lipoproteins are directly or Causes of
mortality
indirectly implicated or related to
many clinical problems:
– Atherosclerosis
– Hypertension
– Coronary artery disease
– Lipoproteinemias (hypo- and hyper-) Worldwide
mortality from
– Fatty Liver disease Cardiovascular
diseases

Pedersen 2019 January 8 5

Abnormal lipoprotein metabolism is implicated in or correlated with many cardiovascular


diseases.
These are a major cause of mortality.

In addition, other diseases, including lipoproteinemias and fatty liver disease are also
related to abnormal lipoprotein metabolism.
Slide 6

Lipoprotein Structure
Overall
• Lipoproteins have two principal
components:
– Lipids
• Differ according to the type of
lipoprotein
• Depends on what is being transported –
different lipids occur in various
combinations
– Apo-lipoproteins
• Structural function
• recognition

Pedersen 2019 January 8 6


Slide 7

Lipoprotein Structure
Lipid Composition
• Lipid Components of
lipoproteins:

• Outer shell:
– Predominantly phospholipids
– Also un-esterified cholesterol
• Core:
– Triglycerides
– Esterified cholesterol (cholesterol
esters, CE)

Ferrier: Figure 18.14


Pedersen 2019 January 8 7
Slide 8

Lipoprotein Structure
Protein Composition
• Protein component: apolipoproteins
– Five Major Classes:
• A-I, A-II
• B-48, B-100
• C-I, C-II, C-III
• D
• E
• Classed according to structure and function
– Some identify particles,
– some interact with LPL (lipoprotein lipase),
– some are recognition sites.
– Some serve a structural role in creating the particle.
• Some exchange between particles

Ferrier: Figure 18.14


Pedersen 2019 January 8 8

Lipoproteins:
The classes are listed in the slide. It is worth familiarizing yourself with these; we will
go through their functions as we cover the lifecycle of the lipoproteins in later slides.
Slide 9

Lipoprotein Types
• Triglyceride transport:
– Chylomicrons from intestine
– VLDL – made in liver

• Cholesterol Transport
– LDL – more free cholesterol
– HDL – more esterified cholesterol
• Higher percentage protein
• Higher percentage phospholipids

Ferrier: Figure 18.19


Pedersen 2019 January 8 9

Triglyceride transport: Chylomicrons and VLDL


Cholesterol transport: LDL and VLDL.
The types of lipoprotein particles:
Chylomicrons:
- Transport dietary triglycerides, cholesterol, lipids, fat soluble vitamins from intestine.
- Synthesized in the intestines
- Highest proportion of triglycerides (TG, TAG)
- remnants removed by the liver.
VLDL:
- Transport triglycerides and cholesterol
- Synthesized in the liver
- Eventually becomes IDL and then LDL
LDL
- Delivery of cholesterol to peripheral tissues.
- Derived from VLDL via IDL.
- Taken up in peripheral tissues and liver.
HDL
- Recycling, uptake of cholesterol.
- Synthesized in the liver and in the intestines.
- Reservoir for several apolipoproteins
- Undergoes lipid exchange with VLDL
- Undergoes apolipoprotein exchange with chylomicrons, VLDL, IDL.
- Delivers cholesterol and fatty acids for TG to liver and is recycled.
LDL and HDL are the principal means of cholesterol trafficking. LDL delivers cholesterol
to the peripheral tissues. HDL scavenges it from the periphery for delivery to the liver.
Slide 10

Lipoprotein Types

• Lipoproteins differ in size,


density, and charge.
• They can be separated on the
basis of these.
• Most common is separation by
centrifugation, which works both
through density and size
differences.

Ferrier: Figure 18.13


Pedersen 2019 January 8 10

Older clinical tests typically relied on cholesterol measurements through precipitation


and chemical detection of cholesterol.

Laboratory studies often rely on centrifugation and electrophoresis to definitely separate


and measure the particles. These are typically too expensive for routine clinical use, but
have been vital for understanding lipoprotein metabolism.

Recent clinical tests can use NMR, but this is not yet widely adopted, though likely more
accurate and complete.
Slide 11

Lipoprotein Types

• Lipoproteins can also be


separated by electrophoresis

Ferrier: Figure 18.15


Pedersen 2019 January 8 11
Slide 12

Chylomicrons

Wikipedia

• Assembled in Golgi of intestinal enterocytes


• Packaged into secretory vesicles
• Secreted into extracellular space
• Travels through lymphatic system to left
subclavian vein
Pedersen 2019 January 8 12

Chylomicron Synthesis:
Assembled in intestinal mucosal cells. Secreted through normal secretory system
(Golgi/secretory vesicles).
Lowest density
Largest size
Highest % of lipids and lowest % proteins
Highest triacylglycerol (dietary origin)
Carry dietary lipids to peripheral tissues, including:
- triglycerides
- cholesterol
- fat soluble vitamins

Responsible for physiological milky appearance of plasma, up to 2 hours after meal,


but can persist as long as 6 hours after eating.

Typical lipid panels are done after overnight fasting to remove chylomicron interference
from the measurement of LDL and HDL cholesterol.
Slide 13

Chylomicrons
• Nascent chylomicrons
contain apo B-48
• HDL contributes apo C-II
and apo E to the chylomicron
• LPL is activated by apo C-II
• LPL hydrolyzes triglycerides
to free fatty acids
• Apo C-II is returned to HDL
• Apo E mediates reuptake of
chylomicron remnants by the
liver.
• Type I hyper-lipoproteinemia
results in accumulation of
chylomicrons
Ferrier: Figure 18.16
Pedersen 2019 January 8 13

The life cycle of Chylomicrons:


• Chylomicrons are synthesized in the instestinal mucosal cells (previous slide).
• They contain apo B-48 (the truncated form of apo B).
• Nascent chylomicrons interact with HDL and pick up apo C-II and apo E
• Chylomicrons deliver TAG to:
• Adipose
• Cardiac Muscle
• Skeletal Muscle
• Lipoprotein lipase (LPL) degrades TAG to glycerol and free fatty acids.
• In the fed state, in the presence of insulin, LPL isozymes are regulated
differently:
• LPL is upregulated in adipose
• LPL is downregulated in muscle
• Cardiac muscle has higher LPL than skeletal reflecting its principal reliance
on FA for energy.
• In the fasted state, in the absence of insulin:
• LPL is upregulated in muscle, by epinephrine
• LPL is downregulated in adipose
• LPL is extracellular and is anchored by heparan sulfate to the endothelial cell
capillary walls. It is in the lumen of the capillaries.
• LPL is activated by the apo C-II on the chylomicron.
• Liver has a similar enzyme called hepatic lipase.
• Depleted chylomicrons exchange apo C-II back to HDL
• Chylomicron remnants are taken up through apo E receptors in the liver.
• Chylomicron remnants are rich in cholesterol and cholesterol esters
• Uptake is by endocytosis.
• Chylomicron specific increases in lipoproteins are Type I hyperlipoproteinemias
• Can be caused by low LPL
• Can be caused by apo C-II defect
• Can be caused by inhibitors of LPL in the bloodstream.
Slide 14

Chylomicrons
Role of LPL (lipoprotein lipase)
• LPL is an extracellular enzyme that is anchored by heparan
sulphate to the capillary lumen walls of most tissue, especially
those of adipose tissue, cardiac and skeletal muscles
• Its synthesis and transfer to luminal surface of the capillary in
adipose tissue is stimulated by insulin
• Activated by apo C-II
• Isomers of lipoprotein lipase have different Km’s for TAG
• LPL is absent in adult liver, which has hepatic lipase on the
endothelial surface. Hepatic Lipase assists mainly in HDL
metabolism.

Pedersen 2019 January 8 14


Slide 15

VLDL
• VLDL is assembled in the
liver and secreted.
• Nascent VLDL has apo
B-100
• Apo C-II and apo E are
transferred from HDL to
VLDL
• TAG is removed by LPL in
the capillary bed  IDL
• Transfer of apo C-II and
apo-E back to HDL,
converts particle to LDL.
• LDL delivers cholesterol to
peripheral tissues (muscle).

Ferrier: Figure 18.17


Pedersen 2019 January 8 15

VLDL Life Cycle


• VLDL is made in the liver. It is made constantly in both fed and fasting states.
• TAG synthesized in the liver from FFA uptake, chylomicron remnant uptake,
and FA synthesis.
• Cholesterol synthesized and esterified in the liver or from uptake.
• Contains full length apo B-100
• VLDL picks up apo C-II and apo E from HDL
• VLDL delivers TAG to peripheral tissues
• Adipose
• Muscle
• LPL degrades the TAG to free fatty acids FAs.
• LPL active is regulated as described for chylomicrons
• VLDL becomes IDL when depleted of TAG
• IDL interacts with HDL and becomes LDL
• IDL can be taken up by the liver through apo E receptors (as for chylomicron
remnants)
• Apo C-II is returned to HDL
• Apo E is returned to HDL
• Residual TAG is transferred to HDL
• Cholesterol esters are transferred from HDL to IDL
• The particle with only apo B-100 is now LDL
• LDL Particles:
• Deliver cholesterol and cholesterol esters to peripheral tissues
• Uptake is via the LDL receptor, which recognizes B-100 (and not B-48)
• Can also be taken up by the liver.
• The LDL receptor also recognizes apo E for uptake of chylomicron remnants
and IDL in the liver.

Fatty liver disease


• Reflects an imbalance between liver TAG synthesis and VLDL production,
resulting in an accumulation of TAG in the liver.

Abetalipoproteinemia
1. A defect in both B-48 and B-100 production and results in a failure of distribution of
lipids from the instestine. As a result, triglycerides accumulate in the intestines and in
the liver.
Slide 16

Low Density Lipoprotein, LDL


• Produced in the circulation as the end product
of VLDLs
• Compared to VLDLs:
– It contains only apo B-100
– Smaller size and more dense
– Less TG
– More cholesterol & cholesterol esters
• Transport cholesterol from liver to peripheral
tissues
• Uptake of LDL at tissue level by:
– LDL receptor-mediated endocytosis
– Recognized by apo B-100

Pedersen 2019 January 8 16


Slide 17

Low Density Lipoprotein, LDL


Receptor mediated endocytosis
• LDL receptor:
• Cell surface glycoprotein
• High-affinity, tightly regulated
• LDL/Receptor binding and
internalization of the complex by
endocytosis
• Release of cholesterol inside the
cells for:
• Utilization
• Storage as cholesterol ester
• Excretion
Ferrier: Figure 18.20
Pedersen 2019 January 8 17

LDL uptake and regulation of Cholesterol synthesis.


Slide 18

Low Density Lipoprotein, LDL


Receptor mediated endocytosis
• Fate of LDL
– Degradation of LDL into amino
acids, phospholipids, fatty acids,
and cholesterol.
• Degradation or recycling of
receptor
• Cholesterol –
– Converted to esters by ACAT for
storage
– Excreted in bile or as bile salts
Ferrier: Figure 18.20
Pedersen 2019 January 8 18

LDL uptake and regulation of Cholesterol synthesis.


Uptake occurs in most cells.
The liver typically synthesizes cholesterol to supply the body.

Synthesis and uptake is regulated via the following mechanisms:


• cholesterol concentration through inhibition of HMG-CoA reductase
• Regulation of LDL receptors on the cell surface
• Regulation of LDL receptor synthesis.

Note: ACAT = AcylCoA:Cholesterol AcylTransferase. Transfers a fatty acid from acylCoA


to cholesterol and makes a cholesteryl ester.

• Cholesterol cannot be catabolized.


• Cholesterol is lost by excretion
• Excess cholesterol can be excreted in the Bile
• Some cholesterol is used for bile acid synthesis
• Most of the excreted bile salts are taken back up and returned to the liver
• Gall stones occur when excess cholesterol is secreted into the bile and exceeds the
capacity of the bile salts to keep it soluble
• Compounds (resins) that bind cholesterol can be used to prevent reabsorption in the
intestine and lower uptake and thereby lower serum cholesterol.
Slide 19

Low Density Lipoprotein, LDL


Receptor mediated endocytosis
• Down-regulation:
– High intracellular cholesterol content:
• Degradation of LDL receptors
• Inhibition of receptor synthesis at gene
level
– Decrease No. of receptors at cell
surface
• Decrease further uptake of LDL
– Decrease de novo synthesis of
cholesterol
– Increase ACAT activity.
Ferrier: Figure 18.20
Pedersen 2019 January 8 19

LDL uptake and regulation of Cholesterol synthesis.


Slide 20

Low Density Lipoprotein, LDL


Receptor mediated endocytosis
• Up-regulation:
– Low intracellular cholesterol content:
• Recycling of LDL receptors
• Stimulation of receptor synthesis at gene
level
– Increase No. of receptors at cell
surface
• Increase uptake of LDL
– Increase de novo synthesis of
cholesterol

Ferrier: Figure 18.20


Pedersen 2019 January 8 20

LDL uptake and regulation of Cholesterol synthesis.


Slide 21

Cholesterol Synthesis and Regulation

• Synthesized mainly in liver


• Liver synthesis balances delivery
from
– Chylomicron remnants
– HDL
• And Loss to:
– Bile synthesis and excretion
– VLDL
• First step is synthesis of
HMG-CoA

Pedersen 2019 January 8 21

Colesterol is synthesized principally in the Liver.


The First steps are the same as for ketone body synthesis.
Slide 22

Cholesterol Synthesis and Regulation

• HMG CoA reductase


– Major regulated step of Cholesterol
synthesis
– Regulated principally by expression
• Insulin upregulates
• Glucagon/glucocorticoids suppress
– Also regulated through phosphorylation
• Major drug target
– Statins are competitive inhibitors of
HMG CoA reductase

Pedersen 2019 January 8 22

Cholesterol is synthesized principally in the Liver.


HMG CoA reductase is the major point of regulation of cholesterol synthesis.
HMG CoA is the target of the statin drugs, which inhibit cholesterol synthesis.
Slide 23

Cholesterol
Synthesis and
Regulation
• Overall synthesis
• Multistep process
• Requires NADPH
• Essentially couples
AcCo in several steps:
– Mevalonate, IPP (5 C)
– Geranyl PP (10 C)
– Farnesyl (15 C)
– Squalene (30 C)

Pedersen 2019 January 8 23

Cholesterol is synthesized principally in the Liver.


Mevalonate conversion to Cholesterol is a long multistep synthesis.

Key Points:
Pyrophosphorylation helps with solubility.
IPP (5C) combines via DPP to make Geranyl-PP (10C)
One more IPP makes Farnesyl-PP. Three total IPPs combine to make farnesyl-PP
Two farnesyl-PP combine to make squalene.
Squalene goes to lanosterol – the first sterol.
Slide 24

Cholesterol Synthesis and Regulation

Pedersen 2019 January 8 24

Cholesterol is synthesized principally in the Liver.


HMG CoA reductase is regulated through enzyme levels and through phosphorylation
and through feedback inhibition by cholesterol (not shown).
Regulation of HMG CoA reductase by transcriptional regulation.
Cholesterol acts through a feedback inhibitory mechanism to inhibit SREBP release,
and thereby hinders transcription.

SRE = steroid regulatory element


SREBP = steroid regulatory element binding protein
SREBP-SCAP = SREBP-activating protein.

Hormonal regulation HMG CoA reductase:


Phosphoprotein phosphatase activates by dephosphorylation (stimulated by insulin and
inhibited somewhat by glucagon or epinephrine). Thus Insulin/glucagon also regulate
cholesterol synthesis.
AMPK inactivates (senses energy level of the hepatocyte).
(Recall that AMPK is a master kinase that regulates many aspects of metabolism)
Slide 25

Low Density Lipoprotein, LDL


Receptor mediated endocytosis
• Familial Hyper-cholesterolemia
– Mutations in LDL receptor
– No LDL uptake in peripheral tissues
– Homozygotes develop severe
atherosclerosis at a very early age
(<20)
– Heterozygotes (1:5,000) develop high
plasma cholesterol and are
substantially more susceptible to
coronary artery disease.

Pedersen 2019 January 8 25

Study of this disease led directly to insights in LDL metabolism and it’s uptake and the
role of LDL in cardiovascular disease, particularly coronary artery disease.

It further led directly to the creation of HMG-CoA reductase inhibitors as a means of


regulating LDL and serum cholesterol levels. Statins were a direct product of this basic
research into the mechanism of a devastating congenital disease.

Mike Brown and Joseph Goldstein were awarded the Nobel prize for this work in 1985.

Defects in LDL uptake leads to excess LDL in the circulation.


In combination with oxidation of LDL, these are taken up by macrophages and form
foam cells.
Foam cells participate directly in atherosclerotic plaque formation.
Slide 26

Low Density Lipoprotein, LDL


Receptor mediated endocytosis

• Role of oxidized LDL


in arterial plaque
formation:
– Oxidation of LDL
– Endothelial cell injury
– Macrophages engulf
excess oxLDL
– Become foam cells
– Foam cells accumulate
and induce smooth
muscle cell migration.

Ferrier: Figure 18.22


Pedersen 2019 January 8 26
Slide 27

Lipoprotein Types
Composition of LDL and HDL
• LDL:
– Mostly free cholesterol
• HDL:
– Mostly chosteryl esters
– Higher percentage protein
– Higher percentage phospholipids

• LDL Carries 70% of plasma


Cholesterol (LDL-C)
• High LDL-C is a major risk factor
for cardiovascular disease,
especially coronary artery disease.

Ferrier: Figure 18.19


Pedersen 2019 January 8 27

LDL and HDL: The yin and yang of cholesterol transport.

HDL particles are smaller and have a higher percentage of protein as a consequence.
They also are made with more phospholipid to provide a fatty acyl chain source for
esterifying free cholesterol to cholesterol esters.
Slide 28

Lipoprotein Structure
Lipid Composition: Table of lipoproteins
Table 25.2 Typical Compositions of Plasma Lipoproteins

Lipid (%)
Lipoprotein Diameter Density
Source Protein (%) Phospho- Cholesterol
Class (nm) (g/cm3) Triglyceride Cholesterol
lipid Esters
Chylomicrons Intestine 100–1000 0.95 1-2 86 8 3 2
Very-low-
density
Liver 30–80 0.95–1.006 6-10 55 18 13 7
lipoprotein
(VLDL)
Intermediate-
density VLDL 25–30 1.006–1.019 15-20 25 21 28 9
lipoprotein (IDL)
Low-density
VLDL,
lipoprotein 20–25 1.019–1.063 22 9 20 40 8
IDL
(LDL)
High-density Liver,
lipoprotein intestine
HDL2 9–12 1.063–1.125 35-45 5 33 17 5
HDL3 5–9 1.125–1.21 50-55 3 28 12 3
Pedersen 2019 January 8 28

General composition of the various lipoprotein particles.


For reference.
Slide 29

High Density Lipoprotein, HDL


• Produced by intestine and liver
• Carries out reverse cholesterol transport
• Reservoir of apo C-II and apo E
• Nascent HDL:
– Disk-shaped
– Contains apo A-I, C-II and E
– Contains primarily phospholipid (PC)
– Collects cholesterol to become HDL3
• HDL3
– Collects cholesterol
– Further matures to HDL2
• HDL2 (mature HDL):
– Depleted in lipids, rich in cholesterol esters
– CE for TAG exchange with VLDL
– Goes to liver to drop off CE and TAG  HDL3
– HDL3 returns to circulation
Pedersen 2019 January 8 29
Slide 30

High Density Lipoprotein, HDL

Pedersen 2019 January 8 30

HDL life cycle


• HDL is synthesized in the Liver and intestines, and also in the blood from secretion
of apo A-I.
• Nascent HDL is discoidal (flattened in shape, not spheroidal).
• Contains apo A-I, apo C-II and apo E
• Serves as a reservoir for apo C-II and apo E
• Exchanges these with VLDL and chylomicrons.
• Contains mostly phospholipids.
• HDL takes up free cholesterol from peripheral tissues
• From other lipoproteins and cell membranes by diffusion and transport
proteins (ABCA1)
• HDL is suitable for uptake of cholesterol because of high content of PC that
both solubilizes cholesterol and acts as a source of fatty acid for cholesterol
esterification
• Apo A-I activates LCAT (lecithin:cholesterol acyl transferase)
• LCAT makes cholesterol esters from free cholesterol and PC (phosphatidyl
choline)
• LCAT also produces lyso-PC as its other product.
• HDL stores the CE in its core
• Collection of CE matures nascent HDL to HDL3
• HDL3 collects Cholesterol and matures further to HDL2
• HDL2 exchanges CE for TAG with VLDL
• The CETP (cholesteryl ester transfer protein) exchanges CE for TAG
• This results in higher CE in VLDL and more TAG in HDL2
• HDL2 drops off cholesterol and cholesterol esters and TAG to the liver
• HDL2 binds to SR-B1, a scavenger receptor
• CE is taken up
• Hepatic lipase degrades TAG for FA uptake
• HDL2 is converted back to HDL3
• HDL3 returns to the circulation
Slide 31

Lipoprotein Structure
Protein Composition: Table of apolipoproteins
Plasma
Apolipoprote Molecular Lipoprotein
Concentration Source Function
in Weight (D) s
(mg/dl)
Major structural proteins of HDL, also
A-I 29,000 130
Liver, intestine in chylomicrons; apo A-I activates
A-II 17,000 40
LCAT
Chylomicron
B-48 241,000 Variable Intestine Structural protein of chylomicrons
s
Structural protein of VLDL, IDL, LDL;
only apoprotein of LDL; mediates
B-100 513,000 80 VLDL, LDL Liver
tissue uptake of LDL (LDL receptor
ligand).
Readily transferred between
C-I 6,600 6
lipoprotein classes
C-II 8,900 3 Liver
C-II activates LPL
C-III 8,800 12 C-III inhibits LPL
D 19,000 10 HDL Unknown
VLDL, IDL, Mediates uptake of chylomicron
E 34,000 5 Liver
chylomicrons remnants and IDL by liver
Pedersen 2019 January 8 31

This Table is for reference.


The role of these will should be clearer from the life-cycle of each type of lipoprotein.
However, there are distinct functions for each type of lipoprotein that is critical to their
role in the distribution of lipids.

A – thought to be structural.
- A-I activates LCAT
- LCAT is Lecithin:Cholesterol Acyl Transferase, needed to esterify cholesterol
extracellularly.

B
- B-48 is a truncated version of B-100 (transcriptional regulation)
- B-48 is specific for chylomicrons
- B-100 is the full length B apolipoprotein
- B-100 is characteristic of VLDL, IDL, and LDL, and the only apolipoprotein in LDL.

C – Regulates lipoprotein Lipase (LPL) for release of fatty acids to peripheral tissues.

D – Function not fully known, but thought to associate with LCAT and link HDL and LDL
during transfer of apolipoproteins.

E – Delivered by HDL to VLDL and chylomicrons. Also in IDL but not in LDL. Serves as
a ligand for chylomicron remnant uptake by the liver.
Slide 32

Lipoprotein(a), Lp(a)
• A Lipoprotein particle like LDL
– Also contains apo-lipoprotein(a), apo(a)
• Simulates LDL but apo(a) covalently linked to
apo B-100
• Concentrations are highly variable among
individuals and genetically determined.
• Not known to be vital
• High Lp(a) is a risk factor for CVD
• Competes with plasminogen for plasminogen
activator
• Genetic element
• Estrogen decreases it while trans fats increases it

Pedersen 2019 January 8 32

From Lippincott’s Illustrated Reviews: Biochemistry, 5th edition. Harvey and Ferrier.

“Lipoprotein (a), or Lp(a), is a particle that, when present in large quantities in the
plasma, is associated with an increased risk of coronary heart disease. Lp(a) is nearly
identical in structure to an LDL particle. Its distinguishing feature is the presence of an
additional apolipoprotein molecule, apo(a), that is covalently linked at a single site to
apo B-100. Circulating levels of Lp(a) are determined primarily by genetics. However,
factors such as diet may play some role, as trans fatty acids have been shown to
increase Lp(a), and estrogen decreases both LDL and Lp(a). [Note: Apo(a) is
structurally homologous to plasminogen—the precursor of a blood protease whose
target is fibrin, the main protein component of blood clots. It is hypothesized that
elevated Lp(a) slows the breakdown of blood clots that trigger heart attacks because it
competes with plasminogen for binding to fibrin. Niacin reduces Lp(a) and raises HDL.]”
Slide 33

Abnormalities in Lipoprotein Metabolism


• Hyperlipidemias – increases in lipids: triglycerides or cholesterol
– Primary: genetic, congenital defect
– Secondary:
• Diabetes
• Drug use: thiazides, beta blockers, estrogens
• Alcoholism
• Hypothyroidism, Kidney failure, Nephrotic syndrome
• Hypercholesterolemias: Cholesterol > 200 mg/dl
– Increased IDL, LDL, or HDL or some combination.
– Caused by:
• Diet (unclear how bad a diet is needed)
• Obstructive jaundice
• Hypothyroidism Arcus Senilis: Cholesterol Deposits
• Familial Hypercholesterolemia in the corneal stroma. Though it
• Diabetes occurs in patients with familial
• Hypertriglyceridemias: > 150 mg/dl hyperlipidemias, it is not predictive
– Increased VLDL, or Chylomicrons, or both. for cardiovascular disease.
Pedersen 2019 January 8 33

Note:
While a consistent high fat diet is known to be deleterious to health and a risk factor, the
limits on dietary cholesterol per se have been generally relaxed. This is because a
directly link between dietary cholesterol and increased risk for cardiovascular disease
has not been firmly established. The most recent dietary guidelines from the US
government provide a less stringent and more general limit on dietary cholesterol.
Slide 34

Abnormalities in Lipoprotein Metabolism


Fredrickson Classification of familial hyperlipidemias
Type I: Hypertriglyceridemia
Hyperlipo- Synonyms Defect Lipoprotei Symptoms Treatment Serum
proteinemi
a
n changes appearan
ce
Type Ia Acute pancreatitis, Diet control Creamy top
Decreased lipemia retinalis, layer
Buerger-Gruetz syndrome or Increased
Lipoprotein eruptive skin
familial hyperchylomicronemia Chylomicrons
lipase (LPL) xanthomas,
hepatosplenomegaly

Type Ib Familial apoprotein CII Altered apo Increased Acute pancreatitis, Diet Control Creamy top
deficiency C2 Chylomicrons lipemia retinalis, layer
eruptive skin
xanthomas,
hepatosplenomegaly

Type Ic LPL Increase Acute pancreatitis, Diet Control Creamy top


inhibitor in Chylomicrons lipemia retinalis, layer
blood eruptive skin
xanthomas,
hepatosplenomegaly

Pedersen 2019 January 8 Wikipedia: https://en.wikipedia.org/wiki/Hyperlipidemia 34

These will be discussed also in Dr Edsall’s lecture, particularly the variety of treatments.
You must know these.

Hyperlipidemias are further classified:


Hypercholesterolemia – excess cholesterol – increases in LDL, IDL, or HDL
Hypertriglyceridemia – excess triglycerides – Increases in chylomicrons or VLDL
Or combined.

Key Points

Type I: An increase in Chylomicrons


• Causes:
• Decreased LPL
• Altered apo C-II  less LPL activation
• LPL inhibitors
• Results – decreased removal of lipids leads to accumulation of chylomicrons.
• Treatment with diet.
Slide 35

Abnormalities in Lipoprotein Metabolism


Fredrickson Classification of familial hyperlipidemias
Type II: Hypercholesterolemias or combined
Hyperlipo- Synonyms Defect Lipoprotei Symptoms Treatment Serum
proteinemi
a
n changes appearan
ce
Type IIa Xanthelasma, arcus Bile acid sequestrants Clear
senilis, tendon Statins
LDL xanthomas Niacin*
Familial hypercholesterolemia receptor Increased LDL
deficiency

Type IIb Familial combined Decreased Increased LDL Acute pancreatitis, Statins Turbid
hyperlipidemia LDL and VLDL lipemia retinalis, Fibrate
receptor eruptive skin Niacin*
and xanthomas,
increased hepatosplenomegaly
apoB

Wikipedia: https://en.wikipedia.org/wiki/Hyperlipidemia
Pedersen 2019 January 8 35

Hyperlipidemias are further classified:


Hypercholesterolemia – excess cholesterol – increases in LDL, IDL, or HDL
Hypertriglyceridemia – excess triglycerides – Increases in chylomicrons or VLDL
Or combined.

Key Points

Type II: Increases in LDL


• Causes:
• Genetic LDL receptor deficiency. Heterozygotes are common. 1:500
incidence.
• Genetic LDL receptor deficiency and apo B increase (increases both LDL and
VLDL); 1:100 incidence (common).
• Results – increases in LDL (both) or LDL and VLDL (type II).
• Treatment – decrease cholesterol synthesis or increase cholesterol excretion.

* Niacin - Note: Niacin is no longer recommended, except in specific clinical situations


(eg, high triglyceride levels [>500 mg/dL], if not able to achieve desired response, or
intolerance to other therapies)
Slide 36

Abnormalities in Lipoprotein Metabolism


Fredrickson Classification of familial hyperlipidemias
Type III-V: Hyperlipidemias
Hyperlipo- Synonyms Defect Lipoprotei Symptoms Treatment Serum
proteinemi
a
n changes appearan
ce
Type III Tuboeruptive Fibrate Turbid
Apo E2 IDL xanthomas and Statins
Familial
synthesis Chylomicron palmar xanthomas
dysbetalipoproteinemia
defect remnants

Type IV Familial Hypertriglyceridemia Increased Increased Can cause Fibrate Turbid


VLDL VLDL pancreatitis at high Statins
production triglyceride levels Niacin*
and
decreased
elimination

Type V Mixed hyperlipidemia Increased Increased Fibrate Creamy top


VLDL VLDL and Niacin* layer
production Chylomicrons Turbid bottom
Altered apo
C2 and
decreased
LPL Wikipedia: https://en.wikipedia.org/wiki/Hyperlipidemia
Pedersen 2019 January 8 36

Hyperlipidemias are further classified:


Hypercholesterolemia – excess cholesterol – increases in LDL, IDL, or HDL
Hypertriglyceridemia – excess triglycerides – Increases in chylomicrons or VLDL
Or combined.

Type III: Increases in IDL (VLDL remnants) and chylomicron remnants. (also called
remnant hyperlipidemia)
• Causes: Defect in apo E2 prevents re-uptake of IDL and chylomicron remnants by
the liver.
• Results – IDL accumulation and chylomicron remnant accumulation.
• Treatment – Prevention of cholesterol synthesis (statins) and change in LPL
apolipoproteins expression (fibrates).
• Rare: 1 in 10,000

Type IV: Increased VLDL


• Cause: congenital, autosomal dominant increase in liver VLDL production.
• Results in increased VLDL
• Treatments – statins, block TAG synthesis (niacin) and and change in LPL
apolipoproteins expression (fibrates).
• Common: 1:100

Type V: Mixed hyperlipidemia


• Cause:
• Related to type I but with increased VLDL as well as chylomicrons
• Due to low LPL or altered apo C-II
• Familial form is also called FCH (familial combined hyperlipidemia), caused
by decreased LDL receptor an increased apoB production (similar to Type
IIb).
• Results: increased VLDL and chylomicrons
• Treatments – fibrates and niacin.

*Niacin – Note: Niacin is no longer recommended, except in specific clinical situations


(eg, high triglyceride levels [>500 mg/dL], if not able to achieve desired response, or
intolerance to other therapies)
Slide 37

Summary
• Lipoproteins:
– Combinations of proteins, phospholipid monomers and TAG/cholesterol ester cores.
– Ferry TAG or cholesterol to and from various tissues.
• Chylomicrons carry dietary lipids including triglycerides, fat soluble vitamins, cholesterol,
and other compounds. They deliver triglycerides to various tissues. Chylomicron remnants
are collected by the liver.
• VLDL is synthesized constantly in the liver. It carries primarily triglycerides to tissues for
energy.
• LDL is depleted VLDL, and carries cholesterol to tissues.
• HDL is a reservoir of apo lipoproteins and carries cholesterol from peripheral tissues to the
liver.
• Cholesterol levels are regulated in the liver through feedback mechanisms on transcription
and by phosphorylation of HMG CoA reductase
• Atherosclerosis is a result of excessive oxidized LDL ingestion by macrophages.
• Know the Fredrickson Classification of hyperlipidemias

Pedersen 2019 January 8 37