Synthesized in the liver

1
VLDL (very low density lipoprotein)

• Synthesized in the liver
• Carry away triacylglycerols synthesized in the
  liver
• in excess of the livers own needs)
• stored fat that has been released
• fatty acids from the conversion of carbohydrate
  to fats
• endogenous cholesterol
• dietary cholesterol brought to the liver
  by chylomicron remnants
• the amount (and size) of VLDL synthesized and
  secreted by the liver is determined primarily by
  degree of saturation
• saturated fatty acids numerous but small
  VLDLs
• polyunsaturated fatty acids less but larger
  VLDLs

Lipids in VLDLs are used essentially the same way
chylomicrons are (degraded by lipoprotein
lipases)
191
2
VLDL are gradually converted into LDL (via an IDL
intermediate)
VLDLs lose their TAGs via lipoprotein
lipase VLDLs lose apo C
IDL (VLDL remnants)
One fate of an IDL (VLDL remnant) uptake in the
liver via receptor mediated endocytosis (
half the circulating VLDL goes in this
direction) similar to chylomicron
remnants half-life for clearance is 1 to 3
hrs Another fate of an IDL (VLDL remnant)
remain in circulation undergo further lipase
activity lose apo E what do you have now?

192
3
LDL (low density lipoprotein)

• LDL is associated with increased heart disease
  bad cholesterol
• all apoproteins (except B-100) are removed from
  VLDL as it transitions to LDL
• LDL now contains the cholesterol the VLDL picked
  up in the liver
• The major carrier of cholesterol in the blood

Cholesterol biosynthesis takes place primarily in
the liver (some in the intestine) the role of
LDL is to transport cholesterol to peripheral
tissues half-life for clearance is _at_ 24hrs
(every day about half the circulating LDL is
removed via receptor mediated endocytosis)
193
4
HDL (high density lipoprotein)

• high HDL levels are associated with decreased
  risk of heart disease
• Good cholesterol
• synthesis begins in the liver as small protein
  rich particles - half life of days
• role is opposite that of LDL
• while LDL carries dietary and endogenous
  cholesterol to peripheral tissues
• one role of HDL is to carry cholesterol back to
  the liver
• cholesterol accumulation on HDL occurs over time
  via the action of LCAT
• (lecithincholesterol acyltransferase)

LCAT 59kD glycoprotein associated with HDL that
catalyzes the formation of cholesterol ester from
lecithin (phosphatidylcholine) and cholesterol
released into the plasma from dying cells and
membranes undergoing turnover
HDL also transfers cholesterol to VLDL via
CETP (VLDL then become cholesterol rich LDL)
194
5
Good (HDL) vs Bad (LDL) carriers of
Cholesterol
first brought to attention by epidemiological
studies supported by laboratory experiements
involving CETP CETP cholesterol ester transfer
protein is a plasma protein that exchanges
neutral lipids (cholesterol ester and TAG among
lipoproteins)
If CETP is present - theoretically - it means
higher cholesterol levels on VLDL (LDL) and lower
cholesterol on HDL
Mice do not express CETP Make a mice that is
transgenic for CETP and you have two populations
of mice that are identical except for one gene
(CETP)
feed both populations of mice a high fat, high
cholesterol diet TOTAL plasma cholesterol levels
will be the same But what about the DISTRIBUTION
of cholesterol the transgenic mice had higher
levels of LDL than HDL and developed
atherosclerotic lesions far more rapidly than
CEPT negative mice Conclusion how cholesterol
is partitioned is more important than the total
amount of cholesterol - (want more HDL than LDL)
195
6
Formation of atherosclerotic lesions
LDL can become oxidized Oxidized LDL is taken up
by macrophages
Macrophages take up so many oxidized LDLs (via
a scavenger receptor) they become foam cells
(this uptake is unregulated as opposed to the
regulated uptake by LDL receptors) Foam cells
become trapped in the walls of blood vessels and
contribute to the formation of atherosclerotic
plaques Atherosclerotic plaques cause arterial
narrowing and lead to heart attacks
A serum esterase (paraoxonase) that degrades
oxidized lipids is found in association with HDL
This may also account for HDLs ability to
protect against coronary disease
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7
197
8
Apolipoproteins
apo designates the protein in its lipid-free
form
Individuals who inherit the APOE4 allele have an
increased risk of late-onset Alzheimers
disease Individuals who are homozygous for the
APOE4 allele have a 16-fold increased risk of
developing the disease
The molecular basis for the association between
apoE4 and Alzheimers disease is not yet known
198
9
The LDL receptor and cholesterol homeostasis
199
10
The LDL uptake by the LDL receptor

• in lysosomes
• hydrolysis of LDL to
• amino acids (from the apoprotein)
• free cholesterol
• the LDL receptor is recycled to the membrane
  surface to pick up more LDL (cycle _at_ 10 minutes)

1910
11
What happens to the free cholesterol in the cell?
much of it goes to the endoplasmic reticulum
where it is used for membrane synthesis it can
also be re-esterified for storage inside the cell
1911
12
Regulatory effects of internalized cholesterol

• suppresion of endogenous cholesterol synthesis by
• inhibition of HMG-CoA reductase
• supression of transcription of HMG-CoA reductase
• acceleration of degradation of HMG-CoA reductase
• activation of acyl CoAcholesterol
  acyltransferase (ACAT)
• enzyme that synthesizes cholesterol esters from
  
• cholesterol and a long-chain acyl-CoA
• (activating the enzyme that promotes
  cholesterol storage)

• 3. regulation of LDL receptor by
• decreasing mRNA for the receptor
• decreased synthesis of the receptor ensures that
  cholesterol will not be taken into the cell in
  excess of the cells needs, even when
  extracellular levels are high

This explains why excessive dietary cholesterol
leads directly to elevations of blood cholesterol
levels With intracellular levels regulated so
well, extracellular cholesterol accumulates and
has no where else to go
1912
13
Theraputic approaches to lowering blood
cholesterol levels
Q Why is there so much interest in drugs that
lower cholesterol levels? A Atherosclerosis is
the leading cause of death in industrialized
societies

• theraputic approaches are focused on
• inhibiting the intestinal reabsorption of bile
  salts
• 2) developing inhibitors of HMG-CoA reductase
  on the assumption that they will depress
  intracellular cholesterol levels and therefore
  increase the production of LDL receptors for
  clearance of extracellular cholesterol from the
  blood
• Example statins (inhibitors of HMG-CoA
  reductase)
• other drugs Probucol blocks intestinal
  cholesterol transport
• (but HDL levels are reduced)

1913
14
Control cholesterol levels through diet

• Cholesterol is found only in animal products
• therefore eating less fat from meat, eggs and
  milk products will help lower dietary cholesterol
  intakes
• note recommended is less than 300 mgs per day

cholesterol contents in common foods grains,
vegetables, fruit 0 mg 1 cup whole milk _at_ 33
mg 3 oz shrimp 165 mg 1 tsp butter 10 mg 3
oz meat 80 mg egg yolk 213 mg egg white 0
mg 1 oz cheese _at_ 28 mg
watersoluble fiber (found in fruits, oats, oat
bran barley, legumes, as opposed to water
insoluble (wheat bran) may be related to
ability to bind bile acids in the intestine
leading to decreased readsorption
omega-3-fatty acids
1914
15
The LDL receptor is a 115kD transmembrane protein
with six different domains
This calcium binding cysteine rich domain is
repeated 7 times at the amino terminus and forms
the LDL-binding domain A set of conserved amino
acid side chains binds calcium Protonation of
these glutamate asnd aspartate side chains in
lysosomes leads to the release of calcium and the
subsequent structural disruption releases LDL
the six-bladed propeller domain and an adjacent
EGF-like domain are also disrupted at low pH
1915
16
Mobilization of stored fat
The transport of dietary fat to storage deposits
is not regulated Whatever is eaten is absorbed
and most of it is transported to adipose tissue
for storage In contrast, the release of fat from
storage deposits in adipose tissue is hormonally
controlled (to meet energy needs) via the cyclic
AMP-dependent phosphorylation of the lipase
involved
1916
17
Mobilization of stored fat
glucagon (during fasting) epinephrine (during
stress) ?-corticotropin (stress) activate
adenylate cyclase which activates protein kinase
which phosphorylates and thereby activates
triacylglycerol lipase (also called
hormone-sensitive lipase) triaclyglycerol lipase
catalyzes the hydrolytic release of fatty acid
from carbon 1 or carbon 3 of the glycerol moiety
and now we have a diacylglycerol diacylglycerol
lipase hydrolyses off another fatty acid and now
we have a monoacylglycerol monoacylglycerol
lipase hydrolyses off the last fatty acid now
we have glycerol and three unesterified fatty
acids which passively diffuse out of adipose
cells into the blood stream
1917
18
fatty acids become bound to serum albumin note
albumin is the most abundant plasma protein and
can bind up to 10 molecules of free fatty
acid fatty acids are released from albumin and
taken up by cells primarily by passive
diffusion glycerol from the blood stream is
taken up by liver cells where it can serve as a
precursor to glucose
REMEMBER although fats need to be hydrolyzed
into glycerol and fatty acids by pancreatic
lipases in order to enter intestinal mucosal
cells, once inside those cells they are
reassembled into triacylglycerols and it is in
this form that they first enter the blood stream
(complexed to chylomicrons) This process is
unregulated Dietary fat will be used for
energy or stored (as triacyglycerols in adipose
cells) This stored fat is mobilized in a
regulated fashion when the stored fat is
required for energy and at this time the
triacylglycerols are hydrolyzed into glycerol and
free fatty acids and it is in this form now that
fats enter the blood stream from adipose cells
1918