Download Hyperlipidemia Intro I

Hyperlipidaemia
History
 Hypercholestrolemia is an inherited
condition and for several years scientists have
studied the effects of high cholesterol on the
circulatory system.
 In one study of young men without known heart
disease.
 cholesterol levels were measured and participants
were observed for 6 years.
CONT…
 Researchers found that the deaths of
those participants who had high
cholesterol levels were typically linked
to heart disease.
 It was concluded that the risk for a
fatal heart attack is about 5 times
higher in those with a cholesterol level
of 300 mg/dL or more, than in those
with a cholesterol level below 200
mg/dL
CONT…
 The Framingham Heart Study is
probably the most famous ongoing
heart study in the world.
 Cholesterol levels, smoking habits,
heart attack rates, and deaths in the
population of an entire town have been
recorded for over 40 years.
Cont…
 After 30 years, over 85% of
people with cholesterol levels of
180 mg/dL or less were still alive.
 almost 33% of those with
cholesterol levels greater than 260
mg/dL had died.
Introduction
 Fats are triacylglycerols containing saturated fatty acids
- solid at room temp
- usually from animal source (however, coconut & palm oil are
saturated).
 Oils are triacylglycerols containing mono- or polyunsaturated
fatty acids
- liquid at room temp
- usually from plant sources (however, fish oils are
polyunsaturated).
 Phospholipids are triacylglycerols that have had a FA replaced
with a phosphate linked FA group.
 The major dietary sterol is cholesterol.
LIPID DIGESTION
 Stomach - lingual lipase and gastric lipase
attack triacylglycerols and hydrolyse a
limited number of FA.
 Small Intestine - acid chyme (stomach
contents) stimulates mucosa cells to
release hormone (choleocystokinin).
Cont…
 This stimulates gall bladder and pancreas
to release bile and digestive enzymes
respectively (bile acids help emulsify fat
droplets thus increasing their surface area).
 Other mucosa cells release secretin which
causes pancreas to release bicarbonate rich
fluid to neutralise chyme.
Enzymic digestion of lipids in small intestine
Cont…
 Enzymic digestion generates more polar products that form
mixed micelles of free fatty acids, 2-monoacylglycerol,
cholesterol & bile salts that are adsorbed (except bile salts which
pass through to ileum .
 Once adsorbed fatty acids and 2-monoacylglycerol are
recombined to form triacylglycerol.
 Triacylglycerol + cholesterol + phospholipid + proteins form a
lipoprotein complex called a chylomicron which transports the
lipids in the circulation.
Lipid transport in the circulation
Lipids are insoluble in plasma. In order to be transported they are combined with
specific proteins to form lipoproteins:
Proteins (apoproteins)
HO
Non polar lipids in core
(TAG and cholesterol esters)
O
R
Cholesterol
O
HO
R
HO
Apoproteins are only weakly associated with a particular lipoprotein and are easily
transferred to another lipoprotein of a different class. Apoproteins have various
functions including:
• Structural role
• Binding sites for receptors
• Activators or co-enzymes for enzymes involved with lipid metabolism
DYSLIPIDEMIA
Dyslipidemia (elevated blood lipid and lipoproteins
has several forms:
 Hyperlipidemia: elevated blood TG & cholesterol
 Hypertriglyceridemia: elevated TG only
 Hypercholesterolemia: only elevated blood
cholesterol concentrations
 Hyperlipoproteinemia: elevated lipoprotein
concentrations
Hyperlipidemia
 What is Cholesterol?
 A soft, waxy substance found among the
lipids (fats) in the bloodstream
 Used to form cell membranes and some
hormones
 High levels in the blood are a major risk
factor for coronary heart disease
 Fats can not dissolve in the blood and
must be transported by lipoprotiens
Hyperlipidemia
 What is HDL Cholesterol?
 High-density lipoprotien
 “Good” cholesterol
 Carries cholesterol away from the arteries
and back to the liver
 May remove excess cholesterol from fatty
plaques and slow their growth
 High levels of HDL appear to protect against
heart attack
 Low HDL indicates a greater risk for heart
attack
Hyperlipidemia
 What is LDL Cholesterol?
 Low-density lipoprotien
 “Bad” cholesterol
 Major cholesterol carrier in the blood
 High levels cause slow build up of plaques in
the walls of the arteries
 A blood clot may form in the area of a plaque
and block the flow of blood causing a heart
attack or stroke
Lipoproteins
 particles found in plasma that transport lipids
including cholesterol
 lipoprotein classes
 chylomicrons: take lipids from small intestine
through lymph cells
 very low density lipoproteins (VLDL)
 intermediate density lipoproteins (IDL)
 low density lipoproteins (LDL)
 high density lipoproteins (HDL)
LIPOPROTEINS
 Pathophysiology of lipoproteins
 Micelle structures with apolipoprotiens surrounding a
lipid core
 Core contains TG, phospholipids & cholesterol
 4 classes of lipoproteins




Chylomicrons – intestinal absorption of dietary TG
VLDL – primary transport for TG
LDL – principle carrier of cholesterol
HDL – reverse transport of cholesterol
Structure of Lipoproteins
Free cholesterol
Phospholipid
Triglyceride
Cholesteryl ester
Apolipoprotein
Major lipoprotein classes
 Chylomicrons (derived from diet)
 density <<1.006 g/cm3
 diameter 80 - 500 nm
 dietary triglycerides
 apoB-48, apoA-I, apoA-II, apoA-IV, apoC-II/C-III,
apoE
 remains at origin in electrophoretic field
Chylomicron
 formed through extrusion of resynthesized
triglycerides from the mucosal cells into the
intestinal lacteals
 flow through the thoracic ducts into the suclavian
veins
 degraded to remnants by the action of
lipoprotein lipase (LpL) which is located on
capillary endothelial cell surface
 remnants are taken up by liver parenchymal cells
due to apoE-III and apoE-IV isoform recognition
sites
Major lipoprotein classes
 VLDL
 density >1.006 g/cm3
 diameter 30 - 80nm
 endogenous triglycerides
 apoB-100, apoE, apoC-II/C-III
 prebeta in electrophoresis
 formed in the liver as nascent VLDL (contains only
triglycerides, apoE and apoB)
VLDL
 nascent VLDLs then interact with HDL to
generate mature VLDLs (with added
cholesterol, apoC-II and apoC-III)
 mature VLDLs are acted upon by LpL to
generate VLDL remnants (IDL)
 IDL are further degraded by hepatic
triglyceride lipase (HTGL) to generate LDLs
VLDL metabolism
Major lipoprotein classes
 IDL (intermediate density lipoproteins)
 density: 1.006 - 1.019
 diameter: 25 - 35nm
 cholesteryl esters and triglycerides
 apoB-100, apoE, apoC-II/C-III
 slow pre-beta
Major lipoprotein classes
 LDL (low density lipoproteins)
 density: 1.019 - 1.063
 diameter: 18-25nm
 cholesteryl esters
 apoB-100
 beta (electrophoresis)
 < 130 LDL cholesterol is desirable, 130-159 is
borderline high and >160 is high
Major lipoprotein classes
 HDL (high density lipoproteins)
 density: 1.063-1.210
 diameter: 5-12nm
 cholesteryl esters and phospholipids
 apoA-I, apoA-II, apoC-II/C-III and apoE
 alpha (electrophoresis)
HDLs
 Several subfamilies exist
 Discoidal HDL :
 contains cholesterol, phospholipid, apoA-I, apoA-II,
apoE and is disc shaped;
 it is formed in liver and intestine
 It interacts with chylomicra remnants and lecithincholesterol acyl transferase (LCAT) to form HDL3
HDLs
 HDL3
 composed of cholesterol, cholesterol ester, phospholipid and
apoA and apoE
 interacts with the cell plasma membranes to remove free
cholesterol
 reaction with LCAT converts HDL3 to HDL2a (an HDL with a
high apoE and cholesterol ester content)
 cholesterol ester-rich HDL2a is then converted to triglyceriderich HDL2b by concomitant transfer of HDL cholesterol esters
to VLDL and VLDL triglycerides to HDL
HDL metabolism
Functions of HDL
 transfers proteins to other lipoproteins
 picks up lipids from other lipoproteins
 picks up cholesterol from cell membranes
 converts cholesterol to cholesterol esters via the
LCAT reaction
 transfers cholesterol esters to other lipoproteins,
which transport them to the liver (referred to as
“reverse cholesterol transport)
Lipoproteins (a)- Lp(a)
 another atherogenic family of
lipoproteins (at least 19 different
alleles)
 they consist of LDL and a protein
designated as (a)
 the apoA is covalently linked to apoB100 by a disulfide linkage
 high risk association with premature
coronary artery disease and stroke