Pathophysiology

p y gy of lipid
p metabolism

• Major plasma lipids are:

– Cholesterol
– Triglycerides
– Fatty acids
Cholesterol
ƒ Essential component of cell membranes
ƒ Required for biosynthesis of hormones
„ progesterone, cortisol, testosterone, estradiol
ƒ Absorbed through lumen of the gut, also secreted
back to intestine as component of bile
ƒ In addition to dietary sources, cholesterol is also
synthesized by body tissues - liver
Cholesterol Synthesis
ƒ Essential during active growth or when dietary
intake is limited
ƒ Increases with a high-energy diet and in obesity
ƒ Enzyme responsible (HMG-CoA reductase) can be
inhibited
„ down-regulated when tissues are supplied with
cholesterol in abundance
„ site of action for “statin” drugs
Triglycerides
ƒ Ideal means of energy storage
ƒ Stored in fat cells: Adipose cell is made up of a rim
of cytoplasm around a central droplet of energy-rich
triglyceride
ƒ Light in weight relative to energy content when
compared to glycogen stores in liver or muscle
ƒ Triglycerides stored in fat around internal organs
serve as “cushions” and also provide layer of
insulation
Fatty Acids
ƒ Triglycerides are synthesized from fatty acids
(circulating or from glucose)
ƒ Enzyme lipoprotein lipase causes fatty acids to be
released from glycerol (to which they are bound in
the stored triglycerides)
ƒ Free fatty acids bind to serum albumin
„ used as fuel/energy for muscle activity
„ resynthesized and stored as a fuel source in adipocytes
„ taken up by the liver or resynthesized back into
triglycerides
What are Lipoproteins?
ƒ Cholesterol and triglycerides are insoluble, therefore
are transported by lipoproteins
ƒ Polar surface of phospholipd allows lipoproteins to
travel in aqueous environments
ƒ Lipoproteins are complex molecules that carry
dietary and stored fat in plasma
„ triglyceride - rich (chylomicrons, VLDL-C)
„ cholesterol - rich (LDL-C, HDL-C)
ƒ Each class varies in size, weight, lipid composition,
density, apolipoprotein content
What are Apolipoproteins?
ƒ Proteins associated with lipoproteins
ƒ Involved in:
„ secretion of lipoproteins
„ structural integrity of lipoprotein
„ co-activate enzyme reactions necessary for lipoprotein
processing
„ facilitate receptor-mediated uptake of lipoproteins and
remnants
Size & Density of Particles
 Lipoprotein Classification
Major Lipid
Lipoprotein Source Apolipoproteins
Component
A-I, A-II, A-IV, Cs,
Chylomicrons Intestine TG
B-48, E
Very low density
lipoprotein Liver TG B-100, Cs, E
(VLDL)
Intermediate
density Catabolism of VLDL CE B-100, Cs, E
lipoprotein (IDL)
Low density
Catabolism of IDL CE B-100
lipoprotein (LDL)
High density Liver, intestine, A-I, A-II, A-IV, C-I,
CE, PL
lipoprotein (HDL) other C-II, C-III, D
TG=triglyceride; CE=cholesteryl ester; PL=phospholipid
Lipoprotein Classification
Chylomicrons
ƒ Largest lipoprotein particle
ƒ Produced in gut following
absorption of digested fat
ƒ Triglyceride-rich particle
ƒ Hydrolyzed by lipoprotein
lipase
ƒ Remnant particles removed
by apoE receptors
VLDL-Cholesterol
ƒ Fatty acids bound to albumin
in plasma are taken up by the
liver and packaged into
VLDL particles
ƒ Triglyceride-rich particle
ƒ Undergoes hydrolysis by
lipoprotein lipase to render
IDL
ƒ About half of IDL is
converted to LDL by hepatic
lipase; remaining IDL is
taken up by liver
LDL-Cholesterol
ƒ Small enough to cross the
capillary endothelium - the
most atherogenic lipoprotein
ƒ LDL receptors migrate to cell
surface to attract LDL
ƒ Heterogeneity in particle
composition arises from
differences in the amount of
cholesterol per particle
(small, dense LDL (“B”) vs.
buoyant LDL (“A”)
HDL-Cholesterol
ƒ Receives excess chol from tissues
and transfers to liver
ƒ LCAT increases the capacity of
HDL to receive cholesterol
ƒ The esterification of free
cholesterol into cholesteryl ester
produces a more hydrophobic
core - enhances HDL density
ƒ CETP mediates transfer of
cholesterol ester form HDL core
between HDL and other
lipoproteins
Apolipoproteins - Examples
ƒ ApoE (E2, E3, E4)
„ mediates uptake of remnant particles, either chylomicron
remnants or VLDL (or IDL) remnants
ƒ ApoB-100
„ present in VLDL and LDL - acts as ligand for the LDL
receptor
ƒ ApoB-48
„ found in chylomicrons and intestinal cells; lipoproteins
coming from intestinal metabolism have ApoB-48;
hepatic lipoproteins have ApoB-100
Apolipoproteins - Examples
ƒ ApoC (CI, CII, CIII)
„ found on chylomicrons and VLDL particles. ApoCII
activates lipoprotein lipase, catabolizing triglycerides.
ApoCIII may inhibit action of lipoprotein lipase
ƒ ApoAI
„ present in chylomicrons and HDL particles. Activates
LCAT enzyme and provides structure to HDL particles
ƒ ApoAII
„ present in chylomicrons and HDL particle. Activates
hepatic lipase which results in HDL2 ¿ HDL3 ¿
nascent HDL
What about Lipoprotein(a)?
ƒ Lp(a) consists of one LDL particle covalently bound
to one or two molecules of apo(a)
ƒ Structurally very similar to plasminogen -appears to
have both atherogenic and thrombogenic properties
ƒ Associated with increased cardiovascular disease
risk
Pathways of Lipid Metabolism
ƒ Exogenous
„ digestion and absorption of dietary fat
ƒ Endogenous
„ cholesterol synthesis by the liver
ƒ “Reverse” Cholesterol Transport
„ delivery of cholesterol from the tissues to the liver
4. Decrease
synthesis

3.Receptor uptake
5. Increase of LDL & remnant
LPL activity particles

1.Rate limiting
enzyme-HMGCoA

2.Fecal excretion
of bile acids
HDL Cholesterol Transport
Putting it all together…...
Primary Dyslipidemia
ƒ Attributed to genetic causes
ƒ Physical manifestations of dyslipidemia important
aspect of diagnosis
ƒ May only be expressed in the presence of exogenous
or environmental factors (obesity, alcohol)
ƒ Fredrickson Classification developed in the 1960’s
 Fredrickson classification of
h
hyperlipidemias
li id i
Lipoprotein(s) Plasma Plasma Athero- Rel.
Phenotype
yp Treatment
elevated
l t d cholesterol
h l t l TG
TGs genicity
i it f
freq.

–
I Chylomicrons Norm. to ↑ ↑↑↑↑ pancreatiti <1% Diet control
s
Bile acid
IIa LDL ↑↑ Norm. +++ 10% sequestrants,
statins, niacin
Statins, niacin,
IIb LDL and VLDL ↑↑ ↑↑ +++ 40%
fibrates
III IDL ↑↑ ↑↑↑ +++ <1% Fibrates
IV VLDL Norm. to ↑ ↑↑ + 45% Niacin, fibrates
+
VLDL and Niacin,, fibrates
V ↑ to ↑↑ ↑↑↑↑ pancreatiti 5%
chylomicrons
s
 Primary
y hypercholesterolemias
yp

Genetic
G ti
Disorder Inheritance Prevalence Clinical features
defect

heteroz.:1/500 premature CAD (ages 30–

5% of MIs <60 yr 50) TC:
TC 7-13
7 13 mM
M
Familial hyper-
dominant
cholesterolemia LDL receptor homoz.: CAD before age 18
1/1 million TC > 13 mM
Familial
premature CAD
defective apo B-100 dominant 1/700
TC: 7-13 mM
apo B-100
Polygenic multiple common
premature CAD
hypercholestero defects and variable 10% of MIs <60
TC: 6.5-9 mM
lemia mechanisms yr
Familial hyper-
less CHD, longer life
alphalipoprotein unknown variable rare
elevated
l d HDL
emia
 Primary
y hypertriglyceridemias
yp gy

Disorder Genetic defect Inheritance Prevalence Clinical features

hepatosplenomegaly
rare
LPL deficiency endothelial LPL recessive abd. cramps, pancreatitis
1/1 million
TG: > 8.5 mM

Apo CC-II
II rare abd cramps,
abd. cramps pancreatitis
Apo C-II recessive
deficiency 1/1 million TG: > 8.5 mM

unknown
Familial hyper- enhanced abd. cramps, pancreatitis
dominant 1/100
t i l
triglyceridemia
id i h
hepatic
ti TG
TG- TG 2
TG: 2.3-6
3 6 mM
M
production
 Primary
y mixed hyperlipidemias
yp p

Genetic
Disorder Inheritance Prevalence Clinical features
defect

Familial A
Apo E recessive premature CAD
dysbeta-
high VLDL, rarely 1/5000 TC: 6.5 -13 mM
lipoproteinemi
chylo. dominant TG: 2.8 – 5.6 mM
a
unknown 1/50 – 1/100 premature CAD
Familial
high Apo B- dominant 15% of MIs <60 TC: 6.5 -13 mM
combined
100 yr TG: 2.8 – 8.5 mM
Secondary Dyslipidemia
ƒ Primary disease affects lipid metabolism, increasing
serum lipid concentrations
ƒ Increases levels of circulating lipoproteins, but may
also alter chemical and physical properties
ƒ May accelerate the progress of the primary disease
(e.g. renal, liver disease)
ƒ May increase morbidity and mortality (e.g. diabetes,
renal disease)
Causes of Secondary Dyslipidemia…
ƒ Endocrine ƒ Drugs
„ diabetes „ ß blockers
„ thyroid disease „ thiazide diuretics
„ pituitary disease „ steroid hormones
„ pregnancy „ retinoic acid derivatives
ƒ Renal ƒ Nutitional
„ nephrotic syndrome „ Obesity
„ chronic renal failure „ alcohol
ƒ Hepatic ƒ Immunoglobulin
„ Cholestasis/ cholelithiasis „ myeloma
„ hepatocellular disease „ SLE
Secondary
y hyperlipidemias
yp p
Disorder VLDL LDL HDL Mechanism

VLDL production ↑,
Diabetes mellitus ↑↑↑ ↑ ↓
LPL ↓, altered LDL
Hypothyreosis ↑ ↑↑↑ ↓ LDL-rec.↓, LPL ↓
Obesity ↑↑ ↑ ↓ VLDL production ↑

Anorexia - ↑↑ - bile secretion ↓, LDL catab. ↓

Nephrotic sy ↑↑ ↑↑↑ ↓ B 100 ↑ LPL ↓ LDL

Apo B-100 LDL-rec
rec. ↓

Uremia, dialysis ↑↑↑ - ↓ LPL ↓, HTGL ↓ (inhibitors ↑)

oestrogen ↑
Pregnancy ↑↑ ↑↑ ↑
VLDL production ↑, LPL ↓

Biliary obstruction Lp-X ↑ ↑

- - ↓
PBC no CAD; xanthomas

↑↑
Alcohol - ↑ dep. on dose, diet, genetics
chylomicr. ↑

Many-many drugs Please allways see for adverse effects before any drug presciption!!!
Metabolic Syndrome
Risk Factor Defining Level*
Waist circ >102cm (men)
Abdominal Obesity
Waist circ >88cm (women)
Triglyceride level > 1.7 mmol/L
< 1.0 mmol/L (men)
HDL-Chol level
< 1.3 mmol/L (women)
Blood Pressure > 130/85
Fasting Glucose Level 6.2 – 7.0 mmol/L
*Must have 3 or more
LDL Oxidation
… High levels of LDL may result in higher levels
… of oxidized LDL in the sub-endothelial space
… • Scavenger Receptor (protein) on
… macrophages -binds to LDL particle that has
… b
been modified
difi d
… • Monocytes and macrophages will function as
… Pac-mans and clean cholesterols
Oxidation of LDL (oxLDL)
( )
… Oxidation = process by which free radicals (oxidants) attack
and damage target molecules / tissues
… Targets of free radical attack:
† DNA - carbohydrates
† Proteins - PUFA’s>>> MUFA’s>>>>> SFA’s

… LDL can be oxidatively damaged: PUFA’s are oxidized and

trigger oxidation of apoB100 protein --> oxLDL

… OxLDL is engulfed by macrophages in subendothelial space

LDL Oxidation
… High levels of LDL may result in higher levels
… of oxidized LDL in the sub-endothelial space
… • Scavenger Receptor (protein) on
… macrophages -binds to LDL particle that has
… b
been modified
difi d
… • Monocytes and macrophages will function as
… Pac-mans and clean cholesterols
Oxidation of LDL (oxLDL)
( )
… Oxidation = process by which free radicals (oxidants) attack
and damage target molecules / tissues
… Targets of free radical attack:
† DNA - carbohydrates
† Proteins - PUFA’s>>> MUFA’s>>>>> SFA’s

… LDL can be oxidatively damaged: PUFA’s are oxidized and

trigger oxidation of apoB100 protein --> oxLDL

… OxLDL is engulfed by macrophages in subendothelial space

Atherosclerosis
Atherosclerosis
A Healthy Endothelium
produces:
Ç PGI2
Ç NO

Maintaining an
anti-coagulant,
anti-thrombotic
surface
A Dysfunctional Endothelium
has decreased:
È PGI2
È NO

Inc
pro-inflam
mo
Ç
ÇT
ÇVCA

Shifting to a
pro-coagulant, pro-thrombotic
surface
… Endothelial dysfunction
y is one of earliest changes
g in
AS
… Mechanical, chemical, inflammatory mediators can
trigger endothelial dysfunction:
† High blood pressure
† Smoking
S ki (f (free radicals
di l that
h oxidatively
id i l damage
d
endothelium)
† Elevated
eva ed homocysteine
o ocys e e
† Inflammatory stimuli
† Hyperlipidemia
Endothelial Dysfunction
( endothelial activation,, impaired
p
endothelial-dependent vasodilation)
… È endothelial synthesis
y of PGI2 (p
(prostacylcin),
y ), & NO
(nitric oxide)
† PGI2 = vasodilator, Èplatelet adhesion/aggregation
† dil t Èplatelet
NO = vasodilator, È l t l t & WBC (monocyte)
( t ) adhesion
dh i

… Ç Adhesion of monocytes
y onto endothelium -->
transmigration into subendothelial space (artery
wall) --> change to macrophages

… Endothelial dysfunction --> increased flux of LDL into

artery wall
Atherosclerosis
Atherosclerosis
Atherosclerosis
Atherosclerosis
Atheroma
Atherosclerotic Plaque
q
… Continued endothelial dysfunction (inflammatory response)
… Accumulation of oxLDL in macrophages (= foam cells)
… Migration and accumulation of:
† smoothh muscle
l cells,
ll
† additional WBC’s (macrophages, T-lymphocytes)
† Calcific deposits
† Change in extracellular proteins, fibrous tissue formation

… High risk = Ç VLDL (ÇTG) Ç LDL È HDL