Hyperlipidemia

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Hyperlipidemia
Dept. of Physiology and Pathophysiology Jinyu Wang
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• 15 million people die of cerebrovascular disease
• Incidence8
• mortality rate50(52 in Beijing)

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Content

• Introduction of lipoprotein.
• Classification of hyperlipidemia.
• Treatment of hyperlipidemia.

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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).

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Introduction

• Phospholipids are triacylglycerols that have had
  a FA replaced with a phosphate linked FA group.
• The major dietary sterol is cholesterol.

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Function of lipid

• Major components of cell membranes.
• Required to solubilise fat soluble vitamins
• Biosynthetic precursors (e.g. steroid hormones
  from cholesterol)
• Protection (e.g. kidneys are shielded with fat in
  fed state)
• Insulation

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Health issues

• Excessive dietary fat intake is associated with
  obesity, diabetes, cancer, hypertension and
  atherosclerosis.
• Not more than 35 of energy intake should come
  from fat. Saturated fat should not make up more
  than 15 of the total fat intake.

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Health issues

• Omega-3 fatty acids (20 carbons) from fish may
  protect against atherosclerosis. American Heart
  association recommends 2-3 fish meals per weak.
  Fish oil supplements should be avoided because
  they may be contain concentrated toxins
  accumulated by the fish.

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Lipid digestion absorption
TG,Ch
Bile acid
micelle
pancreatic lipase PLA2
cholesteryl esterase
2-monoacylglycerol, fatty acid, cholesterol
Lysophosphatide
Bile acid
blood
mixed micelles
recombined
mucosa membrane
chylomicron
apo
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Proteins (apoproteins)
Non polar lipids in core (TAG and cholesterol
esters)
Cholesterol
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Lipid transport in the circulation
Lipids are insoluble in plasma. In order to be
transported they are combined with specific
proteins to form lipoproteins
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The five classes of lipoprotein
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Diameter and density of lipoproteins
?? ??
VLDL
VLDL
0.95
IDL
1.006
?? ??
density (g/ml)
1.02
LDL
HDL2
1.10
HDL3
1.10
1.20
1000
20
40
5
10
60
80
diameter (nm)
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The five classes of lipoprotein(all contain
characteristic amounts TAG, cholesterol,
cholesterol esters, phospholipids and apoproteins)
Increasing density
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Chylomicron metabolism
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Chylomicron summary

• Synthesised in intestine.
• Contain mostly dietary TAG (with a little
  cholesterol, cholesterol ester phospholipid.
• Transport TAG to tissues and deliver remaining
  cholesterol cholesterol ester to the liver.

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VLDL metabolism
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VLDL summary

• Synthesised in liver.
• Contain mostly dietary TAG (with a little
  cholesterol, cholesterol ester phospholipid.
• Converted to LDL which contain an increased
  proportion of cholesterol cholesterol ester
  (due to loss of TAG).
• Transport TAG and cholesterol from liver to
  tissues.
• Cholesterol in LDL referred to as bad
  cholesterol since LDLs are implicated in
  atherosclerosis

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Low density lipoproteins(LDL)
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LDL summary

• density 1.019 - 1.063
• diameter 18-25nm
• cholesteryl esters
• apoB-100
• beta (electrophoresis)

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Low density lipoproteins(LDL)
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Role of LDL in atherosclerosis

• Damage to endothelium (hypertension, smoking
  etc).
• LDLs penetrate vascular wall, deposit in the
  intima and with time are damaged by oxidation.
• Oxidised LDLs attract the attention of
  macrophages which ingest the LDL.
• Macrophages become overloaded with lipid and
  become foam cells which die and release pools
  of lipid in the vessel wall (plaques).

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Role of LDL in atherosclerosis

• A complex processes mediated by cytokines and
  growth factors causes smooth muscle cells to form
  a collagenous cap over the lipid (mature
  atherosclerotic plaque).
• Cap grows and can constrict the vessel (causing
  angina for example).
• Macrophages can degrade the cap while T cells
  can inhibit collagen synthesis the cap can
  rupture to expose collagen and lipids.

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Role of LDL in atherosclerosis

• This leads to aggregation of platelets and blood
  clot formation.
• If the coronary artery is blocked by a clot
• heart attack.
• Blocking of arteries in the brain causes stroke.
• Antioxidants (vitamin E and C) may protect LDL
  from oxidation and so protect against heart
  attack and stroke.

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High density lipoproteins(HDL)
(apoA-I, apoA-II, apoC-II/C-III and apoE)
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HDL metabolism
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HDL summary

• HDL carries used cholesterol (as CE) back to
  the liver. Also donate some CE to circulating
  VLDL for redistribution to tissues.
• HDL taken up by liver and degraded. The
  cholesterol is excreted as bile salts or
  repackaged in VLDL for distribution to tissues.

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HDL summary

• Cholesterol synthesis in the liver is regulated
  by the cholesterol arriving through HDL (and
  dietary cholesterol returned by chylomicron
  remnants).
• Cholesterol (CE) in HDL is referred to as good
  cholesterol.

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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 apoB-100 by a
  disulfide linkage
• high risk association with premature coronary
  artery disease and stroke

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Lipoprotein(a) Lp(a)
apoB100
apo(a)

• Lp(a) is mainly produced in the liver
• Plasma levels in human is 0.1100 mg/dl

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Apolipoprotein
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 

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Apolipoprotein

• A-I (28,300)principal protein in HDL
• 90 120 mg in plasma activates LCAT
• A-II (8,700) occurs as dimer mainly in HDL
• 30 50 mg enhances hepatic lipase activity
• B-48 (240,000) found only in chylomicron
• lt5 mg derived from apo-B-100 gene by RNA
  editing lacks the LDL receptor-binding domain of
  apo-B-100

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Apolipoprotein

• B-100 (500,000) principal protein in LDL
• 80 100 mg binds to LDL receptor
• C-I (7,000)found in chylomicron, VLDL, HDL
• 4 7 mg may also activate LCAT
• C-II (8,800) found in chylomicron, VLDL, HDL
• 3 8 mg activates lipoprotein lipase
• C-III (8,800) found in chylomicron, VLDL, IDL,
  HDL
• 8 15 mg inhibits lipoprotein lipase

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Apolipoprotein

• D (32,500) found in HDL
• 8 10 mg also called cholesterol ester
  transfer protein (CETP)
• E (34,100) found in chylomicron, VLDL, IDL, HDL
• 3 6 mg binds to LDL receptor
• H (50,000)found in chylomicron also known as
  b-2-glycoprotein I (involved in TG metabolism)

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Content

• Introduction of lipoprotein.
• Classification of hyperlipidemia.
• Treatment of hyperlipidemia.

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Classification of hyperlipidemia
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Frederickson -WHO classification

• Type I incr. chylomicrons, reduced HDL, absence
  of lipoprotein lipase deficiency of apo CII
  (hyperchylomironemia)

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Lipoprotein lipase (LPL)

• A glycoprotein with 448 amino acids (6070kD)
• Source mainly from adipose and muscle
• Substrates chylomicrons and VLDL
• ? energy provision and TG
  storage
• Deficiency pancreatitis, eruptive xanthoma
• atherosclerosis?

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LPL transgenic rabbits
Does LPL protect against diet-induced
atherosclerosis in Tg rabbits?
0.3 cholesterol diet for 16 wks
Analyses of plasma lipoproteins and aortic
atherosclerosis
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Overexpession of LPL inhibits Atherosclerosis in
Transgenic Rabbits
nonTg
Tg
Total cholesterol lt 200 mg/dl
600800 mg/dl
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Conclusion

• Overexpression of LPL suppressed the cholesterol
  diet-induced atherosclerosis.
• LPL may improve insulin sensitivity and prevent
  obesity.

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Frederickson -WHO classification

• Type II-A raised LDL decreased catabolism of
  LDL (receptor deficiency or polygenic)
• Type II-B raised VLDL LDL often reduced HDL
  increased production of VLDL impaired LDL
  catabolism

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The LDL receptor

• characterized by Michael Brown and Joseph
  Goldstein (Nobel prize winners in 1985)
• based on work on familial hypercholesterolemia
• receptor also called B/E receptor because of its
  ability to recognize particles containing both
  apos B and E
• activity occurs mainly in the liver

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The LDL receptor

• receptor recognizes apo E more readily than apo
  B-100
• Found in clathrin coated pits (endocytosis)
• After endocytosis the receptor is recycled whilst
  the LDL (or CMR) is degraded to releasing lipid
  cargo. Cholesterol uptake down regulates the
  cells own production of cholesterol and down
  regulates LDL receptor synthesis .

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The LDL receptor

• Mutations in LDL receptors causes increased
  plasma LDL levels (i.e. increased cholesterol
  levels). This accelerates progress of
  atherosclerosis (Familial hyperlipedimias).
• The cholesterol in LDL is often called bad
  cholesterol.

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Representation of the LDL receptor (839
aa) extracellular domain is responsible for
apo-B-100/apo-E binding intracellular domain
is responsible for clustering of LDL receptors
into coated pit region of plasma membrane
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Gene mutation of LDL-R

• null allele
• Transport defective allele
• Binding defective allele
• Internalizing defective allele
• intracellular degradating defective allele
• Recycling defective allele

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Frederickson -WHO classification

• Type III raised IDL (dysbetalipoproteinemia)
  abnormal apolipoprotein E impaired catabolism of
  IDL elevated cholesterol and triglycerides
  (formerly known as broad beta disease)
• Type IV raised VLDL often reduced HDL
  impaired VLDL catabolism dietary indiscretion (
  formerly known as hyperprebetalipoproteinemia)

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Frederickson -WHO classification

• Type V raised chylomicrons VLDL reduced
  HDL reduced lipoprotein lipase VLDL
  hypersecretion (formerly known as mixed lipemia)

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Atherosclerosis

• hardening of the arteries due to the deposition
  of atheromas
• heart disease is the leading cause of death
• caused by the deposition of cholesteryl esters on
  the walls of arteries
• atherosclerosis is correlated with high LDL and
  low HDL

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Photograph of an arterial plaque
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Plasma Lipoproteins

• Atherogenic
• LDL, b-VLDL and Lp(a)
• Anti-atherogenic
• HDL
• Neutral
• Chyomicron and VLDL

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Coronary heart disease and HDL-C Framingham Heart
Study
Women
Men
Gordon, Castelli, et al. Am J Med 1977
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Framingham HDL-C vs LDL-C as a predictor of CHD
risk
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Risk of CAD
2.5
over 4 yrs
2
of follow-
1.5
up
25
1
45
0.5
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HDL - C

• 0

85
100
220
160
LDL- C (mg/dl)
Men aged 50-70
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Atherogenic lipoprotein profile(ALP)

• TG?
• LDL ?
• HDL ?

lipid triad
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Clinical classification of dyslipidemia

• Hypercholesterolemia
• Hypertriglyceridemia
• Mixed hyperlipemia
• Low high density lipoprotein

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Content

• Introduction of lipoprotein.
• Classification of hyperlipidemia.
• Treatment of hyperlipidemia.

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Factors promoting elevated blood lipids

• age
• men gt45 years of age women gt 55 years of age
• family history of CAD
• smoking
• hypertension gt140/90 mm Hg
• low HDL cholesterol
• obesity gt30 overweight
• diabetes mellitus
• inactivity/ lack of exercise

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Lipid assay and judgement
Lipid normal range
border hyperlipidemia
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Treatment of hyperlipidemia

• Adjustment of diet constitution
• Amelioration of life manier
• Drugs
• Gene therapy

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Adjustment of diet constitution

• ??????30,??40,??30
• ????????,??????
• ??????(???,??)
• ????????(??????????)?

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???????????(mg/100g)
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Amelioration of life manier

• ??
• ??
• ????
• ????
• ??????A???

???,???,??????????,???????,???,???????????

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Drugs
a. 3-??-3???????A?????? HMG Co-A
reductase inhibitors,?????,
??????????(???)????? (???)?????(???)?????
(???)????????????(???) ????(?????????)?
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????????????,??TC, LDL-C, VLDL-C?TG,?????????
??????????,????????????????,???
?????20?????????????????????
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b. ???????(???)?????????(???,??)?????(???)?????(?
??,???)?????(???)????(????,???,???,????)?
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?????????????????????(peroxisome proliferator
activated receptor, PPAR)?????????,????PPAR??LPL?a
poA??apoA ? ,??apoC ??????,??LPL?????,??TG????????
????????????
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c. ??????????????(???)?????(???)?
?????????????????,???????????LDL-C??,????????????
????????,????????,????,????????,????????????????
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• ???????????????
• ????(???,????)?

??????cAMP??,?????????,
??VLDL, IDL?LDL??????
???????????????
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e. ????(???)??apoB??,??LDL????????????????????
????????????????????
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f. ???????????????????,???????,???????????????
???????????????? ?????????????????,????????
????,??????,???????????,?????????
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????
a. ?????????????????? ??????LDL-R??????????
?? ????????? b. ?????