1. Prof. Dr. Serdar ÖZTEZCAN
Lipids and Lipoproteins
Prof. Dr. Serdar ÖZTEZCAN

2. Clinical Significance
Lipids and lipoproteins are intimately involved in the development of atherosclerosis
Pathogenesis
Endothelial cell damage of muscular and elastic arteries
Causes of endothelial cell injury
Hypertension, smoking tobacco, homocysteine, LDL
Cell response to endothelial injury
Macrophages and platelets adhere to damaged endothelium
Released cytokines cause hyperplasia of medial smooth muscle cells
Smooth muscle cells migrate to the tunica intima
Cholesterol enters smooth muscle cells and macrophages (called foam cells)
Smooth muscle cells release cytokines that produce extracellular matrix
Matrix components include collagen, proteoglycans, and elastin
Development of fibrous cap (plaque) 2

3. Arteriosclerosis 3

4. Atherosclerosis Sites for atherosclerosis (descending order)
Abdominal aorta
Coronary artery
Popliteal artery
Internal carotid artery
Complications of atherosclerosis
Vessel weakness (e.g., abdominal aortic aneurysm)
Vessel thrombosis
Acute MI (coronary artery)
Stroke (internal carotid artery, middle cerebral artery)
Small bowel infarction (superior mesenteric artery)
Hypertension
Renal artery atherosclerosis may activate the renin-angiotensin-aldosterone system
Peripheral vascular disease
Increased risk of gangrene
Pain in the buttocks and when walking (claudication)
Cerebral atrophy
Atherosclerosis involving circle of Willis vessels or internal carotid artery

5. Lipoproteins
Lipids synthesized in the liver and intestine are transported in macromolecular complexes known as lipoproteins
Lipoprotein are typically spherical particles with
nonpolar neutral lipids (triglyceride and cholesterol ester) in their core
more polar amphipathic lipids (phospholipid and free cholesterol) at their surface
They also contain one or more spesific protein called apolipoprotein, on their surface.

6. Lipoproteins
TG and CE
Apoprotein
Cholesterol
Phospholipids

7. Lipoproteins Chylomicrons VLDL (very low density lipoproteins)
intestine-derived
Chylomicrons
liver-derived
VLDL (very low density lipoproteins)
IDL (intermediate density lipoproteins)
LDL (low density lipoproteins)
HDL (high density lipoproteins)
assembled in circulation
lipoprotein(a) - from LDL and apo-a (liver)

8. Lipoprotein classes

9. Lipoproteins
Composition (lipids and apolipoproteins) different in particular lipoproteins
chylomicrons and VLDL
TAG-rich particles (TAG>Cholesterol)
LDL and HDL
Cholesterol-rich particles (Cholesterol>TAG)

10. Lipoproteins

11. Apolipoprotein Apolipoproteins
help maintain the structural integrity of lipoprotein
serve as ligands for cell receptors
serve as activators and inhibitors of the enzymes (LCAT, LPL) that modify lipoprotein particals
The binding of lipids to apolipoproteins is weak, allows the exchange of lipids and apolipoproteins between
the plasma lipoproteins
cell membranes and lipoproteins

12. Apolipoprotein Particle Apolipoprotein Chilom. apoB-48, A, C, E
VLDL apoB-100, C, E
LDL apoB-100
HDL apoA, C, D, E
Lp(a) apoB-100, apo(a)

13. Apolipoprotein
Various types apolipoprotein control their metabolic fate
all particles containing apoB (apoB-100 or apoB-48) are atherogennic
apoB-48 – binding to the receptor for chylomicron remnants
apoB-100 – binding to LDL receptor
apoC (apoC-II and apoC-III) is a cofactor of lipoprotein lipase (LPL), influence the rate of TAG hydrolysis
apoE influence the removal of lipoprotein “remnants” (chylomicrons and VLDL) by liver
apoA is a part of HDL (binding to HDL receptor) and cofactor of LCAT
low levels are atherogennic

14. Lipoprotein metabolism
The five major pathways
Lipid digestion and absorption
Exogenous
Endogenous
Intracellular-cholesterol transport
Reverse-cholesterol transport

15. 15

16. Intracellular-Cholesterol Transport
LDL are the major lipoproteins responsible for the delivery of exogenous cholesterol to peripheral cells
Cholesterol (in the peripheral cells)
Used for membrane biogenesis
Stored as lipid drops after reesterification by ACAT
Carried from the cell by RCTP
Cholesterol (in the hepatocytes)
are unique in that intracelluler cholesterol has several other possible fates
Repackaged and secreted on lipoproteins
Converted to bile salts
Directly excreted into the bile

17. Intracellular-Cholesterol Transport
Cholesterol ( in the macrophages)
Macrophages are also unique
express scavenger receptors, which recognize oxidized or other modified forms of LDL
Unlike the LDL receptor, these scavenger receptors are not downregulated in response to excess intracellular cholesterol
Macrophages are prone to accumulate excess cholesterol in lipid drops and form foam cells which play a key role in atherosclerotic plaque development

18. Reverse-Cholesterol Transport
remove excess cellular cholesterol from peripheral cells and return it to the liver for excreation
mediated by HDL
Cholesterol is actively pumped out of cells by the ABCA1 (ATP-binding cassette protein A1) transporter onto lipid-poor apoA1, which is made in the liver and intestine
The prosess result in the formation of disc-shaped nascent HDL
Discoidal HDL also interacts with ABCA1 transporter in peripheral cells such as the macrophages and removes additional cholesterol

19. Reverse-Cholesterol Transport
Lecithin-cholesterol acyltransferase (LCAT) which esterifies cholesterol on HDL
plays a key role in reverse-cholesterol transport pathway because
cholesterol esters are much more hydrophobic than cholesterol and remain trapped in the core of HDL until they are removed by the liver
esterification converts the disc-shaped nascent HDL to spherical HDL (the main form in the circulation)

20. Reverse-Cholesterol Transport
In the next stage of the RCTP
the liver selectively removes cholesterol esters from the lipid-rich spherical HDL
lipid-depleted HDL return to the circulation for additional rounds of cholesterol removal from peripheral cells.

22. Clinical Significance
The clinical significance of lipids is primarly associated with their contribution to coronary heart disease (CHD)/vascular disease and various lipoprotein disorders
Lower HDL and higher LDL and triglycerides levels account for much of the observed association with increased risk of premature hearth disease
Concentration of lipoproteins in plasma is a result of an interaction between genetic factors and/or environment/life style factors

23. Hyperlipoproteinemia, dyslipoproteinemia
HLPs are heterogeneous group of metabolic diseases characterised by increased plasma lipoproteins
dyslipoproteinemia is a term often used since not only high but also low levels can be a risk (e.g. HDL)
Etiology
primary – genetic (inherited)
monogenic – single gene
polygenic – complex diseases (thrifty genotype) genetic predisposition + environmental factors
do not respond to dietary interventions, lipid lowering pharmacotherapy is necessary
carriers are endangered by premature cardiovascular disease
secondary – consequence of other disease

24. HLP classification
in the past – Fredrickson classification (phenotypes I - V)
according to lipoprotein mobility spectrum after electrophoretic separation
did not considered HDL
today – simple, therapeutically relevant clinical classification of HLPs considering plasma levels of lipids
Hypercholesterolemia
Hypertriglyceridemia
Mixed disorders

25. Primary HLPs Disorder Cause Type (Fredrickson) Familiar deficit of LPL
LPL gene mutations I
Familiar deficit of apoC I
apoC gene mutations
I or V
Fam. hypercholesterolemia
LDLR gene mutations
IIa
Familiar defective apoB-100
apoB gene mutations
ApoB gene mutations
Polygenic
IIa, IIb
Fam. combined hypelipidemia
Fam. dysbetalipoproteinemia
apoE gene mutations
III
Fam. hypertriglyreridemia
(polygenic) ?

26. Secondary HLPs caused by other primary disease
Diabetes mellitus (type 1) ↑TAG, ↓ HDL
Hypothyroidosis ↑CH
Nephrotic syndrome ↑CH, TAG
Chronic renal insufficiency ↑TG
Cholestasis ↑CH
impact on cardiovascular system is the same as in primary HLPs
treatment involves primary disease and hyperlipidemia
unlike primary ones, secondary HLPs respond well to dietary interventions

27. Arteriosclerosis
In the developed countries, the single leading cause of death and disability
Plaque
in arteries of the arms or legs; peripheral vascular disease,
in heart; coronary artery disease, associated with angina and myocardial infarction
in vessels in the brain; cerebrovascular disease associated with stroke
Many genetic and acquired abnormalities may also lead to lipid deposits in the liver, pancreas and kidney, resulting in imparied function of these vital organs
Lipid deposits in the skin form nodules called xantomas which are a clue to genetic abnormalities.

28. Diagnosis of a dyslipoproteinemia
Diagnosis and the best treatment approach is largely dependent upon the measurement of
Total cholestrol
Triglycerides
HDL cholestrol
LDL cholestrol
Test results must be interpreted in with the risk for developing Coronary Heart Disease (CHD)
The medical history and other lab test results are also important for determining if a dyslipoproteinemia is
the result of a primary lipoprotein disorder or
a consequence of one or more of the secondary causes of hyperlipidemia
will likely alter the treatment approach

29. Risk Evaluation
An assesment should also be made of the risk for CHD. This is based on
Clinical evidence of existing CHD
The presence of conditions that are closely associated with CHD (CHD risk equivalents) such as
Symptomatic carotid artery disease
Peripheral vascular disease
Abdominal aortic aneurysm
Diabetes
Major risk factors

30. Major Risk Factors (Exclusive of LDL Cholesterol) That Modify LDL Goals
Cigarette smoking
Hypertension (BP 140/90 mmHg or on antihypertensive medication)
Low HDL cholesterol (<40 mg/dL)†
Family history of premature CHD
CHD in male first degree relative <55 years
CHD in female first degree relative <65 years
Age (men 45 years; women 55 years or premature menapose for women)
There is currently much interest in risk factors that have been recognized relatively recently, including
hyperfibrinogenaemia,
a high plasma Lp(a) and
an increased plasma concentration of homocysteine.
† HDL cholesterol 60 mg/dL counts as a “negative” risk factor; its presence removes one risk factor from the total count.

31. Lipid and lipoprotein distributions in the population
Serum lipoprotein concentrations differ between adult men and women, primarily as a result of diffences in sex homone levels
women having higher HDL cholesterol levels and lower total cholesterol and triglyceride levels than men
diffences in total cholesterol disappears after menopouse
Men and women both show a tendency toward increased total cholesterol, LDL cholesterol and triglycerides concentration with age

32. LDL cholestrol
The concentration LDL cholestrol is used both to decide the most approriate therapy and monitoring the effectiveness of therapy
LDL Cholesterol (mg/dL)
<100 Optimal
100–129 Near optimal/above optimal
130–159 Borderline high
160–189 High
190 Very high

33. TC and HDL cholesterol Total Cholesterol (mg/dL) <200 Desirable
200–239 Borderline high
240 High
HDL Cholesterol (mg/dL)
<40 Low
60 High

34. LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk Categories Guadelines from NCEP
Risk Category
LDL Goal (mg/dL)
LDL Level at Which to Initiate Therapeutic Lifestyle Changes (TLC) (mg/dL)
LDL Level at Which to Consider Drug Therapy (mg/dL)
CHD or CHD Risk Equivalents (10-year risk >20%)
<100
100
130 (100–129: drug optional)
2+ Risk Factors (10-year risk 20%)
<130
130
10-year risk
10–20%: 130
10-year risk <10%: 160
0–1 Risk Factor
<160
160
190 (160–189: LDL-lowering drug optional)

35. Therapeutic life-style changes (TLC)
Therapeutic life-style changes are the cornerstones of therapy for lipid disorders:
Diet
Weight management
Increased physical activity

36. Therapeutic Lifestyle Changes Nutrient Composition of TLC Diet
Nutrient Recommended Intake
Saturated fat Less than 7% of total calories
Polyunsaturated fat Up to 10% of total calories
Monounsaturated fat Up to 20% of total calories
Total fat 25–35% of total calories
Carbohydrate 50–60% of total calories
Fiber 20–30 grams per day
Protein Approximately 15% of total cal.
Cholesterol Less than 200 mg/day
Plant stanols/sterols 2 g/day
Total calories (energy) Balance energy intake and expenditure to prevent weight gain

37. Treatment
A wide varietyof pharmacological agent for lowering cholestrol in adults are available
Bile acid-binding resins (cholestyramin and colestipol)
Niacin
Gemfibrozil
Ezetimible
HMG-CoA reductase inhibitors (e.g., atorvastatine, fluvastatine, lovestatin, pravastatin, resuvastatin,and simvastatin)
Last group reduce LDL cholestrol as much as 40%
Many of these drugs will modestly increse HDL cholestrol but niacin in particular effective

38. Statins
The main mechanism by which statin drugs decrease the incidence of coronary events is by blocking cholesterol biosyntesis, which results in the upregulation of the LDL receptor
The increased concentration of LDL receptor, particullary in the liver, removes proatherogenic LDL particles form circulation, thus accounting for the antiatherogenic effect of statin-type drugs.

39. Emerging Risk Factors
Other newly developed tests may also be valuable in CHD stratification,
particularly for patient that are at a borderline or intermediate risk based on conventional lipid and lipoprotein test
Lipoprotein (a)
Remnant lipoproteins
Small dense LDL
C-reactive protein (CRP)
increased in patients with disrupted (inflammatory) plaques. Plaques may rupture and produce vessel thrombosis, which leads to acute myocardial infarction (MI). C-reactive protein may be a stronger predictor of cardiovascular events than LDL.
Homocysteine
Prothrombotic factors
Proinflammatory factors
Impaired fasting glucose

40. Lipoprotein(a)
Lipoprotein(a) particles are LDL-like particles that contain one molecule of apo (a) linked to apo B-100 by a disulfide bond
Elevated levels of Lp(a) are thought to confer increased risk for premature coronary heart disease and stroke
Because Lp(a) have a high level of homology with plasminogen, a protein that promotes clot lysis, it has been proposed that Lp(a) may compete with plasminogen for binding sites, thereby promoting clotting, a key contributor to both myocardial infarction and stroke 40

41. Increased homocysteine
Inherited metabolic disease homocystinuria (classically a result of a deficiency of the enzyme cystathionine β-synthase); patients with this disease have a tendency to die from premature vascular disease
However, numerous studies have implicated lesser elevations of homocysteine (than are characteristic of homocystinuria) as a risk factor for vascular disease
Possible mechanisms include promotion of the oxidation of LDL and a direct toxic action of homocysteine on the vascular endothelium
Vitamins B6, B12 and folate act as cofactors in homocysteine metabolism
there is an association between elevated plasma homocysteine concentrations and low folate, raising the possibility that folate supplementation may be of therapeutic benefit in the prevention of vascular disease
Although the results of some clinical trials appear to support this idea, others have been negative and the case for folate supplementation of the diet to reduce the risk of CHD remains unproven