Prof. Dr. Serdar ÖZTEZCAN

Lipids and Lipoproteins

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)

Arteriosclerosis

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

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.

Lipoproteins

TG and CE

CholesterolApoprotein

Phospholipids

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)

Lipoprotein classes

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)

Lipoproteins

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

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)

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

Lipoprotein metabolism

The five major pathways Lipid digestion and absorption Exogenous Endogenous Intracellular-cholesterol transport Reverse-cholesterol transport

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

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

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

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)

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.

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

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

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

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 IIa

ApoB gene mutations Polygenic IIa, IIb

Fam. combined hypelipidemia

Polygenic IIa, IIb

Fam. dysbetalipoproteinemia

apoE gene mutations III

Fam. hypertriglyreridemia (polygenic) ?

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

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.

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

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

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.

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

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 Optimal100–129 Near optimal/above optimal130–159 Borderline high160–189 High190 Very high

TC and HDL cholesterol

Total Cholesterol (mg/dL)

<200 Desirable

200–239 Borderline high

240 High

HDL Cholesterol (mg/dL)

<40 Low

60 High

LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk Categories Guadelines from NCEP

Risk CategoryLDL Goal(mg/dL)

LDL Level at Which to Initiate

Therapeutic Lifestyle Changes

(TLC) (mg/dL)

LDL Level at Which

to ConsiderDrug 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)

Therapeutic life-style changes (TLC)

Therapeutic life-style changes are the cornerstones of therapy for lipid disorders:

Diet Weight management Increased physical activity

Therapeutic Lifestyle ChangesNutrient 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

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

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.

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

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

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