Prof dr serdar ztezcan
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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

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Prof dr serdar ztezcan

Prof. Dr. Serdar ÖZTEZCAN

Lipids and Lipoproteins


Clinical significance

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

Arteriosclerosis


Atherosclerosis

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

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.


Lipoproteins1

Lipoproteins

TG and CE

Apoprotein

Cholesterol

Phospholipids


Lipoproteins2

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

Lipoprotein classes


Lipoproteins3

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)


Lipoproteins4

Lipoproteins


Apolipoprotein

Apolipoprotein

  • Apolipoproteins

    • help maintain the structural integrity of lipoprotein

    • serve as ligands for cell receptors

    • serve as activators and inhibitorsof 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


Apolipoprotein1

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)


Apolipoprotein2

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

Lipoprotein metabolism

  • The five major pathways

    • Lipid digestion and absorption

    • Exogenous

    • Endogenous

    • Intracellular-cholesterol transport

    • Reverse-cholesterol transport


Intracellular cholesterol transport

Intracellular-Cholesterol Transport

  • LDLare 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 transport1

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 inatherosclerotic plaque development


  • Reverse cholesterol transport

    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-poorapoA1, 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 transport1

    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 transport2

    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 significance1

    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

    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

    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

    Primary HLPs


    Secondary hlps

    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


    Arteriosclerosis1

    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 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 secondarycauses of hyperlipidemia

        • will likely alter the treatment approach


    Risk evaluation

    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

    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

    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 towardincreased total cholesterol, LDL cholesterol and triglycerides concentration with age


    Ldl cholestrol

    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)

    <100Optimal

    100–129Near optimal/above optimal

    130–159Borderline high

    160–189High

    190Very high


    Tc and hdl cholesterol

    TC and HDL cholesterol

    Total Cholesterol (mg/dL)

    <200Desirable

    200–239Borderline high

    240High

    HDL Cholesterol (mg/dL)

    <40 Low

    60 High


    Prof dr serdar ztezcan

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


    Therapeutic life style changes tlc

    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 changes nutrient composition of tlc diet

    Therapeutic Lifestyle ChangesNutrient Composition of TLC Diet

    NutrientRecommended Intake

    • Saturated fatLess than 7% of total calories

    • Polyunsaturated fatUp to 10% of total calories

    • Monounsaturated fat Up to 20% of total calories

    • Total fat25–35% of total calories

    • Carbohydrate50–60% of total calories

    • Fiber20–30 grams per day

    • ProteinApproximately 15% of total cal.

    • CholesterolLess than 200 mg/day

    • Plant stanols/sterols 2 g/day

    • Total calories (energy)Balance energy intake and expenditure to prevent weight gain


    Treatment

    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

    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

    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)

    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


    I ncreased homocysteine

    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


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