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)
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 Apoprotein Cholesterol 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)
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)
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
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 • 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 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 • 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 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
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 secondarycauses 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 towardincreased 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 Optimal 100–129 Near optimal/above optimal 130–159 Borderline high 160–189 High 190 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
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 NutrientRecommended 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