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