Presentation on theme: "S-KHALILZADEH. Lipids are hydrophobic molecules that are insoluble in water. They are in cell membranes as a major form of stored nutrients (triglycerides),"— Presentation transcript:
Lipids are hydrophobic molecules that are insoluble in water. They are in cell membranes as a major form of stored nutrients (triglycerides), as precursors of adrenal and gonadal steroids and bile acids as extracellular and intracellular messengers (e.g., prostaglandins, phosphatidylinositol). Lipoproteins provide a vehicle for transporting the complex lipids in the blood as water-soluble complexes and deliver lipids to cells
Fatty acids vary in length and in the number and position of double bonds Saturated fatty acids lack double bonds unsaturated fatty acids have one or more double bonds. Monounsaturated fatty acids have one double bond, and polyunsaturated fatty acids (PUFAs) have two or more.
Cholesterol is a four-ring hydrocarbon with an eight-carbon side chain. It is a major component of cell membranes and as a precursor of steroid hormones (adrenal and gonadal hormones) and bile acids In the blood, about two thirds of the cholesterol is esterified
Triglycerides consist of three fatty acid molecules esterified to a glycerol molecule Triglycerides store fatty acids and form large lipid droplets in adipose tissue. They are also transported as a component of certain lipoproteins. When triglycerides are hydrolyzed in adipocytes, free fatty acid (FFA) are released to be used as a source of energy
Chylomicrons are the largest of the plasma lipoproteins (>1000 Å in diameter),float after ultracentrifugation of plasma. They are composed of 98% to 99% lipid (85%-90% triglyceride) and 1% to 2% protein Chylomicrons are present in postprandial plasma (but are absent after an overnight fast) and contain apo-B48, apo-AI, apo-AIV, apo-E, and the C apolipoproteins
VLDLs are particles 300 to 700 Å They are composed of 85% to 90% lipid (about 55% triglyceride, 20% cholesterol, and 15% phospholipid) and 10% to 15% protein. The distinctive apolipoprotein is apo- B100, the hepatic form of apo-B. VLDLs also contain apo-E and C apolipoproteins
IDLs present in low concentrations in the plasma and are intermediate in size and composition between VLDL and LDL Their proteins are apo-B100 and apo-E. The IDLs are precursors of LDLs and represent metabolic products of VLDL catabolism in the plasma by the action of lipases. IDLs are often considered to be VLDL remnants and to be atherogenic.
LDLs are about 200 Å in diameter, are the major cholesterol-carrying lipoproteins in the plasma; about 70% of total plasma cholesterol is in LDL. LDLs are composed of approximately 75% lipid (about 35% cholesteryl ester, 10% free cholesterol, 10% triglyceride, and 20% phospholipid) and 25% protein. Apo-B100 is the principal protein in these particles, with trace amounts of apo-E
The clearance of LDL is mediated by apo-B100. The affinity of apo-B100 for the LDL receptor is lower than that of apo-E, and clearance of LDL is much slower (with a half-life of 2 to 3 days). Compared with apo-B100– containing LDLs, apo-E–containing lipoproteins have 20-fold greater affinity for the LDL receptor
HDLs are small particles ( Å in diameter) HDLs contain about 50% lipid (25% phospholipid, 15% cholesteryl ester, 5% free cholesterol, and 5% triglyceride) and 50% protein Their major apolipoproteins are apo-AI (65%), apo-AII (25%), and smaller amounts of the C apolipoproteins and apo-E
Apo-E is a minor component of a subclass of HDL referred to as HDL 1, but about 50% of total plasma apo-E is in this HDL fraction. The major classes of HDLs lack apo-E and do not interact with the LDL receptor
Apolipoproteins — Understanding the major functions of the different apolipoproteins is important clinically, because defects in apolipoprotein metabolism lead to abnormalities in lipid handling
Apolipoproteins A-I — Structural protein for HDL; activator of lecithin-cholesterol acyltransferase (LCAT). A-II — Structural protein for HDL; activator of hepatic lipase. A-IV — Activator of lipoprotein lipase (LPL) and LCAT. B-100 — Structural protein for VLDL, IDL, LDL, and Lp(a); ligand for the LDL receptor; required for assembly and secretion of VLDL. B-48 — Contains 48 percent of B-100; required for assembly and secretion of chylomicrons; does not bind to LDL receptor.
C-I — Activator of LCAT. C-II — Essential cofactor for LPL. C-III — Interferes with apo-E mediated clearance of triglyceride-enriched lipoproteins by cellular receptors ; inhibits triglyceride hydrolysis by lipoprotein lipase and hepatic lipase,interferes with normal endothelial function.
D — May be a cofactor for cholesteryl ester transfer protein (CETP). E — Ligand for hepatic chylomicron and VLDL remnant receptor, leading to clearance of these lipoproteins from the circulation; ligand for LDL receptor.
Human LPL is synthesized by adipocytes, by myocytes in skeletal and cardiac muscle, and by macrophages but is not produced by hepatocytes. LPL is transported to the capillary endothelial cells where it interacts with chylomicrons and VLDL in the circulation and mediates the hydrolysis of their triglycerides to FFAs. The fatty acids are stored as triglyceride in adipocytes and in the formation of hepatic VLDL.
Hepatic lipase is primarily a phospholipase but also possesses triglyceride hydrolase activity It is synthesized by hepatocytes Hepatic lipase is transported from the liver to the capillary endothelium of the adrenals, ovaries, and testes, where it functions in the release of lipids from lipoproteins for use in these organs. Its activity is increased by androgens and reduced by estrogens
EXOGENOUS PATHWAY OF LIPID METABOLISM starts with the intestinal absorption of dietary cholesterol and fatty acids The mechanisms regulating the amount of dietary cholesterol that is absorbed are unknown. Sitosterolemia is a rare autosomal recessive disorder associated with hyperabsorption of cholesterol and plant sterols from the intestine.
Within the intestinal cell, free fatty acids combine with glycerol to form triglycerides, and cholesterol is esterified by acyl-coenzyme A:cholesterol acyltransferase (ACAT) to form cholesterol esters Triglycerides and cholesterol are assembled intracellularly as chylomicrons. The main apolipoprotein is B-48, but C-II and E are acquired as the chylomicrons enter the circulation. Apo B-48 permits lipid binding to the chylomicron but not to LDL receptor.
Apo C-II is a cofactor for LPL which makes the chylomicrons smaller by hydrolyzing the core triglycerides and releasing free fatty acids. The free fatty acids are then used as an energy source, converted to triglyceride, or stored in adipose tissue. The end-products of chylomicron are chylomicron remnants that are cleared from the circulation by hepatic chylomicron remnant receptors for which apo E is a high-affinity ligand.
ENDOGENOUS PATHWAY OF LIPID METABOLISM begins with the synthesis of VLDL by the liver Microsomal triglyceride transfer protein is essential for the transfer of the bulk of triglycerides into the endoplasmic reticulum for VLDL assembly They include apo C-II which acts as a cofactor for LPL, apo C-III which inhibits this enzyme, and apo B-100 and E which serve as ligands for LDL receptor
The triglyceride core of VLDL particles is hydrolyzed by lipoprotein lipase. During lipolysis, the core of the VLDL particle is reduced, generating VLDL remnant particles (also called IDL) that are depleted of triglycerides via a process similar to the generation of chylomicron remnants.
Some of the excess surface components in the remnant particle, including phospholipid, unesterified cholesterol, and apolipoproteins A, C and E, are transferred to HDL VLDL remnants can either be cleared from the circulation by the apo B/E (LDL) or the remnant receptors or remodeled by hepatic lipase to form LDL particles.
LDL can be internalized by hepatic and nonhepatic tissues. Hepatic LDL cholesterol can be converted to bile acids and secreted into the intestinal lumen. LDL cholesterol internalized by nonhepatic tissues can be used for hormone production, cell membrane synthesis, or stored in the esterified form
Circulating LDL can also enter macrophages and some other tissues through the unregulated scavenger receptor. This pathway can result in excess accumulation of intracellular cholesterol and the formation of foam cells which contribute to the formation of atheromatous plaques
These cholesterol-enriched cells can rupture, releasing oxidized LDL, intracellular enzymes, and oxygen free radicals that can further damage the vessel wall. Oxidized LDL induces apoptosis of vascular smooth muscle and human endothelial cells via activation of a protease which suggests a mechanism for the response to injury hypothesis of atherosclerosis
anti-atherogenic effect of HDL Apolipoprotein A-I on the surface of HDL serves as a signal to mobilize cholesterol esters from intracellular pools. After diffusion of cholesterol onto HDL, the cholesterol is esterified to cholesterol esters by LCAT, a plasma enzyme that is activated primarily by apolipoprotein A-I. HDL can act as an acceptor for cholesterol released during lipolysis of triglyceride-containing lipoproteins
Diabetes mellitus insulin deficiency and poor glycemic control lead to increases in the plasma levels of triglycerides and apo- B–containing lipoproteins insulin deficiency results in impaired LPL activity and diminished clearance of triglyceride-rich particles. Insulin deficiency also enhances lipolysis, which increases FFA flux to the liver, increased FFA flux drives triglyceride and VLDL synthesis and secretion.
Plasma levels of LDL are increased in some but not all subjects. the hyperlipidemia in type 2 diabetes is often characterized by an increase in small, dense LDLs which are particularly atherogenic a portion of the plasma LDL undergoes glycosylation, which can increase binding to arterial wall proteoglycans and susceptibility to oxidation.
(CHD) are common in industrialized societies There is a direct relation between the plasma levels of total and LDL cholesterol and the risk of CHD and mortality LDL cholesterol lowering in moderate to high-risk patients leads to a reduction in cardiovascular events Abnormalities of plasma lipids (dyslipidemia) other than LDL cholesterol are common in patients with early onset CHD HDL cholesterol levels are related to absolute CHD event rates in treated hypercholesterolemic subjects with and without baseline clinical CHD Screening tests for dyslipidemia are widely available
Guidelines developed by the NCEP in 2001 recommend that a complete plasma lipid profile (total cholesterol, LDL-C, HDL-C, and triglycerides) be measured in all adults 20 years of age and older at least once every 5 years
The ATP III recommendations for the treatment of hypercholesterolemia are based on the LDL-cholesterol (LDL-C)and are influenced by the coexistence of CHD and the number of cardiac risk factors. There are five major steps to determining an individual's risk category, which serves as the basis for the treatment guidelines
Step 1 — The first step in determining patient risk is to obtain a fasting lipid profile
Step 2 — CHD equivalents, that is, risk factors that place the patient at similar risk for CHD events as a history of CHD itself, are identified : Diabetes mellitus Symptomatic carotid artery disease Peripheral arterial disease Abdominal aortic aneurysm Multiple risk factors that confer a 10-year risk of CHD >20 percent
Step 3 — Major CHD factors other than LDL are identified: Cigarette smoking Hypertension (BP ≥140/90 or antihypertensive medication) Low HDL-C (<40 mg/dL) Family history of premature CHD (in male first degree relatives <55 years, in female first degree relative <65 years) Age (men ≥45 years, women ≥55 years) HDL-C ≥60 mg/dL counts as a "negative" risk factor; its presence removes one risk factor from the total count
STEP-4 If two or more risk factors other than LDL (as defined in step 3) are present in a patient without CHD or a CHD equivalent (as defined in step 2), the 10-year risk of CHD is assessed using the ATP III modification of the Framingham risk tables
Step 5 — The last step in risk assessment is to determine the risk category that establishes the LDL goal, when to initiate therapeutic lifestyle changes, and when to consider drug therapy
Total-to-HDL-cholesterol ratio Among men, a ratio of 6.4 or more identified a group at 2 to 14 percent greater risk than predicted from serum total or LDL-C Among women, a ratio of 5.6 or more identified a group at 25 to 45 percent greater risk than predicted from serum total or LDL-C
Non-HDL-cholesterol Non-HDL-C is defined as the difference between the total cholesterol and HDL-C. Non-HDL-C includes all cholesterol present in lipoprotein particles that is considered atherogenic, including LDL,lp(a),IDL and VLDL. It has been suggested that the non-HDL-C fraction may be a better tool for risk assessment than LDL-C
ATP III identifies the non-HDL-C concentration as a secondary target of therapy in people who have high triglycerides ≥200 mg/dl. The goal for non-HDL-C in this circumstance is a concentration that is 30 mg/dL (0.78 mmol/L) higher than that for LDL-C
A standard serum lipid profile consists of total cholesterol, triglycerides, and HDL- cholesterol. Lipoprotein analysis should be performed after 9 to 12 hours of fasting to minimize the influence of postprandial hyperlipidemia. Either a plasma or serum specimen can be used; the serum cholesterol is approximately 3 percent lower than the plasma value
HMG-CoA Reductase Inhibitors Inhibition of cholesterol biosynthesis up-regulates cellular LDL receptors and enhances clearance of LDL from the plasma into cells.
Statins Competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes an early, ratelimiting step in cholesterol biosynthesis
Chemistry The statins possess a side group that is structurally similar to HMG-CoA Mevastatin, lovastatin, simvastatin, and pravaslatin are fungal metabolites fluvastatin, atorvastatin, and rosuvastatin are entirely synthetic Lovastatin and simvastatin are lactone prodrugs that are modified in the liver to active hydroxy acid forms Since they are lactones, they are less soluble in water than are the other statins
Mechanism of Action Statins exert their major effectreduction of LDL levels- through a mevalonic acid-like moiety that competitively inhibits HMG-CoA reductase. By reducing the conversion of HMG-CoA to mevalonate, statins inhibit an early and rate-limiting step in cholesterol biosynthesis
Inhibition of hepatic cholesterol synthesis, results in increased expression of the LDL receptor gene Degradation of LDL receptors also is reduced The greater number of LDL receptors on the surface of hepatocytes results in increased removal of LDL from the blood, statins also can reduce LDL levels by enhancing the removal of LDL precursors (VLDL and IDL) and by decreasing hepatic VLDL production
Triglyceride Reduction by Statins. Triglyceride levels >250 mgldl are reduced substantially by statins, If baseline triglyceride levels are below 250 mg/dl. Reductions in triglycerides do not exceed 25% irrespective of the dose or statin used simvastatin and atorvastatin, 80,mg/day; rosuvastatin, 40 mg/day experience a 35% to 45% reduction in fasting triglyceride levels
Effect of Statins on HDL-C Levels patients with elevated LDL-C levels and gender- appropriate HDL-C levels (40 to 50 mgldl for men; 50 to 60 mg/dl for women). an increase in HDL-C of 5% to 10% was observed, irrespective of the dose or statin employed In patients with reduced HDL-C levels (35 mg/dl) statins may differ in their effects on HDL-C levels (Simvastatin >Atorvastatin)
Effects of Slatins on LDL-C Levels Statins lower LDL-C by 20% to 55% depending on the dose and statin used Maximal effects on plasma cholesterol levels are achieved within 7 to 10 days. The statins are effective in almost all patients with high LDL-C levels. The exception is patients with homozygous familial hypercholesterolemia, the partial response in these patients is due to a reduction in hepatic VLDL synthesis associated with the inhibition of HMG-CoA reductase-mediated cholesterol synthesis
Nonlipid roles of statins Endothelial Function Plaque Stability Inflammation Lipoprotein Oxidation Coagulation
Statins and Endothelial Function Statin therapy enhances endothelial production of the vasodilator nitric oxide, leading to improved endothelial function after a month of therapy
Statins and Plaque Stability. They reportedly inhibit monocyte infiltration into the artery wall in a rabbit model Inhibit macrophage secretion of matrix metalloproteinases in vitro modulate the cellularity of the artery wall by inhibiting proliferation of smooth muscle cells and enhancing apoptotic cell death
Statins and Inflammation Statins decreased the risk of CHD and levels of C- reactive protein (CRP, an independent marker for inflammation and high CHD risk) independently of cholesterol lowering
Coagulation Statins reduce platelet aggregation reduce the deposition of platelet thrombi in the porcine aorta model the different statins have variable effects on fibrinogen levels
SECONDARY BENEFITS Bone metabolism Hypertension Heart failure Dementia Cancer prevention Renal function Sepsis and infections
Hepatotoxicity Elevation in hepatic transaminase to values greater than three times the upper limit of normal Incidence as great as 1% The incidence appeared to be dose related liver failure one case per million person-years of use measure alanine aminotransferase (ALT) at baseline and thereafter when clinically indicated.
Patients taking 80-mg doses (or 40 mg of rosuvastatin) should have their ALT checked after 3 months. If the ALT values are normal, it is not necessary to repeal the ALT test unless clinically indicated
Myopathy myopathy as any muscle disease myalgia as muscle ache or weakness without increased serum CK levels myositis as muscle symptoms with elevated CK levels rhabdomyolysis as muscle symptoms with marked CK elevations (>10 times upper limit of normal [ULN]) plus an elevated serum creatinine. (FDA) defines rhabdomyolysis as organ damage, typically renal insufficiency, with a CK level greater than 10,000 IU/L
Myopathy major adverse effect The incidence of myopathy is quite low (~0.0 1%). but the risk of myopathy and rhabdomyolysis increases in proportion to plasma statin concentrations Factors inhibiting statin catabolism are associated with increased myopathy risk, including advanced age (especially >80 years of age), hepatic or renal dysfunction. perioperative periods. multisystem disease (especially in association with diabetes mellitus), small body size, and untreated hypothyroidism
RISK FACTORS FOR STATIN MYOPATHY conditions that increase statin serum and muscle concentration factors that increase muscle susceptibility to injury
Asymptomatic patients Routine surveillance of CK levels is not required except in high-risk patients If CK measured CK < 5× ULN: reassurance CK ≥5 - <10× ULN: monitor for symptoms and periodical CK determination CK ≥10× ULN: stop statin and reconsider risks and benefits of statin treatment
Factors related to an increase in statin serum level Statin dose Small body frame Decreased statin metabolism and excretion Drug–drug interactions Grapefruit juice (possibly also pomegranate & starfruit) Hypothyroidism and diabetes mellitus Advanced age Liver disease Renal disease
Factors related to muscle predisposition Alcohol consumption Drug abuse (cocaine, amphetamines, heroin) Heavy exercise Baseline muscular disease: Multisystemic diseases: diabetes mellitus, hypothyroidism Inflammatory or inherited metabolic muscle defects
Bile acid sequestrants The bound bile acids are excreted in the feces.The increased excretion of bile acids causes increased oxidation of cholesterol to form bile acids in hepatocytes, and the resultant up-regulation of hepatic LDL receptors in turn lowers plasma LDL concentrations. side effects are limited to local effects in the gastrointestinal system (e.g., bloating, gas, constipation)
these agents can lower plasma cholesterol levels by 15% to 25%. they can increase plasma triglyceride levels and must be used with caution in patients predisposed to hypertriglyceridemia.
because they bind negatively charged molecules in the intestine, these agents can interfere with the absorption of other medications, including levothyroxine, digoxin, warfarin, and thiazide diuretics. Therefore, resins are given at least 4 hours before or 1 hour after other medications. Colesevelam does not bind other drugs to the same extent as the resins cholestyramine and colestipol.
niacin typically 2.0 to 6.0 g/day lower both total and LDL cholesterol by 15% to 30%, lower triglyceride levels by 30% to 40%, and raise HDL-C levels by 15% to 25%. Maximum HDL increases usually occur with therapeutic doses of 1.5 to 2.0 g/day. Niacin also lowers plasma Lp(a) concentrations by up to 40%. The mechanism whereby niacin affects plasma lipids is unclear, but it seems to be associated with decreased hepatic VLDL production.
The most troublesome side effect of niacin is a flushing syndrome that occurs shortly after taking the medicine. Flushing can be minimized by initiating therapy with small doses (e.g., 100 mg) and gradually increasing the dosage to the therapeutic range over weeks to months. taking an aspirin about 1 hour before the niacin can diminish the flushing, possibly by inhibiting prostaglandin-mediated side effects.
The most serious complication of niacin therapy is hepatotoxicity, and therapy should be accompanied by monitoring of serum liver function tests therapy should be discontinued if transaminases reach >3 times normal. Because hepatotoxicity appears to be more common with sustained-release preparations of niacin, the immediate-release form is preferred. Other side effects of niacin therapy include impairment or worsening of glucose tolerance and hyperuricemia.
The fibric acid derivatives clofibrate, gemfibrozil, and fenofibrate— lower plasma triglycerides by about 40% and increase HDL-C levels by about 10% but have only minor effects on LDL-C. These agents act by activating the (PPAR) a, a nuclear hormone receptor that is expressed in the liver and other tissues. This results in increased fatty acid oxidation, increased LPL synthesis, and reduced expression of apo-CIII, all of which contribute to lowering plasma triglycerides.
Side effects include gastrointestinal discomfort and possibly an increased incidence of cholesterol gallstones (documented for clofibrate). Fibric acid derivatives should be used with great caution in the setting of renal insufficiency Fenofibrate, which does not interfere with statin metabolism and has a much lower risk of causing myopathy, is the preferred fibrate to use in combination with a statin.
Omacor is prepared in capsule form containing a gram of oil, which includes a total of 840 mg of EPA plus DHA. At the recommended dosage of four capsules daily given to patients who have triglycerides of mg/dL, Omacor lowers triglycerides by about 50%, raises HDL-C by about 10%, lowers VLDL-C by about 40%, and raises LDL-C by about 50%. Overall the total cholesterol-to-HDL- C ratio is reduced by about 20% and the non-HDL-C is lowered by about 10%
Chylomicronemia Syndrome Patients with the chylomicronemia syndrome often present with acute pancreatitis and severe hypertriglyceridemia (triglycerides >22.6 mm/L [2000 mg/dL]). These patients should be treated with total fat restriction until the triglyceride level falls to a safe range The goal is to maintain the triglyceride level at less than 11.3 mm/L (1000 mg/dL) and preferably less than 4.5 mm/L (400 mg/dL). such patients often require a triglyceride-lowering drug, such as a fibrate or niacin, to maintain the plasma triglyceride level in a range that prevents subsequent episodes of pancreatitis