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DIABETES AND LIPID

DIABETES AND LIPID. S-KHALILZADEH. 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

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DIABETES AND LIPID

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  1. DIABETES AND LIPID S-KHALILZADEH

  2. 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

  3. 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.

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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.

  9. 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

  10. 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

  11. HDLs are small particles (70-120 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

  12. Apo-E is a minor component of a subclass of HDL referred to as HDL1, 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

  13. Apolipoproteins— Understanding the major functions of the different apolipoproteins is important clinically, because defects in apolipoprotein metabolism lead to abnormalities in lipid handling

  14. 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.

  15. 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 .

  16. 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.

  17. 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.

  18. 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

  19. 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 .

  20. 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.

  21. 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.

  22. 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

  23. 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.

  24. 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.

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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.

  30. 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.

  31. (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

  32. 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

  33. 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

  34. Step 1 — The first step in determining patient risk is to obtain a fasting lipid profile

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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

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