Lipoprotein Metabolism PDF

Lipoprotein metabolism ◼ Lipoproteins are complexes of protein and lipids held together by noncovalent bonds and classified into five classes. 1. High density lipoproteins (HDL) 2. Low density lipoproteins (LDL) 3. Intermediate density lipoproteins (IDL) 4. Very low density li...

Lipoprotein metabolism ◼ Lipoproteins are complexes of protein and lipids held together by noncovalent bonds and classified into five classes. 1. High density lipoproteins (HDL) 2. Low density lipoproteins (LDL) 3. Intermediate density lipoproteins (IDL) 4. Very low density lipoproteins (VLDL) 5. Chylomicrons ◼ Lipoproteins are synthesized in the liver or intestine. ◼ After secretion they are modified by enzyme-catalyzed reactions and the remnants are taken up by receptors on cells surfaces. ◼ These processes are regulated by the protein component of the particle (The apolipoproteins). Apolipoproteins Occurrence Functions A Chylomicrons Cofactor for and HDL LCAT B Chylomicrons, Binding to LDL VLDL, IDL and receptor LDL C Chylomicrons, Cofactor for VLDL, IDL and lipoprotein HDL lipase E Chylomicrons, Binding to VLDL, IDL and receptor HDL  Exogenous Lipid Pathways ◼ Fatty acids and cholesterol, released by digestion of dietary fat are absorbed into intestinal mucosal cells where they are reesterified to form triglycerides and cholesterol esters. These, together with phospholipids, apo A and apo B, are secreted from cells into the lymphatic system as chylomicrons. Exogenous Lipid Pathways ◼ The secretion depends on the presence of apo B. ◼ Chylomicrons enter the systemic circulation by the thoracic duct. Apo C and apo E both derived from HDL, are added to them in both lymph and plasma.  CHYLOMICRON METABOLISM ◼ Chylomicrons are metabolized in adipose tissue and muscle. ◼ The enzyme, lipoprotein lipase, located on capillary walls, is activated by apo C hydrolyses triglyceride to glycerol and fatty acids.  CHYLOMICRON METABOLISM ◼ The fatty acids are either taken up by adipose or muscle cells or are bound to albumin in the plasma. ◼ The glycerol enters the hepatic glycolytic pathway. ◼ As the Chylomicron shrinks, surface material containing apo A and some apo C and phospholipids is released and incorporated into HDL.  CHYLOMICRON METABOLISM ◼ The small chylomicron remnants are composed mainly of cholesterol, apo B and apo E. ◼ They rapidly bind to hepatic chylomicron- remnant receptors, which recognize the constituent apoE. ◼ The remnants then enter the liver cells where the protein is catabolized and the cholesterol released.  CHYLOMICRON METABOLISM ◼ At the end of this pathway dietary triglycerides have been delivered to adipose tissue and muscle, and cholesterol to the liver.  Endogenous lipid Pathways ◼ The liver is the main source of endogenous lipids. ◼ Triglycerides are synthesized from glycerol and fatty acids, which may reach the liver from the fat stores or from glucose.  Endogenous lipid Pathways ◼ Hepatic cholesterol may be synthesized locally or be derived from lipoproteins, such as chylomicron remnants, after they have been taken up by liver cells. These lipids are transported from the liver in VLDL.  VLDL METABOLISM ◼ VLDL is a large triglyceride-rich particle incorporating apo B, apo C and apo E. After secretion it incorporates more apo C from HDL. ◼ In peripheral tissues triglycerides are removed after hydrolysis by lipoprotein lipase similar to that of chylomicrons, although it occurs more slowly.  VLDL METABOLISM ◼ The VLDL remnant, or IDL, which contains both triglycerides and cholesterol, as well as apo B and apo E, is either ◼ Rapidly taken up by the liver ◼ Loses the remaining triglycerides and apo E to become LDL.  LDL METIABOLISM ◼ LDL is a small cholesterol-rich lipoprotein containing only apoB. ◼ It is taken up by specific receptors located on cell surfaces (LDL receptors). ◼ Although these are present on all cells, they are most abundant in the liver. They recognize apo B  LDL METIABOLISM ◼ ◼ After entering cells LDL particles are broken down by lysosomes, much of the released cholesterol contributes to membrane formation or, in the adrenal cortex and gonads, to steroid synthesis.  LDL METIABOLISM ◼ Most cells can synthesize cholesterol but several feedback mechanisms prevent its intracellular accumulation. ◼ Most of the plasma LDL is removed by LDL receptors.  LDL METIABOLISM ◼ If plasma concentrations are high some may also enter cells by a passive, unregulated route. ◼ Because of their small size LDL particles can infiltrate tissues, such as those of the arterial wall, and cause damage.  ROLE OF HIGH DENSITY LIPOPROTEIN (HDL) ◼ Cholesterol synthesized in cells would accumulate in there if not removed. ◼ The transport of cholesterol from non- hepatic cells to liver involves HDL.  ROLE OF HIGH DENSITY LIPOPROTEIN (HDL) ◼ HDL is synthesized in hepatic and intestinal cells and secreted from them as small particles containing phospholipids, free cholesterol and apo A and apo E (nascent HDL or discoidal HD )  ROLE OF HIGH DENSITY LIPOPROTEIN (HDL) ◼ Nascent HDL picks up cholesterol from other lipoproteins and from cell of peripheral tissue and converts it to cholesterol esters by the action of LCAT ◼ As the nascent HDL fill with cholesterol ester they become spherical in shape. And transport cholesterol to the liver.  Disorders of lipid metabolism ◼ Most common disorders of lipid metabolism are associated with hyperlipidemia. Disorders of lipid metabolism ◼ They can be caused by 1. Genetic abnormalities 2. Environmental/ lifestyle imbalances 3. They can develop secondarily to other diseases Disorders of lipid metabolism ◼ Disease states (Dyslipidemias) associated with abnormal serum lipids ◼ Are generally caused by 1. Malfunctions in the synthesis 2. Transport 3. Catabolism of lipoproteins.  Dyslipidemias hyperlipoproteinemias hypolipoproteinemias Hyperlipoproteinemias 1. Predominant hypercholesterolemia 2. Predominant hypertriglyceridemia 3. Mixed hyperlipidemia 4. Lipoprotein(a) Elevation  Predominant hypercholesterolemia 1. Primary hypercholesterolemia 2. Secondary hypercholesterolemia  Primary hypercholesterolemia ◼ Also called Familial monogenic hypercholesterolemia) is caused by a LDL receptor defect. ◼ There are several variants, all of which are inherited as autosomal dominant traits.  Primary hypercholesterolemia ◼ The reduced cellular uptake of LDL, particularly by the liver, causes an increase in plasma total and LDL cholesterol concentrations. ◼ Plasma triglyceride concentrations are either normal or only slightly raised. Primary hypercholesterolemia ◼ Homozygous patients rare (1:1 million in the population) ◼ LDL receptors are virtually absent ◼ These patients frequently have their first heart attack when still in their teenage years. Primary hypercholesterolemia ◼ In homozygous patients ◼ Plasma total cholesterol concentrations as high as 800 to 1,000 mg/dL (20–26 mmol/L) ◼ LDL-cholesterol concentrations are three or four times higher than those in normal subjects Primary hypercholesterolemia ◼ In heterozygous patients ◼ Disease are seen much more frequently (1:500 in the population) ◼ The number of LDL receptors is reduced by about 50 percent Primary hypercholesterolemia ◼ In heterozygous patients ◼ The total plasma cholesterol conc. are about twice (300–600 mg/dL = 8–15 mmol/L) those in normal subjects. ◼ They have a 10 to 20-fold higher risk of developing ischemic heart disease than those with normal plasma concentrations Secondary hypercholesterolemia ◼ The commonest disorders that cause hypercholesterolemia are: 1. Primary hypothyroidism 2. Diabetes mellitus 3. Nephritic syndrome. 4. Cholestasis 5. Drugs Predominant Hypertriglyceridemia ◼ Elevated plasma triglyceride concentrations more than 200 mg/dL (2.3 mmol/L) may be due to an increase in plasma VLDL or chylomicrons or both. Predominant Hypertriglyceridemia ◼ Hypertriglyceridemia is usually secondary to another disorder. ◼ Primary hypertriglyceridemia is less common than primary hypercholesterolemia Predominant Hypertriglyceridemia 1. Primary Hypertriglyceridemia ◼ Familial endogenous hypertriglyceridemia ◼ Inherited lipoprotein lipase deficiency (hyperchylomicronemia) 2. Secondary Hypertriglyceridemia  Familial endogenous hypertriglyceridemia ◼ is caused by hepatic triglyceride overproduction with increased VLDL secretion. ◼ The condition is transmitted as an autosomal dominant trait and usually becomes apparent only after the fourth decade.  Familial endogenous hypertriglyceridemia ◼ It is associated with: 1. Obesity 2. Glucose intolerance 3. Decrease in plasma HDL-cholesterol concentration 4. Hyperuricemia. Inherited lipoprotein lipase deficiency (hyperchylomicronemia) may be due to: ◼ True deficiency of the enzyme which usually presents during childhood ◼ Reduced activity of the enzyme because of apo C-II deficiency which is most likely to present in adults. Secondary Hypertriglyceridemia 1. Obesity and excessive carbohydrate intake 2. Alcohol 3. Diabetes mellitus 4. Primary hypothyroidism Secondary Hypertriglyceridemia 4. Nephritic syndrome 5. Renal glomerular dysfunction 6. Acute pancreatitis 7. Drugs such as estrogens, β-blockers and thiazide diuretics  Mixed hyperlipidemia ◼ Combined hyperlipoproteinemia is defined as the presence of elevated levels of serum total cholesterol and triglycerides.  Mixed hyperlipidemia 1. Familial combined hyperlipidemia 2. Familial dysbetalipoproteinemia Familial combined hyperlipidemia ◼ Is associated with excessive hepatic production of apo B, and therefore LDL and VLDL synthesis. Familial dysbetalipoproteinemia ◼ Less commonly, mixed hyperlipidemia ◼ Caused by the accumulation of IDL (VLDL remnant) and chylomicron remnants, which contain both cholesterol and triglyceride. ◼ Is associated with the presence of a rare form of apo E, called apo E2/2. Familial dysbetalipoproteinemia ◼ When VLDL fraction is analyzed by agarose electrophoresis, the particles will migrate in a broad β region, rather than in the normal pre- β region. Familial dysbetalipoproteinemia ◼ Definitive diagnosis requires a determination of apo E isoforms by DNA typing, resulting in 1. apo E2/2 homozygosity 2. apo E mutation or deficiency. Secondary mixed hyperlipidemia ◼ Raised plasma concentrations of both cholesterol and triglycerides are commonest in patients with 1. Poorly controlled diabetes mellitus 2. Severe hypothyroidism 3. Nephritic syndrome. Lipoprotein(a) Elevation ◼ Lipoprotein(a) particles are LDL-like particles that contain one molecule of apo (a) linked to apo B-100 by a disulfide bond. Lipoprotein(a) Elevation ◼ Elevated levels of Lp(a) are thought to increased risk for premature coronary heart disease and stroke. ◼ Because the kringle domains (repeating peptide sequences) of Lp(a) have a high level of homology with plasminogen a protein that promotes Lipoprotein(a) Elevation ◼ It has been proposed that Lp(a) may compete with plasminogen for fibrin binding sites, thereby promoting clotting Hypolipoproteinemia 1. Inherited disorders of HDL deficiency (hypoalphalipoproteinemia) 2. Apo B deficiency 3. LCAT deficiency. Inherited disorders of HDL deficiency ◼ Defined as an HDL cholesterol concentration less than 40 mg/dL (1.0 mmol/L) ◼ An extreme form of hypoalphalipoproteinemia Tangier disease, HDL cholesterol concentrations as low as 1–2 mg/dL (0.03–0.05 mmol/L) in homozygotes by total cholesterol concentrations of 50 to 80 mg/dL (1.3–2.1 mmol/L). Inherited disorders of HDL deficiency ◼ Associated with premature coronary heart disease. ◼ An abnormal apoA leads to an increased rate of catabolism of HDL. ◼ Cholesterol esters accumulate in the reticuloendothelial system (enlargement of the liver and lymph nodes). ◼ Acute, transitory hypoalphalipoproteinemia (decrease HDL cholesterol, as well as total cholesterol) can be seen in cases of severe physiologic stress, such as ◼ Acute infections ◼ Surgical procedures. ◼ But will return to normal levels as recovery proceeds. ◼ For this reason, lipoprotein concentrations drawn during hospitalization or with a known disease state should be reassessed in the healthy, non hospitalized state before intervention is considered. Apo B deficiency ◼ a betalipoproteinaemia, LDL deficiency ◼ Results in impaired synthesis of chylomicrons and LDL ◼ Lipids cannot be transported from the intestine or liver. ◼ The clinical syndrome consists of steatorrhoea, progressive ataxia. LCAT deficiency ◼ LCAT is the enzyme needed to catalyze the esterification of free cholesterol and deficiency results in accumulation of free cholesterol in tissues. LCAT deficiency ◼ Cause 1. Premature atherosclerosis 2. Renal damage 3. Hemolytic anemia due to a cell- membrane defect.  Lipid and Cardiovascular Disease ◼ There is 1. a positive correlation between the risk of developing ischemic heart disease and a raised plasma total and LDL-cholesterol concentrations (100 mg/dl) 2. a negative one with plasma HDL- cholesterol. (40 mg/dl)  Atherosclerosis Infiltration and retention of apoB containing lipoproteins (LDL) in the artery wall is a critical initiating event that sparks an inflammatory response Arterial injury causes endothelial dysfunction promoting modification of apoB containing lipoproteins and infiltration of monocytes into the subendothelial space  Atherosclerosis Internalization of the apoB containing lipoproteins by macrophages promotes foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis. Macrophage inflammatory chemoattractant stimulate infiltration and proliferation of smooth muscle cells..  Atherosclerosis Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets.  Thrombosis Unresolved inflammation results in formation of vulnerable plaques characterized by enhanced macrophage apoptosis resulting in necrotic cell death leading to increased smooth muscle cell death, decreased extracellular matrix production, and collagen degradation by macrophage proteases.  Thrombosis Rupture of the thinning fibrous cap promotes thrombus formation HDL, apoA-I prevent inflammation and oxidative stress and promote cholesterol efflux to reduce lesion formation. ◼  Lipid and Cardiovascular Disease ◼ Lowering high plasma LDL-cholesterol concentrations reduces the risk of cardiovascular disease. ◼ Hypercholesterolemia is just one of the major risk factors of cardiovascular disease, others include smoking and hypertension.