Lipoproteins; Metabolism & Diseases PDF

LIPOPROTEINS; METABOLISM& DISEASES Prof. Dr. Halil RESMİ 10-11.12.2024  CLASSIFICATION of LIPOPROTEINS  The four system (methods) used to isolate, separate and characterize lipoproteins;  Analytical centrifugation,  Preparative centrifugation,...

LIPOPROTEINS; METABOLISM& DISEASES Prof. Dr. Halil RESMİ 10-11.12.2024  CLASSIFICATION of LIPOPROTEINS  The four system (methods) used to isolate, separate and characterize lipoproteins;  Analytical centrifugation,  Preparative centrifugation,  Electrophoresis,  Precipitation techniques. 2 3  https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/lipoprotein https://my.clevelandclinic.org/health/articles/23229-lipoprotein 4  CHYLOMICRONS  Chylomicrons contain mainly triglyceride combined with cholesterol, small amounts of phospholipids, and specific apoproteins.  These apoproteins are;  Apo B-48,  A-I, A-II, C-I, C-II, C-III,  (and) small amount of apo B-100 and,  E-II, E-III and E-IV. 5   Neutral lipids [TG and cholesterol esters (CE)] are partially surrounded by an outer shell of phospholipid, free cholesterol and protein.  Under testing condition (longer than 10 to 12 hours after a meal) no chylomicrons are found in the blood of a healthy person.  The presence of chylomicron make the serum appear turbid or milky. 6  VERY LOW DENSITY LIPOPROTEINS  An average VLDL contains 52% TG, 18% PL, 22% cholesterol and about 8% protein.  The larger the size of a VLDL particle, the greater is the proportion of TG and apo-C (and the smaller is the proportion of PL, apo-B and other apoproteins).  Partially degraded VLDL, the remnant lipoprotein, is a triglyceride-poor lipoprotein, known to be highly atherogenic. 7  LOW DENSITY LIPOPROTEINS  LDL contains, by weight, 80% lipid and 20% protein.  About 50% of LDL lipid is cholesterol,  LDL constitutes 40% to 50% of plasma lipoprotein mass in humans,  LDL is major carrier of cholesterol and considered as atherosclerotic lipoprotein. 8   ApoB-100 is major apoprotein of normal LDL, and LDL apoB represents 90% to 95% of the total plasma apoB-100; LDL apoB is derived almost entirely from VLDL apoB. 9  HIGH DENSITY LIPOPROTEINS  The HDL macromolecule complex contains about 50% protein and 50% lipids.  HDL is the smallest and the highest density (1.063-1.21) lipoprotein.  Quantitatively, the most important HDL lipid is phospholipid, although HDL cholesterol is particular interest.  The major PL is phosphatidylcholine (lecithin) which account for 70% to 80% of total phospholipids. 10  LIPOPROTEIN METABOLISM  The lipoprotein transport system carries the hydrophobic core lipids; triglycerides and cholesteryl esters.  The circulating lipoproteins that contain these lipids are subjected to continuous modeling (modification) by enzymes and proteins in the metabolic cascade. 11   The lipoprotein transport system can be separated into three pathways;  Exogenous,  Endogenous,  Revere. 12   The exogenous pathway transport dietary fat to peripheral tissues.  Whereas the endogenous pathway transport hepatically synthesized lipids, primarily VLDL triglyceride to their site of utilization in peripheral tissues.  In peripheral circulation, chylomicrons and VLDL share a common metabolic removal pathway catalyzed by lipoprotein lipase (LPL). 13   Furthermore the metabolic end product of the lipolytic process (chylomicron remnanats and LDL respectively) are cleared from the plasma by hepatic receptor-mediated processes.  Reverse cholesterol transport is a process that shuttles cholesterol from peripheral tissues to the liver directly via HDL and via other endogenous derived lipoproteins (eg. VLDL, LDL).  HDL occupies center stage in reverse cholesterol transport. 14  Chylomicrons  Chylomicrons are made exclusively in the intestine and traverse the lymphatic system to the thoracic duct, where they then enter the systemic circulation.  The major function of the chylomicron is the transport of dietary triglyceride.  Newly synthesized and secreted chylomicrons from the intestinal mucosa cells ultimately pick up apoC-II from HDL. 15   The hydrolysis results in liberation of NEFA and monoglycerides.  The action of LPL results in progressive depletion of triglyceride and formation of chylomicron remnant particle.  Remnant chylomicron retains its cholesteryl ester and apoB and apoE, which play an important role in he uptake of these particles by the liver. 16 17  Very Low Density Lipoprotein  After a postprandial rise in chylomicron triglyceride, a second rise in triglyceride levels occurs in 4-6 hours after a meal.  Second rise represents predominantly hepatic VLDL triglyceride synthesis from glucose and chylomicron triglyceride not hydrolyzed in peripheral tissues.  VLDL triglycerides undergo the same fate as that triglycerides from chylomicrons. 18   During the catabolism of VLDL, more than 90% of apoC is transferred to HDL, whereas all apoB remains with particle.  The metabolism of VLDL leads to the formation of VLDL-remnanat (IDL) and then cholesterol-rich particle LDL. 19  Intermediate Density Lipoprotein  IDL is a transient particle that usually is present in very low concentration in a fasting person.  After removing all triglycerides, the particle contains almost pure cholesteryl esters in the core and apoB at surface, the resultant particle is LDL. 20 21  Low Density Lipoproteins  In a healthy person, LDL cholesterol constitutes about two-third of total plasma cholesterol,  LDL delivers cholesterol to hepatic and extrahepatic tissues, where it is used , deposited and excreted.  LDL is uptaken by peripheral tissues and degraded by lysosomes to produce free cholesterol. 22   Excess intracellulary cholesterol leads to cholesteryl ester storage,  The net effect of LDL internalization is the reduction of the number of receptors available to bind LDL. 23  High Density Lipoproteins  The liver and the intestine synthesize lipid- poor apoA-1 that interacts with ABCA1 located on arterial macrophages transporting free cholesterol to extracellular lipid-poor HDL.  When this protein is deficient or inactive, as in patient with Tangier Disease (TD), or familial HDL deficiency, cholesterol accumulates in peripheral tissues. 24   ApoE is major component of nescent HDL, whereas mature HDL characterized by a predominance of apoA with minor apoC and apoE.  HDL balances LDL transport by mediating cholesterol removal from peripheral sites to degradative and excretory sites.  This role of HDL in reverse cholesterol transport forms the basis for the protection afforded by HDL, against CVD. 25 26  SR-B1  The scavenger receptor, class B type 1 (SR- B1), is a multiligand membrane receptor protein that functions as a physiologically relevant high-density lipoprotein (HDL) receptor whose primary role is to mediate selective uptake or influx of HDL-derived cholesteryl esters into cells and tissues.  SR-B1 also facilitates the efflux of cholesterol from peripheral tissues, including macrophages, back to liver. 27  PATHOLOGICAL CONDITIONS 28  HYPERLIPIDEMIA  The major plasma lipids of interest are total cholesterol (free cholesterol+cholesterol ester) and the triglyceride.  When one of these major class of plasma lipids is elevated, a condition of referred to as hyperlipidemia exists.  Cholesterol and triglyceride concentrations can be used to detect hyperlipoproteinemia.  More than 90% of persons with hyperlipidemia have hyperlipoproteinemia. 29   Major expectations are individuals with excessive amount of LDL, whose plasma cholesterol is kept within normal limits by concomitant decreased HDL. 30  HYPERLIPOPROTEINEMIA  Hyperlipoproteinemia is an elevation of serum lipoprotein concentrations,  The classification of hyperlipoproteinemia begins with determination of the type of abnormal lipoprotein profile.  Other differentiations and analysis are necessary; 1. Separation of hyperlipoproteinemia into primary and secondary forms, 2. Differentiation of primary hyperlipoproteinemia into heritable or inheritable forms, 3. Determination of the relative concentrations of lipoprotein fractions, that is, VLDL cholesterol, LDL cholesterol and HDL cholesterol. 31   Numerous types of hyperlipoproteinemia have been identified, but most of patients with heritable hyperlipidemia have one of six common abnormal lipoprotein patterns. 32 33 34  METABOLIC SYNDROME  The NCEP ATP III [National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)], guidelines describe the Metabolic Syndrome (MS) as a cluster of interrelated risk factors of metabolic origin that appear to directly promote the development of atherosclerotic CVD.  The syndrome is linked closely to a generalized metabolic disorder called insulin resistance, in which the normal action of insulin are impaired. 35   The most widely recognized CHD risk factors associated with MS are atherogenic dyslipidemia, elevated blood pressure and elevated blood glucose.  Individual with these characteristics commonly manifest a prothrombotic and proinflammatory state. 36   Atherogenic dyslipidemia consist of a combination of lipoprotein abnormalities, including;  Elevated plasma triglyceride and apoB concentrations,  Increased small LDL particles,  Reduced HDL cholesterol levels.  The predominant underlying risk factors for MS appears to be abdominal obesity and insulin resistance. 37  CLINICAL IMPLICATIONS of HYPERLIPIDEMIA  Hyperlipidemia is usually a symptomless biochemical state, that, if present for a sufficient long time, may be associated to development of atherosclerosis and CVD  Occasionally, hyperlipidemia may be associated with specific overt symptoms or signs that are directly attributable to the presence of hyperlipidemia. 38   Example includes abdominal pain, acute pancreatitis and the cutaneous manifestation such as xanthomas and corneal arcus. 39  Coronary Artery Disease  CAD is almost always the result of atherosclerosis, which currently is viewed as an inflammatory disease.  Coronary atherosclerosis primarily result from the accumulation of fatty deposits in the wall of coronary arteries, which leads to the formation of fibrous tissue in the vessel wall.  CAD is the most common type of heart disease and is a leading cause of death in many countries. 40  Risk Factors for CAD https://link.springer.com/article/10.1007/s12350-019-01642-x/figures/1 41  Changes in Analyte in Disease; Therapeutic Guidelines and Treatment  The NCEP ATP III study meet the need to standardize to approach for detection and classification of individuals at high risk for CHD, and to standardize the treatment and monitoring of such individuals. 42  The guideline;  Recommend a complete lipoprotein profile (total, LDL and HDL cholesterol, and triglyceride) measurement as an initial test,  Identifiy LDL cholesterol 100 mg/dL as optimal,  Low HDL cholesterol is 40 mg/dL,  Low cut off point of triglyceride is 150 mg/dL,  The therapeutic goals for person with;  Zero or one risk factor 160 mg/dL,  Two or more risk factor 130 mg/dL,  CHD and CHD risk equivalents 100 mg/dL. 43   RESİM SF. 718-719 BENZERİ 44