Pathophysiology Lec 19 PDF

PATHOPHYSIOLOGY Topic 8: Dyslipidemia * Lecture 19 * Dr. Hiba Fahmawi 15-16/12/2024 Lina Habash Shoroq Abualnaser Topic 8/ Dyslipidemia Pathophysiology Lec 19 Dyslipidemia: Introduct...

PATHOPHYSIOLOGY Topic 8: Dyslipidemia * Lecture 19 * Dr. Hiba Fahmawi 15-16/12/2024 Lina Habash Shoroq Abualnaser Topic 8/ Dyslipidemia Pathophysiology Lec 19 Dyslipidemia: Introduction ❖ Dyslipidemia → Dys: abnormal /emia: blood → the abnormality of lipid content in the blood, it could be hyperlipidemia or hypolipidemia )‫ص في التغذية‬ ً ‫(غالباً بسب‬ ً ‫ب نق‬ ❖ Cholesterol, triglycerides, and phospholipids are the major lipids in the body. *We have 2 sources of lipids: from liver synthesis or from nutrients. *Lipids can’t be circulated in blood in their free form because they are water insoluble, and the blood is an aqueous media. ❖ They are transported as complexes of lipids and proteins known as lipoproteins. *Lipoproteins = Lipids + Proteins, Proteins help in lipid circulation in the blood. ❖ Plasma lipoproteins are spherical particles with surfaces that consist largely of phospholipid, free cholesterol, and protein, and cores that consist mostly of triglyceride and cholesterol ester. *The Surface/ membrane of lipoproteins contains 3 things: phospholipids, free cholesterol and proteins * The core contains: triglycerides and cholesterol ester. * What is the difference between cholesterol and cholesterol ester? Cholesterol is the free form, when we make esterification of it ( by adding free fatty acid ) and convert it into cholesterol ester it become in the stored form (for storage). ❖ The three major classes of lipoproteins found in serum are LDL, HDL, and VLDL. Topic 8/ Dyslipidemia Pathophysiology Lec 19 *LDL (Low Density Lipoprotein) is bad cholesterol because it transports lipids from the liver (‫ )مصنع الكوليسترول‬to the blood and tissues, elevation of LDL increases the risk of atherosclerosis. *HDL (High Density Lipoprotein) is the good/beneficial cholesterol, it transports the lipids from tissues and blood to liver. *VLDL (Very Low-Density Lipoprotein) has the same direction of transport as LDL (from liver to the blood), but it carries triglycerides (TG) MAINLY. VLDL, the major lipoprotein associated with triglycerides, is enriched with cholesterol esters. *So VLDL carries large amounts of Triglycerides, and low amounts of cholesterol esters. ❖ Routine measurement of triglycerides cannot distinguish between the types of VLDL present in plasma. Elevation of triglyceride-rich lipoproteins is associated with low HDL, and this ratio predicts increased risk. * Triglycerides come from all sources (HDL, LDL, VLDL), NOT only from one source, that’s why we measure the total amount of TG and not the VLDL levels. ❖ Hypertriglyceridemia and low HDL are associated with obesity (body mass index [BMI] >30 kg/m2 ), smoking, sedentary lifestyle, blood pressure >130/80 mm Hg, and blood glucose >100 mg/dl. This is thought to be a consequence of the presence of atherogenic lipoproteins. *Hypertriglyceridemia: Increased levels of Triglycerides in the blood → Remember/ “emia” refers to the blood. Topic 8/ Dyslipidemia Pathophysiology Lec 19 *When triglycerides are too high, the risk of atherosclerosis increases. * Hypertriglyceridemia and low HDL are 2 cases but they can happen both for the same patient then we call it “Combined disorder”. ‫ كل وحدة على‬HDL ‫ب‬ ً ‫ أو انخفا‬TG‫ض عن ًدًه بس وحدة منهم اما ارتفاع بال‬ ً ‫ض‬ ً ‫* فممكن أالقي مري‬.‫ض عنده كالهما‬ً ‫حدة و ممكن أالقي مري‬ ❖ Abnormalities of plasma lipoproteins can result in a predisposition ‫ الميل‬to coronary, cerebrovascular, and peripheral vascular arterial disease and constitutes one of the major risk factors for coronary heart disease (CHD) additive to non-lipid CHD risk factors: cigarette smoking, HTN, DM, electrocardiographic abnormalities. *Abnormalities of plasma lipoproteins are high levels of TG, high levels of LDL , high levels of VLDL and low levels f HDL. ❖ Accumulating evidence over the last decades had linked elevated total and LDL cholesterol and reduced HDL to the development of CHD (coronary heart disease) → relationships between total cholesterol , LDL, and an inverse relationship with HDL to coronary artery disease (CAD) & mortality. ❖ Premature coronary atherosclerosis, leading to the manifestations of ischemic heart disease, is the most common and significant consequence of dyslipidemia.. Lipoproteins ‫ هو كل الكوليسترول الموجود بكل أنواع ال‬Total Cholesterol* ً‫ يعنيًاإلصابةًبتصلبًالشرايينًبعمرًأصغر‬Premature coronary atherosclerosis* ً‫منًالعمرًالمتوقعًلإلصابةً(ًيعنيًبكونًلسةًصغيرًبالعمرًوًبنصابًفيه)ًه ًذهًتعتبرًالمشكلةًاألكثر‬ ً ً.ًdyslipidemia ‫عرضةًمنًمشاكلًال‬ Topic 8/ Dyslipidemia Pathophysiology Lec 19 Lipoprotein Metabolism and transport. ❖ Cholesterol and triglycerides, as the major plasma lipids, are essential substrates for: 1) Cell membrane formation 2) Hormone synthesis (Like sex hormones, vit D) 3) Provide a source of free fatty acids (IMP for energy because TG= glycerol + 3 Fatty acids). ❖ Dyslipidemia may be defined as an elevation of total cholesterol (in LDL, HDL,VLDL), elevation in LDL cholesterol, elevation in triglycerides (we measure the total TG not the VLDL alone ) or low HDL cholesterol concentration, or some combination of these abnormalities. *We all have lipids in our blood, but it should NOT exceed the normal ranges that why we make blood testً‫ وانتًصايم‬and compare our results with those ranges. Some patients may have combination of dyslipidemia (such as: elevation in LDL+low HDL at the same time) ❖ Lipids, being water immiscible, are not present in free form in the plasma, but rather circulate as lipoproteins. ❖ Hyperlipoproteinemia describes an increased concentration of the lipoprotein macromolecules that transport lipids in the plasma. ‫ → قسموا الكلمة كالعادة لتسهيل الفهم‬Hyper/lipoprotein/emia Density, composition, size (diameter), and electrophoretic mobility divide lipoproteins into four classes:- * Electrophoretic mobility is the speed of movement in electrophoresis, which is the separation of molecules depending on their sizes and electrical charges.  Topic 8/ Dyslipidemia Pathophysiology Lec 19 VLDL carries about 10 to 15 % of total serum cholesterol and most of TG in fasting state; VLDL=TG/5. ً‫احفظواًالمعادلة راح نحتاجها الحقا‬ *The Major carrier of “Endogenous Triglycerides” LDL carries 60 to 70% of total serum cholesterol; IDL is also included in this group (LDL1) *The Major carrier of “Cholesterol” HDL carries 20 to 30% of total serum cholesterol; reverse transportation of cholesterol. *It’s a carrier of mainly cholesterol too but the special thing about HDL is the “reverse transportation” from tissues and blood to the liver. Chylomicrons, large TG -rich particle. *The Major carrier of “Exogenous Triglycerides” ▪ The protein constituent of lipoproteins is called apolipoproteins. *We already mentioned that these lipids CANNOT circulate in the blood, the apolipoproteins are proteins on the surface of lipoproteins that help with their circulation. Summary of lipoproteins: ‫كيف نحفظهم ؟‬ ً‫ًمنًاسمهمً"كوليسترول"ًمعناتهًهم‬HDLً‫ًوًالكوليسترولًالنافع‬LDL ‫*أول شيءًعناًالكوليسترولًالضار‬ ً‫ًطيبًشوًالفرقً؟ًاالتجاهً!ًالنافعًبلمًليًكلًالكوليسترولًاليًبالدم‬..ًmainly contain cholesterol ً‫الي‬ ً‫وًاألنسجةًوًبروحًفيهًللكبدًتتصرفًمعهًبينماًالضارًبالعكسًبجيبًليًمنًالكبدًالكوليسترولًوًبحطه‬ ً.ً.ً‫بالدمًوًاألنسجة‬ ًChylomicron ‫ًوًال‬VLDL ‫ًاليًهمًال‬triglyceride mainly ً‫*ًاليًضايلينًهمًاليًبيحتوواًعلى‬ ً‫ًفبسميه‬liver ‫ًبتجيبهًمنًال‬VLDL ً‫ًال‬..ًTG ‫طيبًهدولًشوًالفرقًبينهمً؟ًالمصدرًتبعًال‬ ً.ًexogenousً‫ًبتجيبهًمنًاألكلًاليًباألمعاءًفبسميه‬chylomicronً‫ًوًال‬endogenous ً‫ًطيبًشوًهو؟ًكمانًأغلبهًكوليسترولًلكن‬LDL ‫ًاليًمحطوطًبقائمةًال‬IDL ً‫*ًضلًعنديًاشيًواحدًهو‬ LDL1ً=ًintermediate density lipoprotein =ًIDL ‫ًوًال‬..ًLDL ‫أقلًمنًالكميةًالتيًيحتويهاًال‬ Topic 8/ Dyslipidemia Pathophysiology Lec 19 ًً ❖ The figure shows a diagrammatic representation of the structure of low-density lipoprotein (LDL), the LDL receptor, and the binding of LDL to the receptor via apolipoprotein B-100. *What are the functions of the apoproteins? 1) Enhance the stability of the lipoprotein while it moves in the aqueous media “blood”. 2) Ability for Recognition by enzymes 3) Ability for Recognition by receptors *Receptors differ in their locations and types so how the lipoprotein can bind to a specific receptor? by its apolipoprotein. 4) They can determine the density of the lipoprotein. *The higher the protein percentage on the lipoprotein surface → the higher the density → the smaller the size. Sizes and Density Of lipoprotein: Topic 8/ Dyslipidemia Pathophysiology Lec 19 Chylomicrons. (Main carrier of TG.) *Let’s say that a person ate a fatty meal (‫)أكلًمنسف‬, this meal contains high amounts of fats, cholesterol,… these will get absorbed by the intestine and then go to the blood, what helps with this process? -Chylomicrons, they are formed in the intestines and move through the blood. *Then the direction is towards the liver, but before that, an enzyme in the blood (LPL) will recognize the TG in the chylomicrons and convert them to free fatty acids, after this happens the chylomicron’s size decreases (because of catabolism), now it’s called chylomicron remnant, this remnant will go to the liver, and the liver decides best what to do with the remaining lipoproteins (excretion, use them for energy, store them.) ▪ Containing apolipoprotein B-48, B-100, and E ▪ Formed from dietary fat by bile salts in intestinal mucosal cells. ▪ Chylomicrons normally are not present in the plasma after a fast of 12ًto 14 hours. *If a person was fasting for 12 hours, chylomicrons will NOT be found in the blood because it depends on food intake (diet). ▪ Chylomicrons are catabolized taken up by the "remnant receptor” in the liver. ▪ During the catabolism of nascent (new) chylomicrons to remnants, triglyceride is converted to free fatty acids and apolipoproteins A-I, A-II, A-IV (free in plasma), C-I, C-II, and C-III, and phospholipids are transferred to HDL (for its maturation). ▪ Free cholesterol is liberated intracellularly after attachment to the remnant receptor. Topic 8/ Dyslipidemia Pathophysiology Lec 19 ▪ Chylomicrons also function to deliver dietary triglyceride to skeletal muscle and adipose tissue. *ً‫ → نرجعًلليًأكلًمنسف‬Cholesterol and TG are in the intestine and should be absorbed to the blood →Chylomicrons formed in the intestine to make packaging for those lipids “it contains more TG” → In its way to the liver while moving in the blood an enzyme called LPL (lipoprotein lipase) which ً‫ منًاسمه‬makes lipolysis for those lipids into “Glycerol + Free fatty acid” → the free fatty acids are taken by the skeletal muscles and Adipose tissue to use them as source of energy → After losing those lipids from the chylomicron its size will be reduce so we call it “chylomicron remnants” → this remnant will continue its pathway to the liver where the remnant receptor is found → binding of remnant chylomicron on the remnant receptor on the surface of liver will eject all the cholesterol and TG that remains , why specifically the liver? Casuse it is the best organ in dealing with lipids, it can excrete them out of the body or use them for energy or store them. Topic 8/ Dyslipidemia Pathophysiology Lec 19 VLDL. ▪ Hepatic VLDL synthesis is regulated in part by diet and hormones. ▪ VLDL is secreted from the liver and is converted to IDL, and finally, to LDL. *If you didn’t eat any heavy meal for long period of time your body will start synthesizing the TG from liver (endogenously) → Packaged by VLDL → in the blood the LPL enzyme will make lipolysis to it , forming free fatty acids → FA will be used by Muscles and Adipose tissues for energy → the remnant is called IDL → IDL will be converted into LDL(contains cholesterol more than TG) by hepatic lipase → this LDL will bind to LPL receptor in the tissues , the tissue will take the cholesterol ester and all the lipids that it needs → the rest of lipids will come back to the liver. Topic 8/ Dyslipidemia Pathophysiology Lec 19 LDL (the major cholesterol transport lipoprotein). ▪ Having basically apolipoprotein B-100.ًً‫مهمًاحفظوه‬ ▪ Mostly derived from VLDL catabolism and cellular synthesis. *Sources of LDL : 1) VLDL → LDL 2) Denovo cholesterol synthesis by all the tissues by HMG-CoA Reductase. ▪ LDL is catabolized through interaction of cell surface receptors found on liver, adrenal, and peripheral cells. ▪ When normal subjects fast and consume a low-fat diet, most cholesterol is synthesized and used in the extrahepatic organs; most of the cholesterol carried by LDL is taken up by the liver for catabolism (or by any cell that needs them). (approximately 70% of LDL is cleared through the receptor-dependent mechanism. ❖ Homozygous familial hypercholesterolemia (inherited lack of LDL receptors): Enhanced synthesis of LDL may occur because LDL clearance is reduced as a consequence of the lack of LDL receptors. *No/Low LDL receptor → High levels of LDL in the blood → high risk of atherosclerosis and coronary artery diseases. ▪ Increased intracellular cholesterol resulting from LDL catabolism:-ًً *We need a regulation “cholesterol homeostasis” , I need cholesterol inside the cells but the over uptake will cause diseases. 1-Inhibits the activity of HMG-CoA reductase (the rate limiting enzyme for intracellular cholesterol biosynthesis). *Lowers the cellular cholesterol synthesis ً‫مؤقتاًمشًلألب ًد‬ Topic 8/ Dyslipidemia Pathophysiology Lec 19 2-Reduces synthesis of LDL receptors (which limits subsequent cholesterol uptake from the plasma, and accelerated activity of acyl coenzyme A: cholesterol acyltransferase (ACAT) to facilitate cholesterol storage within cells) *Reduction of LDL receptors will : 1) Reduce the uptake of cholesterol in the cells 2)Activate ACAT which is an enzyme inside the cells that makes esterification of cholesterol which is the “storage form” form of cholesterolً‫ًبخزنًالكوليسترولًلحدًماًأحتاجه‬ 3- LDL cholesterol may also be excreted into bile (formed by liver) and become part of the enterohepatic pool or may be lost in the stool. Lp(a) is a cholesterol-rich lipoprotein similar to LDL in composition and density and with close homology to plasminogen. It is reported to be an important independent risk factor for the development of premature cardiovascular disease. *High Lp(a) → high risk of atherosclerosis, Why? 1) LP(a) is similar to LDL and contains cholesterol. 2) Plasminogen → Plasmin (that breaks down the fibrin strands) the LP(a) has same homology (Structure) as plasminogen so the body thinks that we have enough plasminogen → it stops synthesizing the plasmin → Clots are not dissolved anymore → high risk of atherosclerosis. HDL ▪ Derived from liver and gut synthesis primarily in the form of apolipoprotein A-I phospholipid discs. *HDL content is from: 1) liver synthesis 2) diet Topic 8/ Dyslipidemia Pathophysiology Lec 19 ▪ Results also from the esterification of free cholesterol by LCAT (lecithin-cholesterol acyltransferase). ▪ Inhibition of CETP (cholesterol ester transfer protein) leads to elevations in HDL. *LCAT → is an enzyme in the blood , which makes esterification of cholesterol to store it in HDL → ‫شغلهًرائعًألنهًبزيدًليًالكوليسترولًالنافع‬ *CETP→ ً‫ منًاسمه‬transfer → ًTransfer cholesterol ester from HDL to another lipoprotein such as (LDL,VLDL) !!! → ً‫خطوةًجداًسيئةًيعنيًاناًكنت‬ !ً‫كوليسترولًنافعًوًانتًرحتًنقلتنيًللكوليسترولًالضار‬ ً‫ًبحيث‬CETP inhibitors ً‫ًاليًهم‬،ًCETP ‫*ًمنًهونًاجتًفكرةًليشًماًاعملًدواًيثبطًليًال‬ ً‫ًوًفعال‬..ً‫ًالنافع‬HDL ‫ًمنًعملًهذهًالخطوةًالسيئةًوًاحتفظًبالكوليسترولًداخلًال‬CETP‫امنعًال‬ ً‫عملوهًبسًلماًاجواًيدرسواًأثرهًعلىًتقليلًاإلصابةًبتصلبًالشرايينًبينًمعهمًانهًماًعملًأيًتغيير‬ ً‫ًلكنهاًالفكرةًجميلةًتستحقًالذكرًو‬..ً‫ملحوظًفيًخفضًاإلصابةًفيهًوًماًفيهًأدلةًلسهًعنًمدىًفائدته‬ ً.ً‫ماًزالتًتحتًالدراسة‬ ً‫ًاذاًمهتمينًتقرؤواًعنهً"بعدًماًتخلصواًدراسة‬Obicetrapib ً:ً‫*وًفيهًمثالًعلىًهذهًاألدوية‬.ً.ً‫ًنكمل؟‬،ً"‫التفريغ‬ ً ▪ Unfortunately, when CETP inhibitors have been tested in clinical trials, they did NOT induce regression of atherosclerotic plaque. ▪ Apolipoprotein A-I production is increased by estrogens, leading to higher HDL levels in women and in individuals receiving estrogen. * Apolipoprotein A-I is on the surface of HDL, so high production of it by estrogen → high HDL levels , as we said before the estrogen has a cardioprotective effect working on lipid profile. ً‫ وًمعًانخفاضًاالستروجينًلألسفًيصبحنًأكثر‬menopauseً‫*لذلكًالنساءًبعدًانقطاعًالطمث‬.ً‫عرضةًالنخفاضًالكوليسترولًالنافعًوًبالتاليًلتصلبًالشرايينًوًامراضًالقلبًوًالشرايين‬ ً  Topic 8/ Dyslipidemia Pathophysiology Lec 19 Chylomicron VLDL LDL HDL Density (g/ml) LDL >VLDP > Chylomicron *Proteins: HDL > LDL >VLDP > Chylomicron ً ً‫ًطيبًالحجم؟ًبنعكس‬،ً‫*مشًحكيناًكلًماًزادواًالبروتيناتًزادتًالكثافة؟ًاذاًراحًيكونواًنفسًالترتيب‬ *Size/diameter : HDL< LDL