Lipoproteins Lecture Notes PDF

LIPOPROTEINS Transporting fats throughout the body ~ diet vs. genetics... + liver Sian Patterson, Ph.D. Associate Professor, Teaching Stream  Learning Objectives By the end of this lecture, students should be able to: Describe the structure...

LIPOPROTEINS Transporting fats throughout the body ~ diet vs. genetics... + liver Sian Patterson, Ph.D. Associate Professor, Teaching Stream  Learning Objectives By the end of this lecture, students should be able to: Describe the structure and function of lipoproteins. Summarize how lipoproteins are made and how they travel throughout the body. Contrast ‘good’ and ‘bad’ cholesterol and examine the role the liver plays in cholesterol levels. Devise a biochemical strategy to maintain good cardiovascular health. 2  Low Carb Diets All : Acetyl con to mal What is the biochemical basis of low carb diets? FAS fatty : glycolysis - acid - Pete low carb > less - pyruvate -> less Acetyl COA for fut synthesis What are the side effects? CAC for oxaloacetate Less ATP low carb -> less pyruvate -> If fat is in excess , MCAcetyl ConIsleads to ketogenesis 3  CARBOHYDRATES GLYCOGEN LIPIDS GLYCEROL GLUCOSE TAG FATTY ACIDS ENERGY GNG Glycolysis ATP ATP NADPH CO2 PYRUVATE LACTATE PROTEINS Beta Oxidation AMINO ACIDS ACETYL-COA KETONE BODIES ATPNADH N& CHOLESTEROL A D H amphibolic Citric FA Urea D Acid H2 Cycle Cycle Oxidative Phosphorylation NH3 CO2 O2 H2 ATP O 4  Triglyceride (TAG) formation Triglycerides are made starting with phosphatidate. The phosphate is first removed by a - Phosphatase phosphatase producing diacylglycerol. Diacylglycerol acyltransferase adds the 3rd diacylglycerof fatty acyl tail to make tri-acyl-glycerol. transferase anabolic Elevated insulin promotes the activation of all the enzymes involved - - ACC, FAS and acyltransferases. TAGs produced in the liver can be released in the blood stream as lipoproteins for storage or use. 5 Cholesterol estes : amphipatin bind to hydrophobicLipoproteins Lipoproteins are the transport molecules for YReceptors hydrophobic TAGs and cholesterol esters throughout the body. They have a thin monolayer of phospholipids and hydrophobic cholesterol. TAGS The polar portions of the molecules face the aqueous exterior, while the hydrophobic ones face the hydrophobic interior. s Apoproteins are on the surface of the lipoproteins and are oriented with their hydrophilic side chains and TAGs outward and hydrophobic side chains facing inwards. 6  Acetyl CoA carbons Actyl COA Cholesterol Metabolism ATP + NADPHd 30 steps Cholesterol is crucial for membranes and is cholested ↓ metabolized to produce hormones, bile salts and vitamin D3. Cholesterol is made from Acetyl CoA in the R-C-S-CoA + cytoplasm of liver cells using carbons from O fat/protein/carbohydrate catabolism. acyl Acyltransferases Cholesterol can be modified to a hydrophobic, H3C acyl-carrying molecule called a cholesterol Cholesterol CH3 ester (CE) by acyltransferases. este CH3 The production of cholesterol requires NADPH and ATP and is regulated by inhibiting an R-C-HO enzyme called HMG-CoA reductase.p + O + CoA ↳ ↳ when we want to turn off cholesterd making hydrophobic 7  How does exercise lead to the phosphorylation and inhibition of HMG CoA reductase? ↳ lower Cholesterd Exercise ? of Protein Knaus A Cepinephrine buses Acetyl COA through activation ↳ Acetyl COA removed ATPPTHMG- , > HMG Off 8  Inhibition of Cholesterol Synthesis : – "inma – work in rats was the HMG-CoA reductas In the early spring o O a pathologist at Sanky added hens for research pu a joint research proje using his hens. The e Comp > - bindetoHestera success. The plasma c a that received compact inhibition 2 weeks. Soon after, w edicine & profound cholesterol Image taken from Endo, A. (2008) Nature Medicine 14, 1050-1052. Figure 2 A comparison of the structures of four synthese pactin in dogs and 9m Statins bind to HMG CoA Reductase with various Ki values and lead to an increase in Km’, but Vmax can still be achieved. What is the classification of this inhibition? ↳ Competitive inhibition I can still make cholesterd with comp inhibition ↳ achieve Umax ↑ calories = ↑ Acetyl cott , can make cholesterol (outcompetes Hmo) 10  Lipid Transport via TAG Unolesterd Lipoproteins -dietary , & Lipoproteins are made in the liver or intestine. fats As they travel through the body, fatty acids and cholesterol are transferred to the tissues to produce energy, build membranes, or to produce other molecules. Whatever doesn’t get used, returns to the liver as lipoprotein remnants for recycling. Additional cholesterol and/or TAGs are synthesized for the production of new lipoproteins. know structure and functional groups what type of Excess synthesis of fats, defects in the receptors that recycle regulation? lipoproteins, or problems with the expression and/or activity of HMG- CoA Reductase can disrupt the balance of lipid metabolism and lead to high cholesterol and cardiovascular disease (CVD). 11  Lipo-proteins The different lipoproteins can be differentiated by their individual components (apoproteins, % TAGs, % cholesterol) Chylomicrons are made in the small intestine from the diet and are the largest and contain an apoprotein known as Apoprotein 48. can use antibodies Very Low Density Lipoprotein (VLDL) is made by the liver and contains to the ApoB100 protein. differentiate Lipoprotein lipase attacks VLDL, hydrolyzing TAGs to produce Intermediate Density Lipoprotein (IDL) and then Low Density Lipoprotein (LDL). LDL-bad cholestent High Density Lipoprotein (HDL) is the ‘good cholesterol’ that picks up cholesterol (& CEs) and transports them back to the liver for breakdown and recycling. Regulates cholester 12  Lipoproteins in the Body + cholesterol cholesterol Bile salts + albumin + albumin + cholesterol 13  Lipoprotein Metabolism in Circulation Capillary Lipoprotein Endothelium Apoproteins Blood ↳ Lipoprotein TAG binds proteins like lipolipase to e Lipase STALK Free Fatty Acids, Glycerol Apoproteins help with targeting and binding to cells and other proteins via non-covalent interactions. Membrane-bound enzymes help release free fatty acids for cellular use. 14  Lipoproteins Classification Good ③ -most 2 protein liver 8 let density ↓ HDL is known as the ‘good cholesterol’, it travels lowest through the body and picks up cholesterol esters using protein d a lecithin:cholesterol acyl transferase (LCAT) enzyme; highest returning cholesterol to the liver for processing and AGS ↓ breakdown. largest 15  Lipoproteins in the Body + cholesterol cholesterol Bile salts + albumin + albumin + cholesterol return 1 to livey decides - ↳ we need more cholestera 16  3X O Diet or Liver ? which creates more Coolesterd ? Liver 17  ‘Cholesterol’ and Cardiovascular Disease Cholesterol is found in the diet (mainly animal-based products) but it is also synthesized in the liver (~800 mg/day). The liver is responsible for monitoring cholesterol levels and for lipoprotein recycling and the synthesis of new cholesterol. Increased cholesterol intake, synthesis in the liver or decreased lipid turnover and use can lead to cardiovascular disease. Toxidized OxLDL Oxidized LDL particles have been found to be the principal components in arterial plaques ↓ resulting in heart attack or stroke. hydrophobic Other types of ‘fats’ also play a role... TAGS ↳ can't break down 18  gym - inhibits cholesterol synthesis (no acetylon) Hma blocked females Improving - (good) more Cardiovascular HDL Health You can’t fight genetics! The enzymes and receptors in your liver play a major role in the regulation of cholesterol levels. Exercise and proper diet can help increase HDL and lower LDL levels. Proper diet includes monitoring fat intake (decreased trans and saturated fats) but also caloric intake. Stop smoking and decrease stress to lower your blood pressure and prevent arterial damage where oxidized LDL accumulates. Last resort – statin drugs. 19  - > 3rd C has a double kind ω-3 Fatty Acids and Cardiovascular Health 2052 Mozaffarian and Wu Omega 3 Fatty Acids and Cardiovascular Disease JACC Novem Omega 3 fatty acid intake have been associated with the following, all modulated at the cellular or DNA level: oxidized Reduced VLDL synthesis > - prevent Reduced availability of FA chains for TAG synthesis Increase phospholipid synthesis Increased β oxidation : break down fatty acids Reduced hepatic ACC & FAS enzyme to activity bless Actul Aft cos forA Mozzaffarian and Wu. J. Am. Coll. Cardiol. 58:2047-2067 (2011). Figure 3 Physiological Effects of n-3 PUFA That Might Influence CVD Risk 20  Key Messages Cholesterol is made from Acetyl CoA in the liver or comes from dietary sources. HMG-CoA reductase is the regulated step in cholesterol production. Lipoproteins deliver cholesterol and fatty acid chains for use or storage and are recycled by the liver. High LDL and low HDL levels are risk factors for cardiovascular disease. Cardiovascular health can be influenced by diet, exercise, lifestyle and statins. 21