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Lipoproteins II
Track 1 Lecture 4
| Question | Answer |
|---|---|
| PPAR | Peroxisome Proliferator Activated Receptors |
| PPARα PPARγ PPARδ | members of nuclear receptor superfamily of ligand inducible transcription factors |
| PPAR serves as ________________. | transcription factors |
| PPARa = | fibrates (↓ TG, ↑HDL) |
| PPARg = | adiposite differentiations |
| peroxisome proliferator-activated receptors (PPARs) | re a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes |
| PPARs play essential roles in the regulation of | cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. |
| Three types of PPARs have been identified: | alpha, gamma, and delta (beta): |
| α (alpha) | expressed in liver, kidney, heart, muscle, adipose tissue, and others |
| β/δ (beta/delta) | expressed in many tissues but markedly in brain, adipose tissue, and skin |
| All PPARs heterodimerize with the | retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes. These DNA sequences are termed PPREs (peroxisome proliferator hormone response elements). |
| Endogenous ligands for the PPARs | include free fatty acids and eicosanoids |
| PPARα is activated by | leukotriene B |
| Gemfibrozil (e.g. Lopid) Fenofibrate (e.g. TriCor) | Fibrates |
| Fibrates are PPAR agonists? T or F. | True.Mainly activate PPAR alpha |
| Activating PPARs induces the transcription of a number of genes that facilitate | lipid metabolism. |
| What are class of drugs activate PPAR but PPAR gamma? | Thiazolidinediones or TZDs |
| TZDs | Rosiglitazone (Avandia) Pioglitazone (Actos) |
| transcription factor | is a protein that binds to specific DNA sequences, thereby controlling the flow (or transcription) of genetic information from DNA to mRNA |
| Artificial raising of HDL | has not been associated, as of yet, with reduced mortality |
| PPAR are members of what receptor family | nuclear |
| PPAR alpha role in metabolism | fatty acid metabolism lipid homeostasis |
| What are examples of ligands for PPAR alpha | Dietary FA Fibrates ex. Fenofibrate (tricor) |
| What predominate tissue is PPAR alpha expressed in ? | Liver |
| What are PPAR gammas role in metabolism? | glucose metabolism |
| What are ligand examples for PPAR gamma | Dietary FA TZDs ex. Pioglitazone (Actos) |
| What tissue is PPAR gamma predominantly expressed in? | Adipose Tissue |
| WHat is PPAR delta role in metabolism? | Fatty Acid metabolism Lipid Homeostasis |
| What are examples of PPAR delta ligands | Dietary FA Synthetic GW501516 |
| What tissue is PPAR delta predominantly expressed in ? | Nearly ubiquitous tissue expression (expressed in NUMEROUS TISSUES)--but their action is very profound in the Skeletal muscle |
| PPARs expression is very _____ specific | tissue |
| PPARgamma | – glucose metabolism, glitazones, ↑ fat storage , adiposity differentiation. |
| PPAR expression is induced by | FA derived from diet or adipose tissue (breakdown of TG). |
| PPAR | serve as transcription factors for the expression of genes that are involve in lipid metabolism, glucose metabolism or FA oxidation. |
| PPAR alpha | promote fat oxidation |
| PPARd | thought of as more a housekeeping role, highly expressed in skeletal muscle, important function in lipid homeostasis (B-oxidation of FA). |
| Insulin resistance | FA in tissues where its usually not suppose to be (intramyocellular fat) defect in oxidation of fat. |
| Insulin resistance is promoted by | fat =accumulation of fat in unwanted tissue (liver and muscle) don't want fat in muscles and that contributes to insulin resistances in a way that reduces the ability of skeletal muscle to use glucose |
| PPAR delta | focus is diabetes and fat metabolism since it promotes energy metabolism, improved insulin sensitivity and increased fat oxidation |
| PPAR delta | promotes fat oxidation and promotes skeletal muscles to be insulin sensitive |
| PPAR delta | expression in skeletal muscle, heart, pancreatic Beta Cells, and minor expression in white adipocytes |
| What metabolically activates PPARs (most PPARs) | fatty acids |
| PPAR delta have exceptionally ____ ligand-binding pockets that facilitate binding of various ____ | large, fatty acids |
| What types of fatty acids an which one does it have a preference for? | 1. 14-18-Carbon SFA 2. 16-20-Carbon PUFA 3. Naturally occurring eicosanoids Has a preference for the longer PUFA, poly unsaturated fatty acids 4. VLDL-derived FAs 5. Synthetic Agonists (currently under development) |
| What have the VLDL-Fatty Acids been shown to do? | enhance express PPAR delta target genes |
| Individuals with metabolic syndrome are | 1. more insulin resistant 2. tend to have abdominal obesity 3. glucose intolerance 4. atherogenic dyslipidemia (low HDL, small dense LDL) 5. Increase BP 6. Pro-inflammatory state 7. Pro-thrombotic state |
| What to individuals with metabolic syndrome have an increased risk for | 1. Type 2 DM 2. CVD and CV death 3. Fatty liver disease (NASH) |
| In metabolic syndrome what is occurring that is key in relation to PPAR delta | there is accumulation of fat in the skeletal muscles |
| PPARd | weight issue, blood glucose and the atherogenic dyslipidemia |
| What are the therapeutic potentials for PPAR delta in the Management of Metabolic Syndrome | 1. Decrease in weight (decrease waist circumference) 2. Lipid modification (Decrease TG, LDL, increase HDL) 3. Insulin sensitization |
| PPAR delta when activated in the skeletal muscles what does it do? | Cause muscle FUEL and TYPE SWITCHING |
| What type of myofibers are PPAR delta predominately found in? | Type 1 = which are slow twitch oxidative fibers |
| What is skeletal muscle fuels include | 1. glycogen 2. glucose 3. FFA |
| What does skeletal muscles rely on in the resting state? | FFA oxidation |
| What is used in mild-moderate prolonged exercise | FFA oxidation |
| What is used for fueld in high intensity exercise | Glucose glycolysis |
| Duration increases the use of what type of fuel? | FFA oxidation |
| Training increases the use of what type of fuel? | FFA oxidation and decrease in glycogen uses |
| Intensity increases the use of what type of fuel? | Glucose and Glycogen uses |
| Skeletal muscles are heterogeneous myofibers differing in what properties? | 1. Metabolic 2. Contractile |
| Type 1 myofibers are | red, slow, metabolism is via FFA oxidation |
| Type 2 myofibers are | white, fast, metabolism is via Glycolysis (Glucose, Glycogen) |
| PPAR delta activation increases the expression of _____ myofibers and _______ capacity of muscles cells | Type 1, oxidative |
| The increase in the proportion of oxidative Type 1 fibers will | 1. Increase fat disposal in skeletal muscle (increase in insulin sensitivity) 2. Decrease muscle fatigability |
| Decrease in intramyocelluar fat storage | Increase insulin sensitivty |
| Muscles rely on ____ during the fed state and _____ during the fasting state | glucose, FA oxidation |
| PPARd are activated | stimulate type I slow twitching fiber -> relies on fat oxidation for fuel This can be a good thing if the pt has abnormalities in FA oxidation. |
| Individuals that exercise regularly have a high er expression of | PPAR delta |
| When you activate PPAR delta | you increase the expression of TYPE 1 MYOFIBER |
| Where is fat oxidized in the muscles? | In the mitochondria |
| Increase in PPAR | Increase in mitochondria |
| Besides increasing the expression of TYPE 1 what else does activation of PPAR delta change | changes muscle fuel preference |
| What is the fuel expression with more PPAR delta | 1. Favors expression of genes involved in FFA uptake and oxidation 2. Favors expression of genes involved in decrease of CHO oxidaton In turn the skeletal muscle relies on FFA for fuel |
| PPAR delta in increasing expression of FFA uptake and oxidation results in | Increase muscle FFA metabolism |
| PPAR delta in increasing expression of genes that decrease CHO oxidation | decreases muscle glucose oxidation (but increases storage of glycogen) |
| PPAR delta action in ADIPOSE TISSUE | expressed at LOW levels in adipose tissue |
| The activation of PPAR delta in adipose tissue results in | 1. stimulation of fatty acid oxidation but to a lesser extent than in muscles 2. promotes adipose tissue lipolysis |
| Potential for whole body fat dissipation | 1. Stimuation of whole body fat burning and increased energy expenditure 2. Decrease lipid stores in muscle, liver, and adipose tissue 3. Protection from high fat diet-induced weight gain and obesity |
| Overall body effect of PPAR delta (oxidation of fat in skeletal muscle and adipose tissue and adipose tissue lipolysis) | fat dissipation = meaning fat burning |
| Hallmark of metabolic syndrome and ALP (Phenotype B) | Increase TG Decrease HDL-C Increase small dense LDL |
| PPAR delta effects on raising HDL-C | 1. Increase expression of ABCA1 Cholesterol transport 2. Increase concentration ApoA-1 |
| PPAR delta | is 2x as effective in increasing HDL as Fenofibrate in monkeys |
| Therapeutic potential of PPAR delta | improve lipid profile and are particularly potent in increasing HDL-C |
| A persons ability to lose weight relates to their ability to _______ fats | oxidize fats |
| Plasma TG maker may be an indicator of | a person's ability to oxidize more fat. They are more likely to oxidize carbs as oppose to fats. The reason is that in the study the individuals that lost more weight has lower plasma TG at baseline |
| In the study individuals with ALP (phenotype B) | 1. Loss less weight 2. less able to oxidize fat during exercise 3. reduce capacity to oxidize fat was associated with higher plasma TG |
| PPAR delta agonist potential =can you flip the phenotype from B to A | promote fat oxidation and weight loss |
| Will PPAR delta activation promote insulin resistance? | will decrease in glucose oxidation in the muscle (resulting in glucotoxicity) impair insulin sensitivty |
| In the study the PPAR delta agonist were given to individuals w/ predominant Phenotype B at baseline and they | Converted to phenotype A |
| PPAR DELTA agonists | 1. raise HDL by raising particle concentration through high A1 and A2 2. raising ATP binding cassette A1 which favors more Cholesterol eflux from peripheral tissue to the HDl 3. Favor particle size towards larger particles |
| The data shows that PPAR delta does not promote insulin resistance and the 2 proposed hypothesis supporting this are | 1. Carbohydrates not oxidized in skeletal muscle are channeled to liver and oxidized to FA and exported to muscle for oxidation (rather than being stored as TG) |
| The data shows that PPAR delta does not promote insulin resistance and the 2 proposed hypothesis supporting this are | 2. PPAR delta activate FA oxidation in pancreatic Beta cells, thereby protecting the beta cells from lipotoxicity This leads to preservation of Beta Cell capactiy to release insulin and maintain glucose homeostasis |
| PPARd => FA oxidation | ↓ carbohydrate oxidation => hyperglycemia, IR ???? |
| Gluose Metabolism: PPAR delta activation and insulin response is | 1. INcrease response to a glucose stimulus in obese insulin resistant mice 2. INcrease in glucose tolerance |
| PPAR delta and glucose metabolism | PPAR delta INcreases glucose-stimulated insulin secretion |
| Glucose Metabolism: PPAR delta activation and glucose response | 1. DEcrease blood concentration of glucose in hyperglycemic mice 2. No change in glucose level in normoglycemic mice or monkeys |
| PPAR delta acts as insulin secretagogues and sensitizers and _____ glucose | DEcrease |
| The decrease in glucose effect dose not have a HYPOglycemic side effect because? | The effect is less than that of PPAR gamma agonists |
| Therapeutic potential of PPAR delta agonists | As insulin secretagogues/sensitizers |
| PPAR delta does not have | detrimental effects on glucose homeostasis |
| Preservation of insulin sensitivity due to PPAR deltas ability to | oxidize fats in skeletal muscle and liver (unwanted tissue) so you preserve the insulin sensitivity of the tissue |
| Therapeutic Potential of PPAR delta in skeletal muscle | INcrease in FFA oxidation Stimulate TYPE 1 MYOFIBER |
| Therapeutic Potential of PPAR delta in adipose tissue | INcrease adipose tissue lipolysis which leads to decrease in body weight INcreases FFA oxidation (but to a lesser extent than skeletal muscle) |
| Therapeutic Potential of PPAR delta in Lipoprotein metabolism | Improves features of ALP (Significant INCREASE in HDL) Increase in HDL due to ABC1, ApoA1 Increase in larger LDL particles and decrease in small LDL |
| Therapeutic Potential of PPAR delta in GLUOSE HOMEOSTASIS | INcrease insulin sensitivty |
| PPAR delta activation is like _________, benefit wise (the underlying mechanism might not be the same. | exercise |
| In exercise-resistant individuals pharmacological PPAR delta activation might be use as a ________ | exercise pill |
| Professor postulates that for "hard-wire" individuals that LOSE the weight but still do not convert to phenotype A from B | that PPAR delta agonist will NOT work in them |
| Therapies targeting HDL | CETP inhibitors Apo A1 milano Reconstituted HDL |
| HDL – RCT Direct Pathway | Free Cholesterol (in other lipoproteins & peripheral tissues, eg. Foam cells) ==> ApoA-I on HDL and ABCA1 on peripheral tissues so => Free Cholesterol on taken in by HDL and put on surface => converted to Cholester Ester by LCAT on HDL |
| Once LCAT concerts the cholesterol to ester | cholesterol ester brought to the HDL core and it is then mature HDL2 and now the SR-B1 receptors on hepatocytes take up cholesterol and HDL particles are brought back to circulation as HDL3 or HDL2 can be catbolized by the liver |
| HDL-RCT indirect pathway | HDL particles transfer Cholesterol to ApoB containing LDL and VLDL and these transfer TG to HDL in a 1:1 ratio |
| CETP promotes the remodeling of lipoproteins: | Its inhibition creates large CE-rich HDL and TG-rich apoB containing lipoproteins |
| Epidemiological studies indicate that an increase in HDL leads to | DEcrease in CAD risks |
| 1 mg/dL INcrease in HDL leads to a 2-3% decrease in CAD risk | independent of LDL concentration |
| Even when reach LDL target <70 a decrease in HDL still predispose one to CVD events. T or F. | True |
| Defects for HDL constituents are related to an ______ athergogenesis | Increase |
| ATP III guidelines suggest that an independent risk factor for CAD risk is | HDL < 40 |
| HDL Atheroprotection Mechanism | RCT-HDL extracts cholesterol from FOAM CELLS and transports it back to liver |
| Anti-INFLAMMATORY POTENTIAL | HDL inhibits oxidation of LDL HDL inhibits expression of adhesion molecules and chemokines HDL inhibits leukocyte extravasation to subendothelial area |
| What are the current approaches to increasing HDL using statins | Statins =modest decrease in PPAR alpha <10% increase in HDL |
| What are the current approaches to increasing HDL using fibrates | Fibrates = activation of PPAR alpha => increase in apoAI synthesis w/ a 10% increase in HDL |
| What are the current approaches to increasing HDL using Niacin | Niacin = Decrease in ApoA1 HDL catabolism with a 16% increase in HDL |
| What are the lifestyle modifications that can increase HDL | 1. Weight LOSS 2. High levels of aerobic exercise 3. Modest EtOH intake 4. Smoking Cessation |
| Modulation of CETP: | Genetic deficiency in CETP increases HDL |
| Increase in CETP | Increase risk of future CAD in otherwise healthy individuals |
| Rodents (normally deficient in CETP)if you have a high expression of CETP than this | increase risk of atheroschlerosis |
| Inhibition of CETP in rabbits (normally expressed in CETP) | attenuated (reduced) atherosclerosis |
| CETP inhibitor Torcetrapib | Phase III Illumiate study Halted in 2006 due to increased mortality and morbidity despite improvements in lipid profile |
| Was it the molecule or mechanism of CETP inhibitors? | Not Determined |
| Off target toxicity of Torcetrapib (CETP inhibitor) | Increase in BP Increase in aldosterone |
| CETP | moves cholesterol to ApoB containing lipoproteins and if you inhibit it cholesterol is staying in the HDL |
| What is the problem of keeping cholesterol in HDL | Reducing its capacity to acquire cholesterol from more peripheral tissues |
| The large CE-rich HDL consequences | May limit 1st step in RCT of cholesterol efflux from cells to lipid-poor HDL, mediated by ABCA1 transporter |
| What might compensate for the consequence | Increase in SR-B1 medication cholesterol efflux to HDL |
| CETP inhibition may | also inhibit indirect pathway of delivery of CE to liver via apoB containing lipoproteins |
| Apo A1 Milano | Natural mutant found in Italy Carriers protected from CVD Despite Decrease in HDL and Increase TG |
| How is it suggested that Apo A1 MUTANT increases antiatherogenic protection | Possibly by promoting cholesterol efflux from cells through the ABCA1 pathway |
| Apo A1 MUTANT | greater anti-inflammatory and antithrombotic effects |
| Reconstituted HDL-rHDL | consists of apoA1 and phosphatidyl choline Disc shaped particles of controlled size and makeup |
| rHDL | induces effective cholesterol efflux inhibits pro-inflammatory changes inhibits platelet aggregation |
| rHDL show anti-________- effects | atherogenic effects |
| rHDL showed a decrease in coronary | atheroma |
| HDL concentration does not equal | HDL funtionality |
| Ability to characterize HDL functionality will guide | development of effective targets for decreasign CVD risk |
| Recent studies suggest that lipid depleted HDL may NOT be most effective for | RCT Reverse Cholesterol Transport |
| Apo1 mutant individuals in Italy had protection from coronary events despite | low HDL due to the mutant ApoA1 |
| Apo1 and rHDL | have to be injected |
| Apo1 study showed decreased in | plaques |
| rHDL | ERASE study 3.4% reduction in coronary atheroma Compared to baseline there was a significant effect and these were short term studies |
| We are able to accomplish High HDL in Rx | but not getting the results = need to focus on HDL functionality |
| What is a more protective cardio Rx than just raising HDL-Cholesterol | Forming particles that are lipid depleted and consist of Apo A1 and phospholipids |
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