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The Usual Suspects: Cholesterol and Triglyceride.

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1 The Usual Suspects: Cholesterol and Triglyceride

2 Lipid Structure Cholesterol: Membranes Bile Acids Steroid Hormones Protein modification Fatty Acids: Fuel, Prostanoids Glycerol Triglycerides:FA for Fuel, Prostanoids Protein modification Phospholipid: LecithinMembranes 2 nd Messengers

3 Structure of a Typical Lipoprotein Free cholesterol (surface and core) Phospholipid (amphipath at surface only) Triglyceride (core only) Cholesteryl ester (core only) Apolipoprotein (amphipath at surface only)

4 Lipoprotein classes and sub-Classes 1.20 1.10 1.06 1.02 1.006 0.95 51020406080 1000 Chylomicron Remnants VLDL LDL HDL 2 HDL3 Particle Size (nm) Density (g/ml) Chylomicron VLDL Remnants Lp(a) IDL Directly atherogenic (found in plaque) pre-β2 HDL pre-β1 HDL

5 Substrates for Triacylglycerol Synthesis Glucose Glc-6-Pase PEP Pyruvate NEFA Acyl-CoA Synthetase CoA Mitochondria CPT I Acyl-Carnitine CPT II Acyl-CoA Acetyl-CoA Pyruvate Ketone Bodies HMG-CoA Synthase Krebs Cycle CO 2 CPT = Carnitine palmitoyl transferase Glucose-6-P PEPCK Pyruvate kinase ATP Citrate Lyase Acetyl-CoA Acyl-CoA Carboxylase Malonyl-CoA Fatty Acid Synthase Acyl-CoA Triglycerides Beta-oxidationBeta-oxidation Hepatocyte PEP = phosphoenolpyruvate PEPCK = PEP carboxylase Citrate Acyl-CoA Citrate Plasma Multiple steps

6 Structures of Fatty Acids C HO O C O C O C O C O 16:0 (palmitic) cis-18:1  -6 (oleic) trans-18:1  -6 (elaidic) 18:2  -6 (linoleic) 18:3  -3 (alpha linolenic) C HO O 20:5  -3 (EPA)

7 Liver Lymphatic chylomicron Muscle and adipose tissue Lipoprotein lipase Lipoprotein Lipase Plasma chylomicron Fatty acids Bloodstream LDL receptor Hepatocyte Chylomicron Remnant Exogenous (dietary) lipid metabolism Apo C-II enhances and apo C-III inhibits LPL activity Apo B and apo E are ligands for LDL receptor LDL (apo B,E) receptor clears Chylomicron Remnants Xenical blocks diatary fat digestion INTESTINEINTESTINE

8 Liver VLDL Muscle and adipose tissue Lipoprotein lipase Lipoprotein Lipase And hepatic lipase IDL Fatty acids Bloodstream LDL receptor Hepatocyte LDL Endogenous (hepatic) lipid metabolism Apo C-II enhances and apo C-III inhibits LPL activity Apo B and apo E are ligands for LDL receptor LDL (apo B,E) receptor clears VLDL, IDL & LDL

9 Clinical Hypertriglyceridaemia ConditionFeatures SecondaryRelatively common (obesity, diabetes, renal impairment, liver disease, drugs) FamilialOverproduction of apo B lipoproteins Combined H/LTG and TC vary with age and weight PolygenicAccounts for the majority of cases Familial HTGTG predominates. CVD risk varies Predisposes to massive HTG Massive HTGLipoprotein Lipase deficiency or saturation. Risk of pancreatitis

10 Therapy for Hypertriglyceridaemia InterventionFeatures Diet, ExerciseRelatively responsive FibratesEffective in high TG, low HDL Alcohol restrictionOften sufficient in heavy intake Manage 2 o causesDiabetes, renal StatinsMild TG and HDL benefit Fish oils (eg 6gm/d)Benefits TG rather than HDL NiacinEffective, but increases glu, urate. Bile acid resinsContraindicated. Increase TG FutureDGAT 2 Inhibitors?

11 400 mg/day 1,300 mg/day NORMAL CHOLESTEROL ABSORPTION Oil phase

12 400 mg/day 1,300 mg/day NORMAL CHOLESTEROL ABSORPTION Plant sterols compete with cholesterol here Oil phase

13 400 mg/day 1,300 mg/day 17,400 mg/day 850 mg/day NORMAL CHOLESTEROL ABSORPTION Ezetimibe competes with cholesterol here Oil phase

14 400 mg/day 1,300 mg/day 850 mg/day NORMAL CHOLESTEROL ABSORPTION Oil phase 17,400 mg/day

15 Intracellular cholesterol sensing by SREBPs (Sterol Regulatory Element Binding Proteins) WDRegWD bHLH Reg S1P S2P ZN ++ Serine protease Metalloproteinase Golgi Apparatus Lumen Sterols Cytosol SREBP SCAP Nucleus ER SRE SCAP or SREBP activating protein Membrane fluidity reflects intracellular cholesterol. Low levels allow cleavage to active form which binds nuclear receptor to control gene expression. SREBP-2 controls cholesterol synthesis and sterol metabolism SREBP-1c is the major isoform in liver and is a key regulator of fatty acid & triglyceride synthesis Other nuclear receptors: FXR, LXR.

16 LDL Receptor activity reflects intracellular cholesterol homeostasis *[ SREBP] = sterol regulatory element-binding protein. 1.Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438.. Cholesterol delivery via LDL-R alters intracellular membrane cholesterol and SREBP, which a)Reduces synthesis via HMGCoA Reductase b)Reduces LDL-R synthesis c)Increases storage as ester d)Reduces counter-regulatory PCSK9

17 LCAT Hepatic lipase, endothelial lipase ABCA1, ATP-binding cassette protein A1; CETP, cholesterol ester transfer protein; FC, free cholesterol; LCAT, lecithin:cholesterol acyltransferase; SR-A, scavenger receptor class A; SR-BI, scavenger receptor class B type I. PL&UC Bile SR-BI Macrophage VLDL/LDL CETP Spheroidal HDL Pre-β HDL SR-A Oxidation The Role of HDL in Reverse Cholesterol Transport LDL Receptor Liver ABCA1 UC ABCG1 &SR-B1 UC Adapted with permission from Cuchel C et al. Arterioscler Thromb Vasc Biol. 2003;23:1710–1712

18 Clinical Hypercholesterolaemia ConditionFeatures SecondaryRelatively uncommon, but potent (hypothyroidism, nephrotic syndrome, primary biliary cirrhosis) FamilialOverproduction of apo B lipoproteins Combined H/LTG and TC vary with age and weight PolygenicAccounts for the majority of cases Familial Prevalent, Accelerates CVD. Hyperchol’aemiaDue to defects in genes related to LDL-R Increased HDL?OK if LDL not raised?

19 Therapy for Hypercholesterolaemia InterventionFeatures DietPlant sterols, avoid sat & trans FA Manage 2 o causesRarer, but potent: (Thyroid, liver, renal.) StatinsFirst line for LDL reduction Ezetimibe2 nd line. Neutral for TG & HDL Niacin Improves LDL, TG, HDL & Lp(a) Bile acid resinsColesevalam better tolerated FuturePCSK9 Inhibitors, MTP inhibitors? Apo B antisense oligonucleotides

20 Triglyceride and Cholesterol: Why are they linked? Most lipoproteins have TG and/or CE in their core Hepatic Triglyceride rich lipoproteins are precursors of cholesterol-rich LDL Cholesterol-ester transfer protein allows all triglyceride-rich lipoproteins to modify the composition of cholesterol-rich HDL and LDL. As a result, hypertriglyceridaemia is associated with reduced HDL cholersterol as well as “small dense LDL”. The major gene regulators for lipid metabolism affect both TG and Chol

21 Key Regulators of Genes in Fatty Acid and Triglyceride Metabolism LXR RXR PPAR FXR HNF-4α SREBP-1cSREBP-1c NEFANEFA Acyl CoA Apolipoproteins Pyruvate kinase Glucose-6-phosphalase Transferin Bile Acids Unsaturated Saturated Fatty acid metabolism Transport Oxidation Fatty Acid Binding Protein Ketogenesis L-FABP Acetyl CoA Carboxylase Fatty Acid Synthase Spot 14 SHP Bile Acids Adapted from Pegorier JP et al. J Nutr 2004;134:2444S-9S SHP = Short Heterodimer Partner

22 Key Regulators of Genes in Lipid Metabolism Cellular Cholesterol Homeostasis HepatobiliaryHepatobiliary IntestineIntestine Liver X Receptor (LXR) Sterol Regulatory Element Binding Protein (SREBP2) Farnesoid X Receptor (FXR) Peroxisome proliferated activator receptors PPARs SynthesisSynthesisDeliveryDelivery AcquisitionAcquisition ExcretionExcretion

23 Link to mixed HL cases

24 Patient is a 43 year-old male with a strong family history of premature CVD who presents for initial evaluation. He has a 10 year history of dyslipidaemia and hypertension, for which he has received beta blockers in the past. More recently he has been on an ARB/diuretic combination. Three months prior to this visit a fasting lipid profile showed: Total Cholesterol:5.7 mmol/LTriglyceride:2.8 mmol/L HDL-C:0.7 mmol/LLDL-C:3.6 mmol/L He has managed to lose 3 kg and today results include: Case MC Total Cholesterol:6.9 mmol/LTriglyceride:1.8 mmol/L HDL-C:0.8 mmol/LLDL-C:5.2 mmol/L

25 Questions concerning Mr M.C. 1) Is ethnicity an independent risk factor for CVD? Yes / No? 2) In the absence of any symptoms or signs of hypothyroidism, would you perform thyroid function tests? Yes / No? 3) His brother’s lipids include LDL = 5.4 mmol/l, TG = 1.9 mmol/l, HDL = 0.9 mmol/l. What is the most likely cause of MC’s lipid abnormality? A) Dyslipidaemia secondary to Insulin resistance and the Metabolic Syndrome B) Polygenc dyslipidamia C) Familial Combined Hyperlipidaemia D) Familial Hypercholesterolaemia E) Lipids aren’t really an issue in this patient

26 1) Is ethnicity an independent risk factor for CVD? Yes / No? 2) In the absence of any symptoms or signs of hypothyroidism, would you perform thyroid function tests? Yes / No? 3) His brother’s lipids include LDL = 5.4 mmol/l, TG = 1.9 mmol/l, HDL = 0.9 mmol/l. What is the most likely cause of MC’s lipid abnormality? A) Dyslipidaemia secondary to Insulin resistance and the Metabolic Syndrome B) Polygenc dyslipidamia C) Familial Combined Hyperlipidaemia D) Familial Hypercholesterolaemia E) Lipids aren’t really an issue in this patient Patient is a 43 year-old male with a strong family history of premature CVD who presents for initial evaluation. He has a 10 year history of dyslipidaemia. Hypertension, for which he has received beta blockers in the past. More recently he has been on an ARB/diuretic combination. Three months prior to this visit a fasting lipid profile showed: TC: 5.7 Triglyceride: 2.8 mmol/L HDL-C: 0.7 mmol/L LDL-C: 3.6 mmol/L He has managed to lose 3 kg and today results include: TC: 6.9 Triglyceride:1.8 mmol/L HDL-C: 0.8 mmol/L LDL-C: 5.2 mmol/L

27 Is ethnicity an independent risk factor for CVD? Yes / No? YES: NO:

28 Is ethnicity an independent risk factor for CVD? Case for a qualified “Yes”. Same risk factors, different pattern INTERHEART, Joshi et al 2007 INTERHEART, Karthikeyan et al 2009,

29 2) In the absence of any symptoms or signs of hypothyroidism, would you perform thyroid function tests? Yes / No? Yes: No:

30 2) In the absence of any symptoms or signs of hypothyroidism, would you perform thyroid function tests? The case for “Yes”

31 What is the most likely cause of MC’s lipid abnormality? A) Dyslipidaemia secondary to Insulin resistance and the Metabolic Syndrome B) Polygenc dyslipidamia C) Familial Combined Hyperlipidaemia D) Familial Hypercholesterolaemia E) Lipids aren’t really an issue in this patient

32 What is the most likely cause of MC’s lipid abnormality? The case for “C”, maybe “A” or “B ” ConditionFeatures SecondaryRelatively uncommon, but potent (hypothyroidism, nephrotic syndrome, primary biliary cirrhosis) FamilialOverproduction of apo B lipoproteins Combined H/LTG and TC vary with age and weight PolygenicAccounts for the majority of cases Familial Prevalent, Accelerates CVD. Hyperchol’aemiaDue to defects in genes related to LDL-R Increased HDL?OK if LDL not raised?

33 Mr MC started statin, therapy, Atorvastatin 20 mg/ day, but unfortunately he had and inferior AMI still 4 months later. His discuharge medication include: Atorvastatin 20mg, Metoprolol 20 mg, Aspirin 100mg, and his previous ARB/diuretic. Follow-up 2 months later reveals:2 kg weight loss, BP 118 / 78, Fasting tests: Glu 5.3 mmol/l, TC 4.4 mmol/l TG 4.2 mmol/l, HDL 0.7 mmol/l, LDL 1.8 mmol/l Case MC (continued)

34 Case MC: Further questions: Should you stop his beta blocker? Yes / No? Do you trust the LDL-C result? Yes / No? Is it practical to try to manage Mr M.C’s lipid profile to target levels?Yes / No? What is the next lipid-lowering drug that you would add to his therapy? a)Ezetimibe b)Niacin c)I would increase Atorvastatin to 80 mg but I wouldn’t give anything other than a statin d)Fenofibrate e)Fish Oil

35 Should you stop his beta blocker? Yes / No? Do you trust the LDL-C result? Yes / No? Is it practical to try to manage Mr M.C’s lipid profile to target levels?Yes / No? What is the next lipid-lowering drug that you would add to his therapy? a)Ezetimibe b) Niacin c) Increase Atorvastatin to 80 mg but don’t give anything other than a statin d) Fenofibrate e) Fish Oil Mr MC started statin, therapy, Atorvastatin 20 mg/ day, but unfortunately he had and inferior AMI still 4 months later. His discuharge medication include: Atorvastatin 20mg, Metoprolol 20 mg, Aspirin 100mg, and his previous ARB/diuretic. Follow-up 2 months later reveals: 2 kg weight loss, BP 118 / 78, Fasting tests: Glu 5.3 mmol/l, TC 4.4 mmol/l TG 4.2 mmol/l, HDL 0.7 mmol/l, LDL 1.8 mmol/l

36 Should you stop his beta blocker? Yes No

37 Should you stop his beta blocker? The case for “no” Should you stop his beta blocker? The case for “no” Some β-blockers decrease HDL and increase triglycerides. 25 In spite of this, BHAT data showed that propranolol improves survival after MI. 26 Low-dose metoprolol CR/XL alone or in combination with a statin resulted in significant slowing of the progression of carotid artery’s intima-media thickness over a 3- year period. 27 25 26 27 M Gheorghiade et al Circulation.2002; 106: 394-398

38 Do you trust the LDL-C result? Yes No

39 Do you trust the LDL-C result? The case for “No” Do you trust the LDL-C result? The case for “No” Discussion of the effect of Cholesterol ester transfer protein will Explain why LDL-C underestimates risk when TG is elevated

40 Is it practical to try to manage Mr M.C’s lipid profile to target levels? Yes No

41 Is it practical to try to manage Mr M.C’s lipid profile to target levels? The case for “Yes” Combination therapy is safe and effective, but yet to be supported by clinical endpoint data.

42 What is the next lipid-lowering drug that you would add to his therapy? a)Ezetimibe b)Niacin c)I would increase Atorvastatin to 80 mg but I wouldn’t give anything other than a statin d)Fenofibrate e)Fish Oil

43 What is the next lipid-lowering drug that you would add to his therapy? The case for “d” or “b”, possibly “c” or “e” anticipate “residual risk” module What is the next lipid-lowering drug that you would add to his therapy? The case for “d” or “b”, possibly “c” or “e” anticipate “residual risk” module

44 Patient is a 47 year-old female who has been gaining weight for several years. She has a 10 year history of mildly elevated triglyceride. She received therapeutic lifestyle counseling but she has been largely non-compliant. Three months prior to this visit, a fasting lipid profile showed: Total Cholesterol:5.5mmol/L Triglyceride: 2.4mmol/LHDL-C: 1.0mmol/L LDL-C:3.6 mmol/L Now she has symptoms of hyperglycaemia and repeat fasting glucose confirms Type 2 diabetes Case GS

45 Review of Symptoms: Thirst, polyuria, folliculitis, Weight unchanged (increased 2kg, then lost when polyuria commenced BP 118/72 Pulse 72 Wt 85kg Ht 175cm Waist 93 cm BMI 27.8: Physical examination unremarkable Current fasting lipid results surprise you: Total Cholesterol:8.5mmol/L Triglyceride:7.4mmol/L HDL-C:1.0mmol/L LDL-C:unable to be calculated Case GS

46 Questions: How could you obtain an LDL-C result? a)Friedewald equation b)Abusive phonecall to lab c)“Direct method” involving detergents d)Ultracentifugation e)Subtract HDL-C from Total cholesterol Which class or classes of lipoproteins would you expect to be increased? a)Chylomicrons and LDL b)VLDL and LDL c)VLDL and HDL d)IDL and chylmicron “remnants” e)Why bother? It doesn’t matter Which combination of extra tests would be most useful? a) LDL size+HDL subfractions b) Lipid EPG+ApoE phenotype c) LDL subfractions HDL size d) Lp(a)+ homocysteine e) Routine fasting lipids are the only lipid tests that are ever required

47 How could you obtain an LDL-C result? Which class or classes of lipoproteins would you expect to be increased? Which combination of extra tests would be most useful? She has a 10 year history of mildly elevated triglyceride. She received therapeutic lifestyle counseling but she has been largely non-compliant. Three months prior to this visit, a fasting lipid profile showed: Total Cholesterol:5.5mmol/L Triglyceride: 2.4mmol/LHDL-C: 1.0mmol/LLDL-C:3.6 mmol/LNow she has symptoms of hyperglycaemia and repeat fasting glucose confirms Type 2 diabetes. Symptoms: Thirst, polyuria, folliculitis, Weight increased 2kg, then lost when polyuria commenced BP 118/72 Pulse 72 Wt 85kg Ht 175cm Waist 93 cm BMI 27.8: Physical examination unremarkable Current fasting lipid results surprise you: TC:8.5mmol/L TG: 7.4mmol/L HDL-C: 1.0mmol/L LDL-C: unable to be calculated

48 How could you obtain an LDL-C result? a)Friedewald equation b)Abusive phonecall to lab c)“Direct method” involving detergents d)Ultracentifugation e)Subtract HDL-C from Total cholesterol

49 How could you obtain an LDL-C result? The case for “d”, but “c” is misleading Lab Tests Online: “Direct LDL-C is ordered whenever calculation of LDL cholesterol will not be accurate because the person's triglyceridesare significantlytriglycerides elevated. It may be ordered by a doctor when prior test results have indicated high triglycerides. In some laboratories, this direct LDL test will automatically be performed when the triglyceride levels are too high to calculate LDL-C. This saves the doctor time by not needing to order another test, saves the patient time by not needing to have a second blood sample drawn, and speeds up the time to provide the test result.” Ultracentrifuge gives absolute result. Detergent methods assume LDL

50 Which class or classes of lipoproteins would you expect to be increased? a)Chylomicrons and LDL b)VLDL and LDL c)VLDL and HDL d)IDL and chylmicron “remnants” e)Why bother? It doesn’t matter

51 Which class or classes of lipoproteins would you expect to be increased? The case for “b”(orange) or “d” (green)

52 Which combination of extra tests would be most useful? a) LDL size+HDL subfractions b) Lipid EPG+ApoE genotype/phenotype c) LDL subfractions HDL size d) Lp(a)+ homocysteine e) Routine fasting lipids are the only lipid tests that are ever required

53 Which combination of extra tests would be most useful? The case for “b” CM β preβ α ApoE isoforms

54 The patient subsequently complied with diet and started on Simvastatin 40 mg daily and other treatment, which she tolerates without difficulty. Current Medications: 1. Metformin 850 mg bid 2. Enalapril 10 mg q day 3. ASA 81 mg q day 4. Simvastatin 40 mg q day Subsequent results include:LEPG – Broad beta pattern present Apo E Genotype: Apo E2:E2 Case GS (continued)

55 This implies the accumulation of which lipoprotein class(es)? a) VLDL + LDLb) IDL and Chylomicron “remnants” Which lipid-lowering drug is the ideal treatment for this situation? a) Simvastatin b) Nicotinic Acid c) Questran d) Fibrate e) Fish oil f) Ezetimibe Which lipid-lowering therapy is strongly CONTRAindicated? a) Simvastatin b) Nicotinic Acid c) Questran d) Fibrate e) Fish oil f) Ezetimibe Would you stop his statin therapy? Yes / No Do you agree with the use of low-dose aspirin in this patient? Yes / No Questions

56 This implies the accumulation of which lipoprotein class(es)? Which lipid-lowering drug is the ideal treatment for this situation? Which lipid-lowering therapy is strongly CONTRAindicated? Would you stop his statin therapy? Do you agree with the use of low-dose aspirin in this patient? The patient asks you about his risk of Alzheimers’ Disease. Is it increased? The patient subsequently complied with diet and started on Simvastatin 40 mg daily and other treatment, which she tolerates without difficulty. Current Medications: 1. Metformin 850 mg bid 2. Enalapril 10 mg q day 3. ASA 81 mg q day 4. Simvastatin 40 mg q day Subsequent results include:LEPG – Broad beta pattern present Apo E Genotype: Apo E2:E2

57 a) VLDL + LDL b) IDL and Chylomicron “remnants” This implies the accumulation of which lipoprotein class(es)?

58 This implies the accumulation of which lipoprotein class(es)? The case for “b”

59 a) Simvastatin b) Nicotinic Acid c) Questran d) Fibrate e) Fish oil f) Ezetimibe Which lipid-lowering drug is the ideal treatment for this situation?

60 Which lipid-lowering drug is the ideal treatment for this situation? The case for “d”

61 a) Simvastatin b) Nicotinic Acid c) Questran d) Fibrate e) Fish oil f) Ezetimibe Which lipid-lowering therapy is strongly CONTRAindicated?

62 Which lipid-lowering therapy is strongly CONTRAindicated? The case for “c” Hepatocyte Bile Duct Acetyl CoA SREPB-1c FA, TG VLDL (TG levels) MDRP2/ 3 Heterodimerizatio n with RXR Phospholipid s FXR

63 Do you agree with the aspirin dose? Comment on the role of aspirin in this patient. Yes No

64 Do you agree with the aspirin dose? Comment on the role of aspirin in this patient. Evidence and opinion tending towards “no”?


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