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The Usual Suspects: Cholesterol and Triglyceride. Lipid Structure. Cholesterol: Membranes Bile Acids Steroid Hormones Protein modification. HO. Fatty Acids: Fuel, Prostanoids. Triglycerides: FA for Fuel, Prostanoids Protein modification. COOH. COO. COOH. COO. COOH.

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lipid structure
Lipid Structure

Cholesterol: Membranes

Bile Acids

Steroid Hormones

Protein modification

HO

Fatty Acids: Fuel,

Prostanoids

Triglycerides: FA for Fuel, Prostanoids

Protein modification

COOH

COO

COOH

COO

COOH

COO

Phospholipid: Lecithin Membranes

2nd Messengers

HO

+

Glycerol

COO

HO

COO

HO

+

OPOO

N

structure of a typical lipoprotein
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)

lipoprotein classes and sub classes

VLDL

VLDL

Remnants

Chylomicron

Remnants

Directly atherogenic

(found in plaque)

HDL2

Lipoprotein classes and sub-Classes

Chylomicron

0.95

1.006

IDL

Density (g/ml)

1.02

LDL

1.06

Lp(a)

1.10

HDL3

pre-β2 HDL

1.20

pre-β1 HDL

1000

5

10

20

40

60

80

Particle Size (nm)

substrates for triacylglycerol synthesis

CPT I

Acyl-Carnitine

CPT II

Substrates for Triacylglycerol Synthesis

Plasma

NEFA

Triglycerides

Glucose

Acyl-CoA Synthetase

Glc-6-Pase

CoA

Acyl-CoA

Multiple steps

Glucose-6-P

Acyl-CoA

PEPCK

Mitochondria

Pyruvate kinase

Fatty Acid Synthase

Hepatocyte

Malonyl-CoA

PEP

Acyl-CoA

Acyl-CoA Carboxylase

Krebs Cycle

Acetyl-CoA

Citrate

Pyruvate

ATP Citrate Lyase

Acetyl-CoA

CO2

Pyruvate

Citrate

HMG-CoA Synthase

Ketone Bodies

Beta-oxidation

PEP = phosphoenolpyruvate PEPCK = PEP carboxylase

CPT = Carnitine palmitoyl transferase

structures of fatty acids
Structures of Fatty Acids

O

16:0 (palmitic)

C

HO

O

C

cis-18:1 -6 (oleic)

HO

O

trans-18:1 -6 (elaidic)

C

HO

O

C

18:2 -6 (linoleic)

HO

(alpha

linolenic)

O

18:3 -3

C

HO

O

20:5 -3 (EPA)

C

HO

slide7

Exogenous (dietary) lipid metabolism

Muscle and adipose tissue

Fatty acids

Lipoprotein lipase

Lipoprotein Lipase

Apo C-II enhances

and apo C-III inhibits

LPL activity

Chylomicron

Remnant

Bloodstream

Plasma

chylomicron

Apo B and apo E are ligandsfor LDL receptor

LDL (apo B,E) receptor clears Chylomicron

Remnants

I

N

T

E

S

T

I

N

E

LDL

receptor

Lymphatic

chylomicron

Hepatocyte

Liver

Xenical blocks diatary

fat digestion

slide8

Endogenous (hepatic) lipid metabolism

Muscle and adipose tissue

Fatty acids

Lipoprotein lipase

Lipoprotein Lipase

And hepatic lipase

Apo C-II enhances

and apo C-III inhibits

LPL activity

LDL

Bloodstream

IDL

Apo B and apo E are ligandsfor LDL receptor

LDL (apo B,E) receptor clears VLDL, IDL & LDL

LDL

receptor

VLDL

Hepatocyte

Liver

clinical hypertriglyceridaemia
Clinical Hypertriglyceridaemia

Condition Features

Secondary Relatively common (obesity, diabetes,

renal impairment, liver disease, drugs)

Polygenic Accounts for the majority of cases

Familial HTG TG predominates. CVD risk varies

Predisposes to massive HTG

Familial Overproduction of apo B lipoproteins

Combined H/L TG and TC vary with age and weight

Massive HTG Lipoprotein Lipase deficiency or

saturation. Risk of pancreatitis

therapy for hypertriglyceridaemia
Therapy for Hypertriglyceridaemia

Intervention Features

Diet, Exercise Relatively responsive

Alcohol restriction Often sufficient in heavy intake

Manage 2o causes Diabetes, renal

Fibrates Effective in high TG, low HDL

Statins Mild TG and HDL benefit

Fish oils (eg 6gm/d) Benefits TG rather than HDL

Niacin Effective, but increases glu, urate.

Future DGAT 2 Inhibitors?

Bile acid resins Contraindicated. Increase TG

slide11

NORMAL CHOLESTEROL ABSORPTION

1,300 mg/day

400 mg/day

Oil phase

slide12

NORMAL CHOLESTEROL ABSORPTION

1,300 mg/day

400 mg/day

Oil phase

Plant sterols compete

with cholesterol here

slide13

NORMAL CHOLESTEROL ABSORPTION

1,300 mg/day

400 mg/day

17,400 mg/day

Oil phase

850 mg/day

Ezetimibe competes

with cholesterol here

slide14

NORMAL CHOLESTEROL ABSORPTION

1,300 mg/day

400 mg/day

17,400 mg/day

Oil phase

850 mg/day

intracellular cholesterol sensing by srebps sterol regulatory element binding proteins
Intracellular cholesterol sensing by SREBPs (Sterol Regulatory Element Binding Proteins)
  • Membrane fluidity reflects intracellular cholesterol. Low levels allow cleavage to active form which binds nuclear receptor to control gene expression.

SCAP or SREBP activating protein

Reg

WD

bHLH

bHLH

bHLH

bHLH

Reg

WD

Nucleus

SCAP

SREBP

SRE

ER

Cytosol

  • SREBP-2 controls cholesterol synthesis and sterol metabolism

Lumen

Sterols

  • SREBP-1c is the major isoform in liver and is a key regulator of fatty acid & triglyceride synthesis

Golgi Apparatus

ZN++

S1P

S2P

Metalloproteinase

Serine protease

Other nuclear receptors: FXR, LXR.

ldl receptor activity reflects intracellular cholesterol homeostasis
LDL Receptor activity reflects intracellular cholesterol homeostasis

Cholesterol delivery via LDL-R alters intracellular membrane cholesterol and SREBP, which

Reduces synthesis via HMGCoAReductase

Reduces LDL-R synthesis

Increases storage as ester

Reduces counter-regulatory PCSK9

*[SREBP] = sterol regulatory element-binding protein.

Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438..

the role of hdl in reverse cholesterol transport
The Role of HDL inReverse Cholesterol Transport

Bile

ABCG1 &SR-B1

Spheroidal HDL

Pre-β HDL

UC

Liver

LCAT

ABCA1

UC

Hepatic lipase, endothelial lipase

PL&UC

SR-BI

SR-A

CETP

LDLReceptor

Macrophage

Oxidation

VLDL/LDL

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.

Adapted with permission from Cuchel C et al. Arterioscler Thromb Vasc Biol. 2003;23:1710–1712

clinical hypercholesterolaemia
Clinical Hypercholesterolaemia

Condition Features

Secondary Relatively uncommon, but potent

(hypothyroidism, nephrotic syndrome,

primary biliary cirrhosis)

Polygenic Accounts for the majority of cases

Familial Prevalent, Accelerates CVD.

Hyperchol’aemia Due to defects in genes related to LDL-R

Familial Overproduction of apo B lipoproteins

Combined H/L TG and TC vary with age and weight

Increased HDL ?OK if LDL not raised?

therapy for hypercholesterolaemia
Therapy for Hypercholesterolaemia

Intervention Features

Diet Plant sterols, avoid sat & trans FA

Manage 2o causes Rarer, but potent: (Thyroid, liver,

renal.)

Statins First line for LDL reduction

Ezetimibe 2nd line. Neutral for TG & HDL

Niacin Improves LDL, TG, HDL & Lp(a)

Bile acid resins Colesevalam better tolerated

Future PCSK9 Inhibitors, MTP inhibitors?

Apo B antisense oligonucleotides

triglyceride and cholesterol why are they linked
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

key regulators of genes in fatty acid and triglyceride metabolism

SHP

LXR

PPAR

RXR

Key Regulators of Genes in Fatty Acid and Triglyceride Metabolism

Bile Acids

SHP = Short Heterodimer Partner

SREBP-1c

FXR

Acetyl CoA Carboxylase Fatty Acid Synthase Spot 14

Acyl CoA

NEFA

Unsaturated

Saturated

HNF-4α

L-FABP

Fatty acid metabolism

Transport Oxidation Fatty Acid Binding Protein Ketogenesis

Apolipoproteins Pyruvatekinase Glucose-6-phosphalase Transferin Bile Acids

Adapted from Pegorier JP et al. J Nutr 2004;134:2444S-9S

key regulators of genes in lipid metabolism
Key Regulators of Genes in Lipid Metabolism

Sterol Regulatory Element Binding Protein (SREBP2)

Peroxisome proliferated activator receptors PPARs

Synthesis

Delivery

Acquisition

Cellular Cholesterol Homeostasis

Excretion

Intestine

Hepatobiliary

Liver X Receptor (LXR)

Farnesoid X Receptor (FXR)

slide24

Case MC

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/L Triglyceride: 2.8 mmol/LHDL-C: 0.7 mmol/L LDL-C: 3.6 mmol/L

He has managed to lose 3 kg and today results include:

Total Cholesterol: 6.9 mmol/L Triglyceride: 1.8 mmol/L HDL-C: 0.8 mmol/L LDL-C: 5.2 mmol/L

questions concerning mr m c
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) Polygencdyslipidamia
      • C) Familial Combined Hyperlipidaemia
      • D) Familial Hypercholesterolaemia
      • E) Lipids aren’t really an issue in this patient
slide26

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

  • 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) Polygencdyslipidamia
      • C) Familial Combined Hyperlipidaemia
      • D) Familial Hypercholesterolaemia
      • E) Lipids aren’t really an issue in this patient
slide28
Is ethnicity an independent risk factor for CVD? Case for a qualified “Yes”.Same risk factors, different pattern

 INTERHEART, Karthikeyan et al 2009,

INTERHEART, Joshi et al 2007

slide29
2) In the absence of any symptoms or signs of hypothyroidism, would you perform thyroid function tests? Yes / No?

Yes:

No:

slide30
2) In the absence of any symptoms or signs of hypothyroidism, would you perform thyroid function tests? The case for “Yes”
what is the most likely cause of mc s lipid abnormality
What is the most likely cause of MC’s lipid abnormality?
  • A) Dyslipidaemia secondary to Insulin resistance and the Metabolic Syndrome
  • B) Polygencdyslipidamia
  • C) Familial Combined Hyperlipidaemia
  • D) Familial Hypercholesterolaemia
  • E) Lipids aren’t really an issue in this patient
what is the most likely cause of mc s lipid abnormality the case for c maybe a or b
What is the most likely cause of MC’s lipid abnormality? The case for “C”, maybe “A” or “B”

Condition Features

Secondary Relatively uncommon, but potent

(hypothyroidism, nephrotic syndrome,

primary biliary cirrhosis)

Polygenic Accounts for the majority of cases

Familial Prevalent, Accelerates CVD.

Hyperchol’aemia Due to defects in genes related to LDL-R

Familial Overproduction of apo B lipoproteins

Combined H/L TG and TC vary with age and weight

Increased HDL ?OK if LDL not raised?

slide33

Case MC (continued)

  • 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
slide34

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?
  • Ezetimibe
  • Niacin
  • I would increase Atorvastatin to 80 mg but I wouldn’t give anything other than a statin
  • Fenofibrate
  • Fish Oil
slide35

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
  • 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?
  • Ezetimibe b) Niacin c) Increase Atorvastatin to 80 mg but don’t give anything other than a statin
  • d) Fenofibrate e) Fish Oil
slide37

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

M Gheorghiade et al Circulation.2002; 106: 394-398

slide39

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

slide41

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.

slide42

What is the next lipid-lowering drug that you would add to his therapy?

  • Ezetimibe
  • Niacin
  • I would increase Atorvastatin to 80 mg but I wouldn’t give anything other than a statin
  • Fenofibrate
  • Fish Oil
slide43

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

slide44

Case GS

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

slide45

Case GS

      • 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
slide46

Questions:

  • How could you obtain an LDL-C result?
  • Friedewald equation
  • Abusive phonecall to lab
  • “Direct method” involving detergents
  • Ultracentifugation
  • Subtract HDL-C from Total cholesterol
  • Which class or classes of lipoproteins would you expect to be increased?
  • Chylomicrons and LDL
  • VLDL and LDL
  • VLDL and HDL
  • IDL and chylmicron “remnants”
  • Why bother? It doesn’t matter Which combination of extra tests would be most useful?
  • a) LDL size+HDLsubfractions b) Lipid EPG+ApoEphenotype c) LDL subfractions HDL size d) Lp(a)+ homocysteine
  • e) Routine fasting lipids are the only lipid tests that are ever required
slide47

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/L HDL-C: 1.0mmol/L LDL-C:3.6 mmol/L Now 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
  • 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?
slide48

How could you obtain an LDL-C result?

  • Friedewald equation
  • Abusive phonecall to lab
  • “Direct method” involving detergents
  • Ultracentifugation
  • Subtract HDL-C from Total cholesterol
slide49

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 significantly

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

slide50

Which class or classes of lipoproteins would you expect to be increased?

  • Chylomicrons and LDL
  • VLDL and LDL
  • VLDL and HDL
  • IDL and chylmicron “remnants”
  • Why bother? It doesn’t matter
slide51

Which class or classes of lipoproteins would you expect to be increased?

  • The case for “b”(orange) or “d” (green)
which combination of extra tests would be most useful
Which combination of extra tests would be most useful?
  • a) LDL size+HDLsubfractions
  • 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
which combination of extra tests would be most useful the case for b
Which combination of extra tests would be most useful?The case for “b”

CM βpreβα

ApoEisoforms

slide54

Case GS (continued)

  • 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

slide55

Questions

This implies the accumulation of which lipoprotein class(es)?

a) VLDL + LDL b) 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

slide56

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

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?

slide57

This implies the accumulation of which lipoprotein class(es)?

a) VLDL + LDL

b) IDL and Chylomicron “remnants”

slide59

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

slide61

Which lipid-lowering therapy is strongly CONTRAindicated?

a) Simvastatin

b) Nicotinic Acid

c) Questran

d) Fibrate

e) Fish oil

f) Ezetimibe

slide62

MDRP2/3

Which lipid-lowering therapy is strongly CONTRAindicated? The case for “c”

Hepatocyte

Heterodimerization with RXR

Acetyl CoA

SREPB-1c

Bile Duct

FA, TG

FXR

VLDL (TG levels)

Phospholipids

slide64
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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