The Cholesterol Conundrum DRAFT

The Cholesterol Conundrum
What does the Latest Science Say?
Ivor Cummins BE (Chem)
March 21st 2014
2013 Ivor Cummins BE(Chem) MIEI

Why are we in this room today
- How does this come about?
Academic /
Educational History
Problem Solving
Experience / Aptitude

Quick Update from my last Seminar
At last, The unbiased experts
are stepping up to the plate:
• Six teaspoons max in 24 hours?
• That’s less than a single can of
your favorite sugary beverage, and
assumes NO other sugar for the
rest of the day?
• Looks like the Emperor’s suit is
getting frayed…..
• Gloves off lads, better pour some
money into the lobbying chest, and
shut this thing down quick

1. The Key Molecules
2. The Key Particles
3. Our Common Enemy
4. The Risk Factors
5. How the Cholesterol Processing
System Works – High Level
6. The $1M Question – What Drives up
the Risk Factors?
The Conundrum Content:

1. The Key Molecules

Cholesterol and Triglyceride
• Cholesterol is a Sterol Molecule that is used to build
cells, hormones and other core physiological elements
• Is critical, and fundamental for life to exist
• Is a key element of your bodies damage repair system
• Is a precursor to the synthesis of Vitamin D, which in
turn is one of the most important agents for mortality
deferral – we’ll look at this later….
• Finally, cholesterol generally gets blamed for disease
pretty much as a paramedic on the scene might be
blamed for the car crash
Cholesterol – for Life Itself
• Triglyceride (aka Triacylglycerol) is a form of fat
• Is three Fatty Acids on a glycerol (sugar-like) backbone
• Enters the body via fat-containing food
• Is also synthesized by the body (neolipogenisis) for
various reasons
• Can be good or bad: depends on source, location and
quantity….
Trigylceride – for Energy

2. The Key Particles

The Lipoprotein Particles – Boats for Cargo
Trigylceride/
Cholesterol
An Apo-
Lipoprotein
Phospholipids  The LIPOPROTEIN PARTICLES are transport vessels
(“boats”) created in the body to deliver
Triglyceride and Cholesterol (“cargo”), for energy
transfer, critical synthesis, and healing purposes….
 HDL is the so-called “GOOD Cholesterol”
 LDL (from VLDL) is the so-called “BAD Cholesterol”
 The Chylomicron is the big one, created to ferry
dietary fat and cholesterol, for energy and healing
Chylomicron
100 to 1000nm
sdLDL
<25nm
 VLDL is made in the liver to ferry Trigs and Chol…
 Small Dense LDL is the real “BAD Cholesterol”
HDL
5-15nm
LDL
>26nm
VLDL
30 to 80nm

And now, a word from
our Sponsor…..

3. Our Common Enemy

Atherosclerosis and CVD Mechanism
 Ingress of Lipoprotein Particles through Endothelium (inner wall)
 Uptake of these by immune system Macrophage
 Subsequent transformation into “Foam Cells” and buildup of Plaque
 Ultimately a decline in vascular health, then breakouts, blockages…..
The Disease Sequence:
+ Ch
Ch Ch
Macrophage
=
FOAM CELL
 The Million Dollar Question: What mediates this inflammatory process?
TgCh
ChCh
B100

4. The Risk Factors

Key Predictors of Mortality
– Dysfunctional Lipoprotein Status
• LDL/HDL Ratio
• Serum Triglyceride Levels
• Small Dense LDL and associated LDL Particle COUNT
– Insulin Levels and Insulin Resistance Status
– Blood Glucose Level and HbA1C
– High Blood Pressure (generally driven by the
above scenarios)
– Other markers of Systemic Inflammation

Total Cholesterol as a predictive factor?
Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the
Norwegian HUNT 2 study (>58,000 Participants)
Halfdan Petursson MD,1 Johann A. Sigurdsson MD Dr med,2 Calle Bengtsson MD Dr med,3
Tom I. L. Nilsen Dr Philos4 and Linn Getz MD PhD5
Cardiovascular
Death
IncreasedRisk
IncreasedRisk
Ischemic Heart
Disease Death

Total Cholesterol as a predictive factor?
Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the
Norwegian HUNT 2 study (>58,000 Participants)
Halfdan Petursson MD,1 Johann A. Sigurdsson MD Dr med,2 Calle Bengtsson MD Dr med,3
Tom I. L. Nilsen Dr Philos4 and Linn Getz MD PhD5
 Age Confounding is a serious issue
 US Versus Other Geographies is an issue
 Diagnosing via Total Cholesterol no
longer supported by the science
ALL CAUSE
DEATH….
IncreasedRisk
Key Takeaways:
 Total Cholesterol effectively not
considered any more by leading edge
researchers
 Economics / Hubris retain bad science

LDL-C & HDL-C as predictive factors?
Diagram adapted from article in Journal of Cardiovascular Medicine 2011, Vol 00, No 00
2.58 4.13 5.68
HDL=0.65
HDL = 1.16
HDL = 1.68
HDL = 2.20
RiskofHeartDiseaseafter4Years
LDL (the “Bad Cholesterol”)
 HDL being adequate/higher is VERY important
 The benefit of LDL being low………depends on the HDL status
 Risk is determined primarily by the RATIO of these parameters
 Diagnosing via LDL is minimally useful in the face of the current science
Heart Disease Risk Vs LDL & HDL
Data from the Framingham Heart Study showing incidence of CAD over 4 years in men 50-70 years old

LDL-C & HDL-C as predictive factors?
Diagram adapted from article in Journal of Cardiovascular Medicine 2011, Vol 00, No 00
2.58 4.13 5.68
HDL=0.65
HDL = 1.16
HDL = 1.68
HDL = 2.20
RiskofHeartDiseaseafter4Years
LDL (the “Bad Cholesterol”)
 HDL being adequate/higher is VERY important
 The benefit of LDL being low………depends on the HDL status
 Risk is determined primarily by the RATIO of these parameters
 Diagnosing via LDL is minimally useful in the face of the current science
Heart Disease Risk Vs LDL & HDL
Data from the Framingham Heart Study showing incidence of CAD over 4 years in men 50-70 years old
XXX
Guess Who?

SERUM TRIGLYCERIDE as a Predictive Factor
Assmann G, Schulte H. Am J Cardiol. 1992;70:733–737.
Data from the PROCAM Munster Study
 Blood Triglyceride Levels are an important Risk Factor for Coronary Disease
 However, they should not be judged alone – vital to balance with other factors
 Again we see the importance of LDL/HDL Ratios and interactions with Trigs
Key Takeaways:

SERUM INSULIN as a Predictive Factor
Data from the PROCAM Munster Study (from "Interesting slideset around…):
 Insulin is fundamental to Coronary Disease and Mortality Risk
 Insulin has been grossly underemphasized as a risk factor for decades
 Triglyceride risk outgunned by Insulin Status here
Key Takeaways:
Data from the Quebec Study Cardiovascular Study:
Despres JP, et al. N Engl J Med. 1996;334:952-957.

Data taken from Table 2: Association of Hemoglobin A1c with Cardiovascular Disease and Mortality in
Adults: The European Prospective Investigation into Cancer in Norfolk
Kay-Tee Khaw, MBBChir, FRCP; Nicholas Wareham, MBBS, FRCP; Sheila Bingham, PhD; Robert Luben, BSc; Ailsa Welch, BSc;
and Nicholas Day, PhD
Glucose Levels Anyone? - HbA1c as a Risk Factor
 HbA1c is the alteration of Red Blood Cells driven by blood glucose levels
 This again is closely related to Insulin & Insulin Resistance Status
 HbA1c from this particular study is also an independent risk factor
Key Takeaways:

SERUM INSULIN and LDL Particle Count
Data from the Quebec Study Cardiovascular Study:
 Again Insulin is key, but significant interaction with LDL Particle Count (ApoB)
 LDL Particle Count tracks with Small Dense LDL – I’ll explain this shortly!
 Interaction is the operative word – synergy closely follows
Key Takeaways:
Lamarche B, et al. Circulation. 1997;95:69-75.

Small Dense LDL as a Predictive Factor
 Small Dense LDL and associated LDL Particle Count are Key
 These, along with Insulin / Insulin Resistance Status, are Master Markers
 So Let’s look at how it all works, shall we?
Key Takeaways:
Reprinted from St-Pierre AC, et al. Circulation. 2001;104:
2295–2299, with permission from Wolters Kluwer Health.

4. How the Cholesterol
Processing System
Works - High Level
(Hope appreciate the artwork here,
it took me a while!)

CHYLOMICRON: for dietary Fat and Chol
Dietary
Fats
Triglycerides
Cholesterol
CHYLOMICRON
B48
TgTgCh
TgTgTg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
TgCh
Tg Tg Tg

Dietary
Fats
Triglycerides
Cholesterol
E
C II
CHYLOMICRON
B48
TgTgCh
TgTgTg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
CHYLOMICRON
B48
TgTgCh
TgTgTg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
TgCh
Tg Tg Tg

Dietary
Fats
Triglycerides
Cholesterol
E
C II
CHYLOMICRON
B48
TgTgCh
TgTgTg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
CHYLOMICRON
B48
TgTgCh
TgTgTg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
B48 CHYLO REMNANT
Ch TgTg TgE
Ch
Tg Tg Tg

Dietary
Fats
Triglycerides
Cholesterol
E
C II
CHYLOMICRON
B48
TgTgCh
TgTgTg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
CHYLOMICRON
B48
TgTgCh
TgTgTg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
B48 CHYLO REMNANT
Ch TgTg TgELDLR
SR-B1
Ch
Tg Tg Tg

Dietary
Fats
Triglycerides
Cholesterol
E
C II
CHYLOMICRON
B48
TgTgCh
TgTgTg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
CHYLOMICRON
B48
TgTgCh
TgTgTg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
B48 CHYLO REMNANT
Ch TgTg TgE
Ch
Ch
Ch
LDLR
SR-B1
Ch
Tg Tg Tg

Chylomicron Summary
Dietary Fat and Cholesterol is packaged into the
Large Chylomicrons (100-1000nm)
The latter deliver Triglyceride Molecules For
Energy Use in the Heart / Skeletal Muscles
Following this energy transfer, the Chylomicron
remnants have a short half-life of ~20min in the
bloodstream, and are readily taken up by the liver,
thus completing the cycle
However, the latter description assumes moderate
carbohydrate ingestion and insulin secretion….high
carb will spike insulin, suppress Triglyceride utilization,
and increase remnant residence time….

VLDL, IDL,LDL…..and Small Dense LDL
LDLR
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
SR-B1
Ch
Ch
Ch

C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
SR-B1
Ch
Ch
Ch

C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
SR-B1
Ch
Ch
Ch

C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
SR-B1
HL
Ch
Ch
Ch
HSL
XXX
Tg
Tg

C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
TgCh
ChCh
B100
LDL
SR-B1
HL
Ch
Ch
Ch
HSL
XXX
Tg
Tg

C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
TgCh
ChCh
B100
LDL
SR-B1
HL
Ch
Ch
Ch
HSL
XXX
Ch
Tg
Tg
Ch
To tissues and cells

C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
TgCh
ChCh
B100
LDL
SR-B1
HL
Ch
Ch
Ch
HSL
XXX
Ch
Tg
Tg
Ch

C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
TgCh
ChCh
B100
LDL
SR-B1
TgCh
ChCh
B100
LDL
SD
HL
HL
Ch
Ch
Ch
HSL
XXX
Ch
Tg
Tg
Tg
Ch
TgCh
ChCh
B100
LDL
OX

C II
LDLR
C II
LPL
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
IDL
TgTg
Tg
Ch
Ch
Ch
Ch
E
B100
TgCh
ChCh
B100
LDL
SR-B1
TgCh
ChCh
B100
LDL
SD
HL
HL
Ch
Ch
Ch
Ch
Ch Ch
IMMUNE SYSTEM
MACROPHAGE / FOAM CELL
HSL
XXX
Ch
Tg
Tg
Tg
Ch
TgCh
ChCh
B100
LDL
OX

VLDL to LDL Summary
VLDL is produced by the liver to transport Triglyceride
cargo for energy uses, and Cholesterol for building tasks
As Triglyceride is depleted, Apo CII is shed and the
VLDL becomes an IDL; further depletion and shedding
of Apo E results in an LDL particle with Apo B100 only
LDL should deliver cholesterol and ideally be taken up
by the liver receptors before it becomes sdLDL or is
oxidized (bad boats, increasing numbers, more risk!)
Oxidised LDL reduces takeup by liver – and enhances
takeup by macrophage – inflammation and the disease
process is augmented

HDL…..and Reverse Cholesterol Transport
LDLR
SR-B1
Ch
Ch
Ch
Ch
A
HDL
Tg
E

LDLR
SR-B1
Ch
Ch
Ch
Ch
A
HDL
Tg
E
Ch Adrenal Cortex and
Gonads

LDLR
SR-B1
Ch
Ch
Ch
Ch
A
HDL
Tg
E
Gonads
Ch
From tissues and cells
ABC A1
ABC G1
LCAT

LDLR
SR-B1
Ch
Ch
Ch
Ch
A
HDL
Tg
E
Gonads
Ch
ABC A1
ABC G1
LCAT
Ch
Ch Ch
IMMUNE SYSTEM
ABC A1
ABC G1

LDLR
SR-B1
Ch
Ch
Ch
Ch
Ch Ch
IMMUNE SYSTEM
Ch
A
HDL
Tg
E
Ch
ABC A1
ABC G1
LCAT
LCAT
ABC A1
ABC G1
Gonads
+ Antioxidant
Agents….!

LDLR
VLDL
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Tg
Ch
Ch
Ch
Ch
E
C II
B100
TgCh
ChCh
B100
LDL
SR-B1
Ch
Ch
Ch
Ch
Ch Ch
IMMUNE SYSTEM
Ch
A
HDL
Tg
E
Ch
ABC A1
ABC G1
LCAT
LCAT
Ch
Ch
Tg
Tg
ABC A1
ABC G1
Gonads
+ Antioxidant
Agents….!

HDL Summary
HDL has many functions, one of which is to
remove Cholesterol excess from problematic areas
Low / dysfunctional HDL relative ratios generally track
with high blood triglyceride, higher sdLDL and higher
inflammatory status
Thus the various risk factors are connected and
synergistic – and have common drivers
We’ll see how to influence HDL health shortly – and it’s
not as hard as you might think!
HDL’s other key role is in moderating oxidation in
general, and of LDL specifically

6. The $1M Question –
What Primarily
Drives up the Risk
Factors???

Improving the Total Chol / HDL RatioTotCholesterol/HDL
 Tot Chol / HDL is a good
metric
 Increasingly Lower Carb
delivers dose-response
increased improvement
 Low Carb exceeds benefits of
low fat regime – even with
NO dieting
 Even during the starvation
period, Low Fat regime
struggles
Separate effects of reduced carbohydrate intake and weight loss on
atherogenic dyslipidemia1–3
Ronald M Krauss, Patricia J Blanche, Robin S Rawlings, Harriett S Fernstrom, and Paul T Williams
Data adapted from from Jeff Volek Summary of:

Improving the LDL / HDL Particle Ratio
ApoB/ApoA
 LDL / HDL key (here we have
even better metric – the
particle COUNT ratio)
 Low Carb far exceeds
benefits of low fat regime –
even with NO dieting
period, Low Fat regime fails

Improving the Serum Triglyceride Level
TrigReduction
 Serum Triglyceride –
important to keep this down
benefits of low fat regime –
even with NO dieting

Improving LDL Particle DiameterLDLParticleDiameter
 LDL Particle Diameter is a
serious metric
benefits of low fat regime,
especially if you don’t diet
period, Low Fat regime
struggles

Improving HDL LevelsHDL“good”Chol
 HDL – the higher the better
benefits of low fat regime,
again even with no dieting

Another Recent Trial
xxxxx.
 ALL markers better with Low Carb regime – including all Inflammation
 Only Low Carb enhances HDL, improves small LDL, and ApoB/ApoA ratio
 Scientifically this appears to be a fundamental rule, but rigorously challenged?

For ref....
Another of Many….
 ALL markers better with Low Carb regime – including all Inflammation
 Only Low Carb enhances HDL, though low GI has a go (!)
 Scientifically this appears to be a fundamental rule, but rigorously challenged?

Moderate
High
Metabolically
Compromised/obese
Athletes
Naturally lean
Overweight/obeseSlide from:
Jeff Volek - The Many Facets of
Keto-Adaptation
Google the Youtube video of
this – it’s superb

Driving Risk Factors: Where are you?
Disease Risk
Marker
High Carb
Low Fat
Low Carb /
High Fat*
Is Lean / Fit
Kcal Control / active
Carb Tolerant
(~30% of people?)
Is Not Lean / Is Not Fit
High Kcal / Sedentary
Carb Intolerant
(~70% of people?)
Enables:
Lean / Fit
Kcal Control / Active
Health and Wellbeing
Visceral Fat: Waist+
HDL
Tot Chol / HDL
Serum Glucose
Serum Insulin
Blood Pressure
Serum Triglyceride
Blood Pressure
Visceral Fat
LDL **
* Following Metabolic Adaptation period of 3 weeks to 2 months
** Not a primary marker, particularly requires analysis of other factors to interpret

Fundamental Truth
• To successfully gain excellent health and years of
extra life, I believe that you must actually
understand this science to a reasonable degree,
not just “follow the diet”. To achieve this
understanding will likely be the best thing you
ever do for yourself.
• Also, everyone has a different genetic makeup,
and this must be understood also – it’s not one
size fits all – know your phenotype!
(but the key drivers do have much commonality)

THE CRITICAL BIOCHEMISTRY OF
VITAMIN D
• Content in this draft slidepack for latest
science on 25 Hydroxy Vitamin D and related
mortality statistics will follow …..

The Cholesterol Conundrum DRAFT

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