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 SolvingExperience / 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 Molecules2. The Key Particles3. Our Common Enemy4. The Risk Factors5. How the Cholesterol Processing

System Works – High Level6. 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 CargoTrigylceride/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

Chylomicron100 to 1000nm

sdLDL<25nm

VLDL is made in the liver to ferry Trigs and Chol…

Small Dense LDL is the real “BAD Cholesterol”

HDL5-15nm

LDL>26nm

VLDL30 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:

+ ChCh Ch

Macrophage

=FOAM CELL

The Million Dollar Question: What mediates this inflammatory process?

TgChChCh

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

CardiovascularDeath

Incr

ease

d R

isk

Incr

ease

d R

isk

Ischemic HeartDisease 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 CAUSEDEATH….

Incr

ease

d R

isk

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

Ris

k o

f H

ear

t D

ise

ase

aft

er

4 Y

ear

s

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

Ris

k o

f H

ear

t D

ise

ase

aft

er

4 Y

ear

s

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

Assmann G, Schulte H. Am J Cardiol. 1992;70:733–737.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 NorfolkKay-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!)

The Lipoprotein Particles – Boats for CargoTrigylceride/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

Chylomicron100 to 1000nm

sdLDL<25nm

VLDL is made in the liver to ferry Trigs and Chol…

Small Dense LDL is the real “BAD Cholesterol”

HDL5-15nm

LDL>26nm

VLDL30 to 80nm


CHYLOMICRON: for dietary Fat and Chol

DietaryFats

Triglycerides

Cholesterol

CHYLOMICRONB48

TgTgChTgTgTg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

TgCh

Tg Tg Tg



DietaryFats

Triglycerides

Cholesterol

E

C II

CHYLOMICRONB48

TgTgChTgTgTg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

CHYLOMICRONB48

TgTgChTgTgTg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

TgCh

Tg Tg Tg



DietaryFats

Triglycerides

Cholesterol

E

C II

CHYLOMICRONB48

TgTgChTgTgTg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

CHYLOMICRONB48

TgTgChTgTgTg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

B48CHYLO REMNANT

Ch TgTg TgE

Ch

Tg Tg Tg



DietaryFats

Triglycerides

Cholesterol

E

C II

CHYLOMICRONB48

TgTgChTgTgTg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

CHYLOMICRONB48

TgTgChTgTgTg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

B48CHYLO REMNANT

Ch TgTg TgELDLR

SR-B1

Ch

Tg Tg Tg



DietaryFats

Triglycerides

Cholesterol

E

C II

CHYLOMICRONB48

TgTgChTgTgTg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

CHYLOMICRONB48

TgTgChTgTgTg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

Tg

B48CHYLO 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

VLDLTg

Tg

Tg

Tg

Tg

Tg

Tg

TgChCh

ChCh

E

C II

B100

SR-B1Ch

Ch

Ch



C II

LDLR

C II

LPL

VLDLTg

Tg

Tg

Tg

Tg

Tg

Tg

TgChCh

ChCh

E

C II

B100

SR-B1Ch

Ch

Ch



C II

LDLR

C II

LPL

VLDLTg

Tg

Tg

Tg

Tg

Tg

Tg

TgChCh

ChCh

E

C II

B100

IDLTgTg

TgChCh

ChCh

E

B100

SR-B1Ch

Ch

Ch



C II

LDLR

C II

LPL

VLDLTg

Tg

Tg

Tg

Tg

Tg

Tg

TgChCh

ChCh

E

C II

B100

IDLTgTg

TgChCh

ChCh

E

B100

SR-B1

HL

Ch

Ch

Ch

HSLXXX

Tg

Tg



C II

LDLR

C II

LPL

VLDLTg

Tg

Tg

Tg

Tg

Tg

Tg

TgChCh

ChCh

E

C II

B100

IDLTgTg

TgChCh

ChCh

E

B100

TgChChCh

B100 LDL

SR-B1

HL

Ch

Ch

Ch

HSLXXX

Tg

Tg



C II

LDLR

C II

LPL

VLDLTg

Tg

Tg

Tg

Tg

Tg

Tg

TgChCh

ChCh

E

C II

B100

IDLTgTg

TgChCh

ChCh

E

B100

TgChChCh

B100 LDL

SR-B1

HL

Ch

Ch

Ch

HSLXXX

Ch

Tg

Tg

ChTo tissues and cells



C II

LDLR

C II

LPL

VLDLTg

Tg

Tg

Tg

Tg

Tg

Tg

TgChCh

ChCh

E

C II

B100

IDLTgTg

TgChCh

ChCh

E

B100

TgChChCh

B100 LDL

SR-B1

HL

Ch

Ch

Ch

HSLXXX

Ch

To tissues and cells

Tg

Tg

Ch



C II

LDLR

C II

LPL

VLDLTg

Tg

Tg

Tg

Tg

Tg

Tg

TgChCh

ChCh

E

C II

B100

IDLTgTg

TgChCh

ChCh

E

B100

TgChChCh

B100 LDL

SR-B1

TgChChCh

B100 LDLSD

HL

HL

Ch

Ch

Ch

HSLXXX

Ch

Tg

Tg

TgCh

TgChChCh

B100 LDLOX

To tissues and cells2013 Ivor Cummins BE(Chem) MIEI


C II

LDLR

C II

LPL

VLDLTg

Tg

Tg

Tg

Tg

Tg

Tg

TgChCh

ChCh

E

C II

B100

IDLTgTg

TgChCh

ChCh

E

B100

TgChChCh

B100 LDL

SR-B1

TgChChCh

B100 LDLSD

HL

HL

Ch

Ch

Ch

ChCh Ch

IMMUNE SYSTEM MACROPHAGE / FOAM CELL

HSLXXX

Ch

Tg

Tg

TgCh

TgChChCh

B100 LDLOX

To tissues and cells2013 Ivor Cummins BE(Chem) MIEI

VLDL to LDL SummaryVLDL 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-B1Ch

Ch

Ch

Ch

A HDLTg

E



LDLR

SR-B1Ch

Ch

Ch

Ch

A HDLTg

E

Ch Adrenal Cortex and Gonads



LDLR

SR-B1Ch

Ch

Ch

Ch

A HDLTg

E


Ch

From tissues and cells

ABC A1ABC G1

LCAT



LDLR

SR-B1Ch

Ch

Ch

Ch

A HDLTg

E


ChABC A1ABC G1

LCAT

ChCh Ch


ABC A1ABC G1




LDLR

SR-B1Ch

Ch

Ch

ChCh Ch


Ch

A HDLTg

ECh

ABC A1ABC G1

LCAT

LCAT

ABC A1ABC G1




+ Antioxidant Agents….!


LDLR

VLDLTg

Tg

Tg

Tg

Tg

Tg

Tg

TgChCh

ChCh

E

C II

B100

TgChChCh

B100 LDL

SR-B1Ch

Ch

Ch

ChCh Ch


Ch

A HDLTg

ECh

ABC A1ABC G1

LCAT

LCAT

Ch

Ch

Tg

Tg

ABC A1ABC G1




+ 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 Ratio

Tot C

ho

lesterol/H

DL


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 onatherogenic dyslipidemia1–3Ronald 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



Ap

o B

/ Ap

o A

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

Even during the starvation period, Low Fat regime fails

Improving the Serum Triglyceride Level

Trig Red

uctio

n


Serum Triglyceride –important to keep this down





Low Carb far exceeds benefits of low fat regime –even with NO dieting

Improving LDL Particle DiameterLD

L Pa

rtic

le D

iam

eter


LDL Particle Diameter is a serious metric


Low Carb far exceeds benefits of low fat regime, especially if you don’t diet

Even during the starvation period, Low Fat regime struggles



Improving HDL LevelsH

DL

“go

od

” C

ho

l


HDL – the higher the better


Low Carb far exceeds 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-AdaptationGoogle the Youtube video of this – it’s superb

Driving Risk Factors: Where are you?Disease Risk

MarkerHigh CarbLow Fat

Low Carb /High Fat*

Is Lean / FitKcal Control / active

Carb Tolerant(~30% of people?)

Is Not Lean / Is Not FitHigh Kcal / Sedentary

Carb Intolerant(~70% of people?)

Enables:Lean / Fit

Kcal Control / ActiveHealth 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

Education

Transcript of The Cholesterol Conundrum DRAFT