A 72-Year Metabolic Mystery Unfolds. The Cholesterol Times, Issue #005

[Guest guest]

Sat, 10 Sep 2005 06:55:07 UT

" Christopher Masterjohn "

<The_Cholesterol_Times

The Cholesterol Times, Issue #005 -- A 72-Year Metabolic

Mystery Unfolds

 

 

 

 

Research Watch

 

A 72-Year Metabolic Mystery Unfolds: Why Eating Cholesterol Doesn't

Raise Cholesterol Levels

 

In 1933, Rudolph Schoenheimer discovered the first evidence of a

biofeedback system where the end product of a synthetic pathway

inhibited that synthetic pathway, when he discovered that mice fed

large amounts of cholesterol made very little of it in their bodies,

while mice fed very small amounts of cholesterol made large amounts of

it in their bodies.

 

In the 1950s, Gordon Gould found that this system operated

specifically in the liver. A new study published in the Journal of

Clinical Investigation continues to unravel the intricate workings of

this biofeedback system.

 

Proteins called " sterol regulatory element-binding proteins " (SREBPs)

start out in the endoplasmic reticulum (ER), from which they are

transported by vesicles to the Golgi Complex, permitted by their

complexing to another protein called Scap. Once at the Golgi, SREBPs

are modified in a way that they can gain access to DNA in the nucleus

and stimulate the production of enzymes that synthesize cholesterol.

 

Yet when cholesterol concentrations rise, cholesterol binds to Scap,

which causes Scap to change shape and become bound to other ER

proteins called Insigs, which anchor Scap to the ER, so that the

Scap-SREBPs complex cannot leave to be transported to the Golgi. Thus,

cholesterol synthesis drops.

 

In addition, Insigs cause the degradation of HMG CoA-Reductase, an

enzyme involved in cholesterol synthesis-- the same enzyme inhibited

by cholesterol-lowering statin drugs. (See our flow chart.)

 

This study found that knocking out the genes for Insig 1 and Insig 2

in mice caused a dramatic decrease in the ability to regulate

cholesterol synthesis in response to diet.

 

Knocking out the Insig genes did not effect the level of SREBPs--

since Insigs are involved in anchoring them, not making them-- but

caused dramatic elevation of HMG CoA-reductase, as well as the RNA

that makes it-- since Insigs are involved in both its degradation and

the prevention of its synthesis. This led to an up to 6-fold increase

in liver triglycerides (fats), and a 15-fold increase in liver

cholesterol esters.

 

In the genetically altered mice, cholesterol synthesis did not alter

in response to cholesterol feeding. But in the normal mice,

cholesterol synthesis declined dramatically in response to feeding

cholesterol, so that the highest amount of cholesterol (1.5% of diet

by weight-- a massive amount), resulted in a 93% reduction in

cholesterol synthesis.

 

Brain cholesterol was not affected by diet whatsoever, either in the

control mice or the genetically altered mice. Even though the evidence

suggests that eating cholesterol has no effect on brain cholesterol,

if you've read our article debunking the myth that cholesterol causes

Alzheimer's Disease you're familar with the bogus idea that a

" brain-healthy " diet is one low in cholesterol.

 

Engelking et al., " Schoenheimer effect explained - feedback regulation

of cholesterol synthesis in mice mediated by Insig proteins, " J Clin

Invest. 2005 Sep;115(9):2489-98. Epub 2005 Aug 11.

 

Omega-3 Fatty Acids Are More Effective than Statins and Other Drugs at

Reducing Mortality and Heart disease

 

A review in the Archives of Internal Medicine looked at all of the

trials to date with lipid-lowering agents that studied a single

treatment, were randomized, controlled, involved followup, and

measured mortality data, and found that omega-3 fatty acids are more

protective than any drug out there, as well as the standard dietary

advice.

 

Omega-3 fatty acids reduced the risk of overall mortality by 23%,

compared to statins, which reduced the risk of overall mortality by

13%. Omega-3 fatty acids also beat statins for reducing cardiac

mortality specifically, 32% to 22%.

 

The review found that the older form of cholesterol-lowering drugs

called fibrates had no effect on overall mortality, but were

positively associated with non-cardiac mortality, and found " little

evidence " that dietary intervention reduced the risk of heart disease.

 

Interestingly, omega-3 fatty acids had no effect on cholesterol

levels. On average, they reduced cholesterol by 2% (inconsistently),

but some subsets of omega-3 trials found that they raise cholesterol

slightly. Yet they were much more effective (almost twice as much) at

reducing mortality than statins, which lowered cholesterol by 20% on

average.

 

Niacin, which reduced cholesterol by 11%, had only a

non-statistically-significant 4% reduction of overall mortality, with

an 81% lilihood of this correlation being due to chance. Fibrates

reduced cholesterol by 8%, but had no effect on mortality. Diet

reduced cholesterol by 10%, but had only a non-statistically

significant (likely to be due to chance) 3% reduction in mortality.

 

Quite clearly, the effect on mortality has no relationship whatsoever

to the effectiveness of cholesterol-lowering.

 

The meta-regression analysis indicated a " positive association of

fibrates with overall mortality. " Figure C, showing Mortality From

Causes Other Than Cardiovascular Diseases shows that diet, niacin,

resin, and fibrate trials tended to show more benefit to control

groups than those taking the treatment (meaning the treatment was

harmful), while only omega-3 fatty acids and statins favored the

treatment group (meaning the treatment was helpful).

 

Table 2 shows that trials were much less likely to show a positive

effect for statins when allocation of statins was blinded (about half

as likely), as well as when the patients and caregivers were blinded,

whereas omega-3 fatty acids were equally likely to show positive

effects regardless of whether allocation was blinded, and were more

than twice as likely to show benefit when the patients and caregivers

were blinded.

 

In trials where patients and caregivers were blinded, omega-3 fatty

acids reduced mortality by 41%, while statins reduced mortality by 13%.

 

By contrast, statins were more likely to be effective when outcome

assessors were blinded. Yet omega-3 fatty acids showed the same trend

to a greater degree, so that omega-3 fatty acids were shown to be

almost twice as protective as statins when outcome assessment was blinded.

 

On the other hand, a greater follow-up was associated with a better

outcome for statins and a lower outcome for omega-3s, though the

latter was still considerably more effective than the former.

 

On the whole, the trend is that higher-quality statin trials found

lower effectiveness, while higher-quality omega-3 trials found more

effectiveness.

 

This study not only shows that cholesterol-lowering treatments show no

relationship between their ability to lower cholesterol and their

ability to treat diseases, but also shows how unsound it is to fund a

$26 billion/year-- and rapidly growing-- statin industry, when much

more effective, safer, and wildly cheaper nutritional supplements are

available without a prescription, with other benefits, and without the

side effects.

 

Unfortunately, this study did not address the separation of

current-use, ever-use, former-use, and never-use for statin patients.

In Issue #003 I reported on a study that seemed to indicate that about

1/3 of statin users were dropping statins between one and three years

of use, probably because of side effects, and were suffering for this

short-term use of statins with a dramatically increased risk of

dementia. Therefore, simply looking at " statin use " is too vague a

category to tell us the truth about what is going on here, and whether

or not statins are damaging some people considerably despite helping

others.

 

Studer, et al., " Effect of different antilipidemic agents and diets on

mortality: a systematic review, " Arch Intern Med. 2005 Apr

11;165(7):725-30. Review.

 

Breaking News in Research

 

The following two studies were not yet available in full-text at the

time this newsletter was prepared. The information reported is based

on the abstracts only.

 

Cholesterol Kills Candida

 

Some oxygenated derivatives of cholesterol have been found to have

effective anti-fungal activity against the common pathogenic fungus

Candida albicans, which is now the fourth most common blood infection

in the United States, the organism responsible for thrush, vaginal

yeast infections, and many other health problems.

 

The highest activity was found with hydroxy-ketone 2, a cholesterol

derivative that exhibited high activity against candida, including

strains of candida that are resistant to the anti-fungal drugs

Amphotericine B and miconazole.

 

Brunel et al., " Synthesis and antifungal activity of oxygenated

cholesterol derivatives, " Steroids. 2005 Aug 31; [Epub ahead of print]

 

Chemical in Red Wine Lowers Heart Disease -- But Doesn't Lower Cholesterol

 

A study due to be published in October found that red wine,

dealcoholized red wine, and resveratrol, a chemical found in red wine,

effectively lowered paramaters of vascular disease in

hypercholesterolemic rabbits, without lowering cholesterol.

 

The rabbits-- which are, unlike humans, herbivorous animals-- were fed

a 1.5% cholesterol diet, which is equivalent to a human on a 2000

calorie diet eating 23 egg yolks per day, which produced

atherosclerotic lesions and reduced the flow-mediated dilation of

blood vessels by 25%.

 

Yet the feeding of red wine, dealcoholized red wine, or resveratrol

effectively reduced the size, density, and mean area of the

atherosclerotic placques and the thickness of the intima layer, and

completely abolished the reduction in flow-mediated dilation. These

changes were effected despite no reduction in cholesterol levels!

 

This study is yet one more showing that protection against heart

disease is simply not about lowering cholesterol levels.

 

Wang, et al, " Dealcoholized red wine containing known amounts of

resveratrol suppresses atherosclerosis in hypercholesterolemic rabbits

without affecting plasma lipid levels. " Int J Mol Med. 2005

Oct;16(4):533-40.

 

Weston A. Price Foundation Annual Conference

 

Conference Details

 

Friday, November 11, through Sunday, November 13, The Weston A. Price

Foundation will be holding its Sixth Annual Wise Traditions Conference.

 

Conferences in the past have featured Dr. Uffe Ravnskov's presentation

of his hypothesis that cholesterol protects against infectious

diseases, Dr. Kilmer McCully discussing his revolutionary work on

homocysteine, Dr. Russel Blaylock's presentation of his work on

excitotoxins, and many other excellent presentations.

 

This year's conference will feature social activities, workshops on

fertility awareness and fermentation of beverages, 2 main tracks on

heart disease and cancer, and a long list of featured speakers,

including Dr. John Cannell, President of the Vitamin D Council, and

Dr. Noel Solomons, Director of the CeSSIAM International Nutrition

Foundation.

 

For more information on the conference,

 

Travel and Lodging.

 

You can get a conference-related discount at the Westfield Marriot

where the conference is being held of $139/night for double, triple,

and quadruple occupancy by making reservations here.

 

If you need to make travel arrangements, we encourage you to use Price

Line, with which you can search for the cheapest price according to

your own specifications.

 

You can also use PriceLine for hotel accomodations if those at the

West Marriot are too pricey. Plus, you'll help

Cholesterol-And-Health.com by using the link below: