Monounsaturated Fats and CVD - The Final Nail?

[Guest guest]

Hi folks:

I am afraid this is gonna be a long post. But, in my (insufficiently modest)

opinion, it may be found to be well worth the time required to read it, perhaps

all the way to the end.

This post originates from material Jeff Novick unearthed, which seems to roundly

confirm the suspicions many of us here have had for quite some time .......

that, contrary to the widely accepted conventional wisdom, monounsaturated fats

(olive oil, for example) DO clog your arteries. Indeed, according to the first

paper below, monos clog arteries every bit as well as saturated fats.

These research results seem to lead to some inescapable and highly significant

conclusions .......... for example, that lard - yes LARD - may be less

unhealthy than olive oil.

If this sounds interesting, read on. If not then please ignore the rest of this

and go on to the next post : ^ )))

Here is source of the paper Jeff unearthed:

From: Journal of Clinical Lipidology (2009) 3, 303–314

'Discussion on dietary fat'

W. Virgil Brown, MD*, Wahida Karmally, RD, DrPH,

Penny Kris-Etherton, PhD, RD, Lawrence R. Rudel, PhD

FOR ME THE KEY EXCERPT FROM THIS PAPER IS THE FOLLOWING:

Dr. Rudel: " We began studies on monounsaturated fat after Fred Mattson and

Grundy initially questioned whether the fatty acid is neutral or is it really

good. From the studies that were done in the 1950s and 1960s with Keys and

Hegsted and others, it was thought monos were neutral, but you could substitute

polyunsaturated fats for

saturated and reduce total cholesterol and protect against coronary heart

disease. Monunsaturated fats were considered neutral as risk producers.

" Mattson and Grundy performed human experiments on lipoprotein changes and said,

well it's really not neutral, it lowers LDL as well as polyunsaturated fats but

it doesn't lower HDL. Therefore, it's probably just as good as polyunsaturated

fats based on a risk factor prediction from lipoprotein concentrations.

" So that paper raised a very important question. In Winston-Salem, we had

monkeys that we could study regarding dietary fat effects. We modeled a study in

primates using diets very similar to those of the Mattson and Grundy human

dietary studies. We used exactly the same oils they used in the veterans in San

Diego. And we got exactly the same effects on LDL and HDL. We lowered LDL

significantly with monounsaturated fats to same extent as we did with N-6

polyunsaturates. As expected, the LDL was highest on saturated fat feeding. As

in the humans, HDL was also lowered by polyunsaturated fat and was not lowered

by monounsaturates. The best LDL/HDL ratio was in the mono group. So we would

have predicted that the arteries would document that monos are the best dietary

fat.

" But when we looked at the coronary arteries, much to our surprise there was

just as much atherosclerosis in monounsaturated fat fed monkeys as there was in

saturated fat fed monkeys. And the only fat that seemed to protect was the

polyunsaturates. We didn't have a good explanation for that finding. So we

looked at the composition of the lipoproteins in plasma. We found that with the

monounsaturates, we had completely shifted the cholesteryl ester composition in

the LDLs to be very high in cholesteryl oleate. Then I remembered a comment from

an old friend, Kritchevsky, many years ago, when he came up to me in a

meeting and said ``cholesteryl oleate is atherogenic.'' I never understood why

he said that. But here in our study we found this strong correlation. The

assumption at the time was that cholesteryl oleate would be a tissue-derived

cholesteryl ester, whereas most of the plasma cholesteryl ester usually comes

from the plasma enzyme lecithin-cholesterol acyltransferase (ie, LCAT), where

the product is cholesteryl linoleate.

" We examined the liver from those monkeys and performed isolated liver perfusion

studies and made the striking observation that the correlation between coronary

artery atherosclerosis extent and the hepatic cholesteryl ester secretion rate

was r = 0.85. It was just ridiculously high.

" We concluded that the nature of the cholesterol ester secreted by the liver

seems to be really important. Further, the livers of the diet group that

secreted the most cholesteryl oleate were from the monounsaturated group. We now

know that the enzyme in the liver that's important is ACAT2, and ACAT2

specifically esterifies oleate to cholesterol and make cholesteryl oleate; it

gets secreted, accumulates in plasma, and it looks like it's associated with

more atherosclerosis. These days you can do the experiment with no ACAT2 through

use of genetically altered animals, ACAT2 knockout mice. The hypothesis that

reducing the cholesterol oleate production by the liver reduces atherogenesis

was confirmed in these animals. These animals on a high oleate diet had very

little plasma cholesteryl oleate and there was an 80% or so reduction in

atherosclerosis.

" You seem to have little risk of atherosclerosis if you take that enzyme away.

So it looks to me like monounsaturated fat in the liver offers some liability.

And that liability comes from the stimulation of cholesteryl esterification and

cholesteryl ester accumulation, which is secreted in very low-density

lipoprotein (ie, VLDL) particles, accumulates in LDL, giving a more atherogenic

plasma lipoprotein profile. It's deceptive because it does lower LDL cholesterol

concentration. It also leaves HDL cholesterol concentration higher, but it

changes the composition of the lipoproteins and for some reason or other, it

makes things much more atherogenic. "

-----------------------------------------------

Below I add a few additional papers on this topic also authored by Dr. Rudel.

Please note that I have not read the full texts of these. They are provided in

case someone wishes to investigate this issue further.

-----------------------------------------------

From: J Lipid Res. 2010 Feb 11.

Dietary n-3 LCPUFA from fish oil but not {alpha}-linolenic acid-derived LCPUFA

confers atheroprotection in mice.

Degirolamo C, Kelley KL, MD, Rudel LL.

Wake Forest University School of Medicine, United States.

Abstract

The atheroprotective potential of n-3 alpha-linolenic acid (ALA) has not yet

been fully determined, even in murine models of atherosclerosis. We tested

whether ALA-derived n-3 long chain polyunsaturated fatty acids (LCPUFA) could

offer atheroprotection in a dose-dependent manner. ApoB100/100LDLr -/- mice were

fed with diets containing two levels of ALA from flaxseed oil for 16 weeks. Fish

oil- and cis-monounsaturated fat-enriched diets were used as positive and

negative controls, respectively. The mice fed cis-monounsaturated fat and

ALA-enriched diets exhibited equivalent plasma total cholesterol (TPC) and LDL-c

levels; only mice fed the fish oil diet had lower TPC and LDL-c concentrations.

Plasma LDL-CE fatty acid composition analysis showed that ALA-enriched diets

lowered the percentage of atherogenic cholesteryl oleate compared to

cis-monounsaturated fat diet (44% vs. 55.6) but not as efficiently as fish oil

diet (32.4%). Although both ALA and fish oil diets equally enriched hepatic

phospholipids with eicosapentaenoic acid (EPA) and ALA-enriched diets lowered

hepatic CE levels compared to cis-monounsaturated fat diet, only fish oil

strongly protected from atherosclerosis. These outcomes indicate that dietary

n-3 LCPUFA from fish oil and n-3 LCPUFA (mostly EPA) synthesized endogenously

from ALA were not equally atheroprotective in these mice.

PMID: 20154006. Free Article

---------------------------------

From: Lipid Res. 2009 Apr;50 Suppl:S434-9. Epub 2008 Nov 22.

" LDL cholesteryl oleate as a predictor for atherosclerosis: evidence from human

and animal studies on dietary fat. "

Degirolamo C, Shelness GS, Rudel LL.

Department of Pathology, Section on Lipid Sciences, Wake Forest University

School of Medicine, Winston-Salem NC 27157, USA.

Abstract

This review focuses on the relationships among dietary fat type, plasma and

liver lipid, and lipoprotein metabolism and atherosclerosis. Dietary

polyunsaturated fatty acids are beneficial for the prevention of coronary artery

atherosclerosis. By contrast, dietary monounsaturated fatty acids appear to

alter hepatic lipoprotein metabolism, promote cholesteryl oleate accumulation,

and confer atherogenic properties to lipoproteins as shown in data from

experimental animal studies. Polyunsaturated fat appears to provide

atheroprotection, at least in part, because it limits the accumulation of

cholesteryl oleate in favor of cholesteryl linoleate in plasma lipoproteins.

PMID: 19029117. PMCID: PMC2674687. Free PMC Article

---------------------

From: Curr Atheroscler Rep. 2007 Dec;9(6):494-500.

" Monounsaturated fatty acids and atherosclerosis: opposing views from

epidemiology and experimental animal models. "

Brown JM, Shelness GS, Rudel LL.

Wake Forest University School of Medicine, Medical Center Boulevard,

Winston-Salem, NC 27157-1040, USA.

Abstract

A substantial body of epidemiologic data has shed light on the potential

protective effects of the Mediterranean diet against atherosclerosis in humans.

Many believe the reason the Mediterranean diet is atheroprotective is the

elevated consumption of olive oil, an oil poor in saturated fatty acids (SFA)

and highly enriched in monounsaturated fatty acids (MUFA). Based on human

feeding studies, the American Heart Association and the US Food and Drug

Administration have advocated for the consumption of MUFA as a more healthy

replacement for SFA. However, using experimental animal models in which extent

of atherosclerosis can be directly measured following dietary intervention, it

has been demonstrated that MUFA-enriched diets are not atheroprotective when

compared with SFA-enriched diets. Hence, the current body of experimental

evidence refutes the idea that MUFAs per se are atheroprotective; therefore much

additional work is needed to determine which aspects of the Mediterranean diet

are indeed heart healthy.

PMID: 18377790

---------------------------------------

From: Curr Opin Lipidol. 2003 Feb;14(1):41-6.

" Dietary monounsaturated versus polyunsaturated fatty acids: which is really

better for protection from coronary heart disease? "

Lada AT, Rudel LL.

Department of Pathology, Wake Forest University School of Medicine,

Winston-Salem, North Carolina 27157, USA.

Abstract

PURPOSE OF REVIEW: The purpose is to evaluate recent findings concerning dietary

fats and the risk of coronary heart disease. Monounsaturated fatty acids are

often regarded as healthy, and many have recommended their consumption instead

of saturated fatty acids and polyunsaturated fatty acids. Support for the

benefits of monounsaturated fatty acids comes largely from epidemiological data,

but they have not been an isolated, single variable in such studies. Beneficial

effects on the plasma lipid profile and LDL oxidation rates have also been

identified. More recent findings have questioned the impact of suspected

beneficial effects on coronary heart disease, indicating that studies with more

conclusive endpoints are needed. RECENT FINDINGS: Human dietary studies often

produce conflicting results regarding the effects of monounsaturated and

polyunsaturated fatty acids on the plasma lipid profile. Monounsaturated and

polyunsaturated fatty acids both appear to reduce total and LDL-cholesterol

compared with saturated fatty acids; however, the effect on HDL is less clear.

Lowered HDL levels in response to low-fat or polyunsaturated fatty acid diets

and the decreased protection from oxidation of polyunsaturated fatty

acid-enriched LDL may not indicate increased coronary heart disease risk.

Several lines of evidence also suggest that polyunsaturated fatty acids may

protect against atherosclerosis. SUMMARY: Recommendations to substitute

monounsaturated fatty acids for polyunsaturated fatty acids or a low-fat

carbohydrate diet seem premature without more research into the effects on the

development of atherosclerosis. Current opinions favoring monounsaturated fatty

acids are based on epidemiological data and risk factor analysis, but are

questioned by the demonstrated detrimental effects on atherosclerosis in animal

models.

PMID: 12544660

-------------------------------------------

From: J Clin Invest. 1997 Jul 1;100(1):74-83.

Hepatic origin of cholesteryl oleate in coronary artery atherosclerosis in

African green monkeys. Enrichment by dietary monounsaturated fat.

Rudel LL, Haines J, Sawyer JK, Shah R, MS, Carr TP.

Department of Comparative Medicine, Bowman Gray School of Medicine of Wake

Forest University, Winston Salem, North Carolina 27157, USA. lrudel@...

Abstract

Relationships among plasma lipoprotein cholesterol, cholesterol secretion by the

isolated, perfused liver, and coronary artery atherosclerosis were examined in

African green monkeys fed diets containing cholesterol and 35% of calories as

fat enriched in polyunsaturated, monounsaturated, or saturated fatty acids. The

livers of animals fed monounsaturated fat had significantly higher cholesteryl

ester concentrations (8.5 mg/g wet wt) than the livers of the other diet groups

(3.65 and 3.37 mg/g wet wt for saturated and polyunsaturated fat groups,

respectively) and this concentration was highly correlated with plasma

cholesterol and apoB concentrations in each diet group. Cholesteryl oleate was

58% and 74.5% of the liver cholesteryl ester in the saturated and

monounsaturated fat groups. In each diet group, perfusate cholesteryl ester

accumulation rate was highly correlated to liver and plasma cholesterol

concentrations, and to plasma LDL cholesteryl ester content. Cholesteryl oleate

was 48% and 67% of the cholesteryl esters that accumulated in perfusate in the

saturated and monounsaturated fat animals, and this percentage was very highly

correlated (r = -0.9) with plasma apoB concentration. Finally, in these two diet

groups, liver perfusate cholesteryl ester accumulation rate was well correlated

(r >/= 0.8) to coronary artery cholesteryl ester concentration, a measure of the

extent of coronary artery atherosclerosis that occurred over the five years of

diet induction in these animals. These data define an important role for the

liver in the cholesteryl oleate enrichment of the plasma lipoproteins in the

saturated and monounsaturated fat groups, and demonstrate strong relationships

among hepatic cholesteryl ester concentration, cholesteryl ester secretion, and

LDL particle cholesteryl ester content. The high correlation between liver

cholesteryl ester secretion and coronary artery atherosclerosis provides the

first direct demonstration of the high degree of importance of hepatic

cholesteryl ester secretion in the development of this disease process. The

remarkable degree of enrichment of cholesteryl oleate in plasma cholesteryl

esters of the monounsaturated fat group may account for the relatively high

amount of coronary artery atherosclerosis in this group.

PMID: 9202059. PMCID: PMC508167. Free PMC Article

--------------------------------------

Here are some comments I have on the entire 'Discussion on dietary fat' paper:

Dr Rudel says monos are just as atherogenic as the saturated fats, with the bad

guy being the cholesteryl oleate that is created in the liver when monos are

ingested. While total LDL is lower, they say, the very worst VLDL is much higher

with monos. I have never believed monos to be healthy, but I never guessed they

would be found to be as bad as the saturated fats. So if this is correct, for

measuring the likely comparative dangers of individual foods we should,

presumably, be measuring sat+mono as a percentage of total fat (higher is

worse)? Or, perhaps better, and which amounts to the same thing, the amounts of

polys as a percent of total fats (higher is better).

Using data from CRON-o-Meter, percentage calculations of this kind yield very

interesting results. Among the oils, it is of no surprise that high-linoleic

safflower is by far the best - at 78.4% polys. But lard (11.7% polys) is better

than olive oil (10.8% polys). And canola, although a lot better than olive, is a

lot worse than those at the top of the list. Here are the data, for a few oils,

for polys as a percent of total fat:

Safflower (high linoleic) 78.4%

Sunflower (high linoleic) 68.8

Corn 57.4

Canola 28.5

Safflower (high oleic) 15.1

Lard 11.7

Olive 10.8

Palm 9.7

Sunflower (high oleic) 3.9

Coconut 1.9

Palm kernel 1.7

How are those data for an eyeful?! They do confirm the finding previously

discussed here, that the comparatively small proportion of people who suffer CVD

in Crete are those who consume the most olive oil.

The authors are saying that 25% to 35% dietary fat is appropriate. I have two

problems with this. First we know that Ornish, and perhaps others, have shown

regression of stenosis at ~10% fat calories as a percent of total. Has anyone

seen studies claiming regression of stenosis at anywhere remotely close to 25%

to 35% dietary fat? If so I am not aware of it. They claim it is not the

amount of fat but the ratios that are critical. I would like to see the evidence

which supports that. Also, they apparently completely ignore what happens to CVD

risk factors under caloric restriction! CR may very well be found, when someone

gets around to doing a carefully organized study, to be as important, or perhaps

even more so, for prevention of atherosclerosis than the types of fats consumed!

While it seems clear that polyunsaturated fats are protective against CVD, this

claim always seems to be stated in the context of: " compared with saturated,

trans or monounsaturated fats " . No one ever seems to address the question as to

whether a diet with - all else equal - 10% polyunsaturated, is healthier or less

healthy than one with 30% polyunsaturated. I suspect Ornish would believe the

lower poly diet would be healthier than the higher poly intake.

They say lauric, myristic and palmitic all raise cholesterol, with myristic

being the worst. Not much new in that. They also say stearic may not be a

problem, but also say that 20% of stearic consumed is turned into monos in the

liver.

They also say that linolenic acid is NOT protective against CVD. I find this

quite surprising. But EPA directly added to the diet, they say, provides the

greatest protection. About one gram a day of EPA+DHA they seem to regard as

appropriate. Both appear to be excellent for heart health, but DHA also has

benefits for the brain - also not new information. The increased bleeding times

associated with omega-3s was news to me.

It was also notable that one participant said that fish with very low levels of

omega-3s (from inland waterways) are also associated with substantially improved

heart health. This raises the question as to whether the health benefits seen

from fish intake really are a function of the fats, or may be some other

characteristic of fish entirely. Although, IIRC, the benefit to telomeres in a

recent study was found to result from the ingestion of fish oil capsules, not

from consumption of the whole fish.

I think Dr. Brown was out by one decimal place when he suggested one gram of

these daily would amount to 4% of a 2000 calorie diet. I think it is 0.4%. But

it doesn't make any sense to me to suggest that polys should be limited to 10%

of caloric intake when talking about a 25% to 35% total fat intake. How is it

possible to minimize hydrogenated, saturated and mono fats, if only 10% is to

come from polys? !!!!!

Indeed, this line of reasoning very much supports the Pritikin/Ornish

hypothesis. If trans, sats and monos need to be minimized, and you do not want

too much polys because of possible problems with oxidation, then surely the only

logical conclusion has to be a very low fat diet (10% of calories) with most of

that coming from polys?

Incidentally, among a few fish I checked the data for, salmon, menhaden and

sardine had the highest percentage of polys.

Of course, if anyone is aware of published *empirical* research which conflicts

with all the above - that is studies showing less atherosclerosis in humans or

animals consuming monos, compared with those consuming polys - please post it so

we can see both sides of the argument ............ if there indeed is

another side to it, which I am increasingly becoming convinced there isn't!

Rodney.

[Guest guest]

Dietary fats, carbohydrate, and progression of coronary atherosclerosis in postmenopausal women.Mozaffarian D, Rimm EB, Herrington DM.Am J Clin Nutr. 2004 Nov;80(5):1175-84. Erratum in: Am J Clin Nutr. 2005 Jan;81(1):199. PMID: 15531663 [PubMed - indexed for MEDLINE]Free PMC ArticleFree texthttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1270002/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1270002/figure/F1/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1270002/table/T2/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1270002/table/T3/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1270002/table/T4/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1270002/table/T5/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1270002/pdf/nihms2818.pdf

Abstract

BACKGROUND: The influence of diet on atherosclerotic progression is not well established, particularly in postmenopausal women, in whom risk factors for progression may differ from those for men. OBJECTIVE: The objective was to investigate associations between dietary macronutrients and progression of coronary atherosclerosis among postmenopausal women. DESIGN: Quantitative coronary angiography was performed at baseline and after a mean follow-up of 3.1 y in 2243 coronary segments in 235 postmenopausal women with established coronary heart disease. Usual dietary intake was assessed at baseline. RESULTS: The mean (+/-SD) total fat intake was 25 +/- 6% of energy. In multivariate analyses, a higher saturated fat intake was associated with a smaller decline in mean minimal coronary diameter (P = 0.001) and less progression of coronary stenosis (P = 0.002) during follow-up. Compared with a 0.22-mm decline in the lowest quartile of intake, there was a

0.10-mm decline in the second quartile (P = 0.002), a 0.07-mm decline in the third quartile (P = 0.002), and no decline in the fourth quartile (P < 0.001); P for trend = 0.001. This inverse association was more pronounced among women with lower monounsaturated fat (P for interaction = 0.04) and higher carbohydrate (P for interaction = 0.004) intakes and possibly lower total fat intake (P for interaction = 0.09). Carbohydrate intake was positively associated with atherosclerotic progression (P = 0.001), particularly when the glycemic index was high. Polyunsaturated fat intake was positively associated with progression when replacing other fats (P = 0.04) but not when replacing carbohydrate or protein. Monounsaturated and total fat intakes were not associated with progression. CONCLUSIONS: In postmenopausal women with relatively low total fat intake, a greater saturated fat intake is associated with less progression of coronary atherosclerosis, whereas

carbohydrate intake is associated with a greater progression.-- Aalt Pater

From: perspect1111 <perspect1111@...>Subject: [ ] Monounsaturated Fats and CVD - The Final Nail? Received: Sunday, April 11, 2010, 8:11 AM

Hi folks: I am afraid this is gonna be a long post. But, in my (insufficiently modest) opinion, it may be found to be well worth the time required to read it, perhaps all the way to the end. This post originates from material Jeff Novick unearthed, which seems to roundly confirm the suspicions many of us here have had for quite some time ....... that, contrary to the widely accepted conventional wisdom, monounsaturated fats (olive oil, for example) DO clog your arteries. Indeed, according to the first paper below, monos clog arteries every bit as well as saturated fats. These research results seem to lead to some inescapable and highly significant conclusions .......... for example, that lard - yes LARD - may be less unhealthy than olive oil. If this sounds interesting, read on. If not then please ignore the rest of this and go on to the next post : ^ ))) Here is source of the paper Jeff unearthed:

From: Journal of Clinical Lipidology (2009) 3, 303–314 'Discussion on dietary fat' W. Virgil Brown, MD*, Wahida Karmally, RD, DrPH, Penny Kris-Etherton, PhD, RD, Lawrence R. Rudel, PhDFOR ME THE KEY EXCERPT FROM THIS PAPER IS THE FOLLOWING:Dr. Rudel: "We began studies on monounsaturated fat after Fred Mattson and Grundy initially questioned whether the fatty acid is neutral or is it really good. From the studies that were done in the 1950s and 1960s with Keys and Hegsted and others, it was thought monos were neutral, but you could substitute polyunsaturated fats for saturated and reduce total cholesterol and protect against coronary heart disease. Monunsaturated fats were considered neutral as risk producers. "Mattson and Grundy performed human experiments on lipoprotein changes and said, well it's really not neutral, it lowers LDL as well as polyunsaturated fats but it doesn't lower

HDL. Therefore, it's probably just as good as polyunsaturated fats based on a risk factor prediction from lipoprotein concentrations. "So that paper raised a very important question. In Winston-Salem, we had monkeys that we could study regarding dietary fat effects. We modeled a study in primates using diets very similar to those of the Mattson and Grundy human dietary studies. We used exactly the same oils they used in the veterans in San Diego. And we got exactly the same effects on LDL and HDL. We lowered LDL significantly with monounsaturated fats to same extent as we did with N-6 polyunsaturates. As expected, the LDL was highest on saturated fat feeding. As in the humans, HDL was also lowered by polyunsaturated fat and was not lowered by monounsaturates. The best LDL/HDL ratio was in the mono group. So we would have predicted that the arteries would document that monos are the best dietary fat. "But when we looked at the coronary

arteries, much to our surprise there was just as much atherosclerosis in monounsaturated fat fed monkeys as there was in saturated fat fed monkeys. And the only fat that seemed to protect was the polyunsaturates. We didn't have a good explanation for that finding. So we looked at the composition of the lipoproteins in plasma. We found that with the monounsaturates, we had completely shifted the cholesteryl ester composition in the LDLs to be very high in cholesteryl oleate. Then I remembered a comment from an old friend, Kritchevsky, many years ago, when he came up to me in a meeting and said ``cholesteryl oleate is atherogenic. '' I never understood why he said that. But here in our study we found this strong correlation. The assumption at the time was that cholesteryl oleate would be a tissue-derived cholesteryl ester, whereas most of the plasma cholesteryl ester usually comes from the plasma enzyme lecithin-cholestero l acyltransferase (ie,

LCAT), where the product is cholesteryl linoleate. "We examined the liver from those monkeys and performed isolated liver perfusion studies and made the striking observation that the correlation between coronary artery atherosclerosis extent and the hepatic cholesteryl ester secretion rate was r = 0.85. It was just ridiculously high. "We concluded that the nature of the cholesterol ester secreted by the liver seems to be really important. Further, the livers of the diet group that secreted the most cholesteryl oleate were from the monounsaturated group. We now know that the enzyme in the liver that's important is ACAT2, and ACAT2 specifically esterifies oleate to cholesterol and make cholesteryl oleate; it gets secreted, accumulates in plasma, and it looks like it's associated with more atherosclerosis. These days you can do the experiment with no ACAT2 through use of genetically altered animals, ACAT2 knockout mice. The hypothesis that

reducing the cholesterol oleate production by the liver reduces atherogenesis was confirmed in these animals. These animals on a high oleate diet had very little plasma cholesteryl oleate and there was an 80% or so reduction in atherosclerosis. "You seem to have little risk of atherosclerosis if you take that enzyme away. So it looks to me like monounsaturated fat in the liver offers some liability. And that liability comes from the stimulation of cholesteryl esterification and cholesteryl ester accumulation, which is secreted in very low-density lipoprotein (ie, VLDL) particles, accumulates in LDL, giving a more atherogenic plasma lipoprotein profile. It's deceptive because it does lower LDL cholesterol concentration. It also leaves HDL cholesterol concentration higher, but it changes the composition of the lipoproteins and for some reason or other, it makes things much more atherogenic. " ------------ --------- --------- ---------

-------- Below I add a few additional papers on this topic also authored by Dr. Rudel. Please note that I have not read the full texts of these. They are provided in case someone wishes to investigate this issue further. ------------ --------- --------- --------- -------- From: J Lipid Res. 2010 Feb 11.Dietary n-3 LCPUFA from fish oil but not {alpha}-linolenic acid-derived LCPUFA confers atheroprotection in mice.Degirolamo C, Kelley KL, MD, Rudel LL. Wake Forest University School of Medicine, United States. AbstractThe atheroprotective potential of n-3 alpha-linolenic acid (ALA) has not yet been fully determined, even in murine models of atherosclerosis. We tested whether ALA-derived n-3 long chain polyunsaturated fatty acids (LCPUFA) could offer atheroprotection in a dose-dependent manner. ApoB100/100LDLr -/- mice were fed with diets containing two levels of ALA from flaxseed oil for 16

weeks. Fish oil- and cis-monounsaturated fat-enriched diets were used as positive and negative controls, respectively. The mice fed cis-monounsaturated fat and ALA-enriched diets exhibited equivalent plasma total cholesterol (TPC) and LDL-c levels; only mice fed the fish oil diet had lower TPC and LDL-c concentrations. Plasma LDL-CE fatty acid composition analysis showed that ALA-enriched diets lowered the percentage of atherogenic cholesteryl oleate compared to cis-monounsaturated fat diet (44% vs. 55.6) but not as efficiently as fish oil diet (32.4%). Although both ALA and fish oil diets equally enriched hepatic phospholipids with eicosapentaenoic acid (EPA) and ALA-enriched diets lowered hepatic CE levels compared to cis-monounsaturated fat diet, only fish oil strongly protected from atherosclerosis. These outcomes indicate that dietary n-3 LCPUFA from fish oil and n-3 LCPUFA (mostly EPA) synthesized endogenously from ALA were not equally

atheroprotective in these mice.PMID: 20154006. Free Article ------------ --------- --------- --- From: Lipid Res. 2009 Apr;50 Suppl:S434-9. Epub 2008 Nov 22. "LDL cholesteryl oleate as a predictor for atherosclerosis: evidence from human and animal studies on dietary fat."Degirolamo C, Shelness GS, Rudel LL. Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem NC 27157, USA. AbstractThis review focuses on the relationships among dietary fat type, plasma and liver lipid, and lipoprotein metabolism and atherosclerosis. Dietary polyunsaturated fatty acids are beneficial for the prevention of coronary artery atherosclerosis. By contrast, dietary monounsaturated fatty acids appear to alter hepatic lipoprotein metabolism, promote cholesteryl oleate accumulation, and confer atherogenic properties to lipoproteins as shown in data from

experimental animal studies. Polyunsaturated fat appears to provide atheroprotection, at least in part, because it limits the accumulation of cholesteryl oleate in favor of cholesteryl linoleate in plasma lipoproteins.PMID: 19029117. PMCID: PMC2674687. Free PMC Article ------------ --------- From: Curr Atheroscler Rep. 2007 Dec;9(6):494- 500. "Monounsaturated fatty acids and atherosclerosis: opposing views from epidemiology and experimental animal models."Brown JM, Shelness GS, Rudel LL. Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040, USA. AbstractA substantial body of epidemiologic data has shed light on the potential protective effects of the Mediterranean diet against atherosclerosis in humans. Many believe the reason the Mediterranean diet is atheroprotective is the elevated consumption of olive oil, an oil poor in saturated fatty acids

(SFA) and highly enriched in monounsaturated fatty acids (MUFA). Based on human feeding studies, the American Heart Association and the US Food and Drug Administration have advocated for the consumption of MUFA as a more healthy replacement for SFA. However, using experimental animal models in which extent of atherosclerosis can be directly measured following dietary intervention, it has been demonstrated that MUFA-enriched diets are not atheroprotective when compared with SFA-enriched diets. Hence, the current body of experimental evidence refutes the idea that MUFAs per se are atheroprotective; therefore much additional work is needed to determine which aspects of the Mediterranean diet are indeed heart healthy.PMID: 18377790 ------------ --------- --------- --------- From: Curr Opin Lipidol. 2003 Feb;14(1):41- 6. "Dietary monounsaturated versus polyunsaturated fatty acids: which is really better for protection from

coronary heart disease?"Lada AT, Rudel LL. Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. AbstractPURPOSE OF REVIEW: The purpose is to evaluate recent findings concerning dietary fats and the risk of coronary heart disease. Monounsaturated fatty acids are often regarded as healthy, and many have recommended their consumption instead of saturated fatty acids and polyunsaturated fatty acids. Support for the benefits of monounsaturated fatty acids comes largely from epidemiological data, but they have not been an isolated, single variable in such studies. Beneficial effects on the plasma lipid profile and LDL oxidation rates have also been identified. More recent findings have questioned the impact of suspected beneficial effects on coronary heart disease, indicating that studies with more conclusive endpoints are needed. RECENT FINDINGS: Human dietary studies often

produce conflicting results regarding the effects of monounsaturated and polyunsaturated fatty acids on the plasma lipid profile. Monounsaturated and polyunsaturated fatty acids both appear to reduce total and LDL-cholesterol compared with saturated fatty acids; however, the effect on HDL is less clear. Lowered HDL levels in response to low-fat or polyunsaturated fatty acid diets and the decreased protection from oxidation of polyunsaturated fatty acid-enriched LDL may not indicate increased coronary heart disease risk. Several lines of evidence also suggest that polyunsaturated fatty acids may protect against atherosclerosis. SUMMARY: Recommendations to substitute monounsaturated fatty acids for polyunsaturated fatty acids or a low-fat carbohydrate diet seem premature without more research into the effects on the development of atherosclerosis. Current opinions favoring monounsaturated fatty acids are based on epidemiological data and risk factor

analysis, but are questioned by the demonstrated detrimental effects on atherosclerosis in animal models.PMID: 12544660 ------------ --------- --------- --------- ---- From: J Clin Invest. 1997 Jul 1;100(1):74- 83. Hepatic origin of cholesteryl oleate in coronary artery atherosclerosis in African green monkeys. Enrichment by dietary monounsaturated fat.Rudel LL, Haines J, Sawyer JK, Shah R, MS, Carr TP. Department of Comparative Medicine, Bowman Gray School of Medicine of Wake Forest University, Winston Salem, North Carolina 27157, USA. lrudelbgsm (DOT) edu AbstractRelationships among plasma lipoprotein cholesterol, cholesterol secretion by the isolated, perfused liver, and coronary artery atherosclerosis were examined in African green monkeys fed

diets containing cholesterol and 35% of calories as fat enriched in polyunsaturated, monounsaturated, or saturated fatty acids. The livers of animals fed monounsaturated fat had significantly higher cholesteryl ester concentrations (8.5 mg/g wet wt) than the livers of the other diet groups (3.65 and 3.37 mg/g wet wt for saturated and polyunsaturated fat groups, respectively) and this concentration was highly correlated with plasma cholesterol and apoB concentrations in each diet group. Cholesteryl oleate was 58% and 74.5% of the liver cholesteryl ester in the saturated and monounsaturated fat groups. In each diet group, perfusate cholesteryl ester accumulation rate was highly correlated to liver and plasma cholesterol concentrations, and to plasma LDL cholesteryl ester content. Cholesteryl oleate was 48% and 67% of the cholesteryl esters that accumulated in perfusate in the saturated and monounsaturated fat animals, and this percentage was very highly

correlated (r = -0.9) with plasma apoB concentration. Finally, in these two diet groups, liver perfusate cholesteryl ester accumulation rate was well correlated (r >/= 0.8) to coronary artery cholesteryl ester concentration, a measure of the extent of coronary artery atherosclerosis that occurred over the five years of diet induction in these animals. These data define an important role for the liver in the cholesteryl oleate enrichment of the plasma lipoproteins in the saturated and monounsaturated fat groups, and demonstrate strong relationships among hepatic cholesteryl ester concentration, cholesteryl ester secretion, and LDL particle cholesteryl ester content. The high correlation between liver cholesteryl ester secretion and coronary artery atherosclerosis provides the first direct demonstration of the high degree of importance of hepatic cholesteryl ester secretion in the development of this disease process. The remarkable degree of enrichment

of cholesteryl oleate in plasma cholesteryl esters of the monounsaturated fat group may account for the relatively high amount of coronary artery atherosclerosis in this group.PMID: 9202059. PMCID: PMC508167. Free PMC Article ------------ --------- --------- -------- Here are some comments I have on the entire 'Discussion on dietary fat' paper: Dr Rudel says monos are just as atherogenic as the saturated fats, with the bad guy being the cholesteryl oleate that is created in the liver when monos are ingested. While total LDL is lower, they say, the very worst VLDL is much higher with monos. I have never believed monos to be healthy, but I never guessed they would be found to be as bad as the saturated fats. So if this is correct, for measuring the likely comparative dangers of individual foods we should, presumably, be measuring sat+mono as a percentage of total fat (higher is worse)? Or, perhaps better, and which amounts

to the same thing, the amounts of polys as a percent of total fats (higher is better). Using data from CRON-o-Meter, percentage calculations of this kind yield very interesting results. Among the oils, it is of no surprise that high-linoleic safflower is by far the best - at 78.4% polys. But lard (11.7% polys) is better than olive oil (10.8% polys). And canola, although a lot better than olive, is a lot worse than those at the top of the list. Here are the data, for a few oils, for polys as a percent of total fat:Safflower (high linoleic) 78.4% Sunflower (high linoleic) 68.8 Corn 57.4Canola 28.5 Safflower (high oleic) 15.1 Lard 11.7Olive 10.8 Palm 9.7Sunflower (high oleic) 3.9 Coconut 1.9 Palm kernel 1.7 How are those data for an eyeful?! They do confirm the finding previously discussed here, that the comparatively small proportion of people who suffer CVD in Crete are those who consume the

most olive oil. The authors are saying that 25% to 35% dietary fat is appropriate. I have two problems with this. First we know that Ornish, and perhaps others, have shown regression of stenosis at ~10% fat calories as a percent of total. Has anyone seen studies claiming regression of stenosis at anywhere remotely close to 25% to 35% dietary fat? If so I am not aware of it. They claim it is not the amount of fat but the ratios that are critical. I would like to see the evidence which supports that. Also, they apparently completely ignore what happens to CVD risk factors under caloric restriction! CR may very well be found, when someone gets around to doing a carefully organized study, to be as important, or perhaps even more so, for prevention of atherosclerosis than the types of fats consumed! While it seems clear that polyunsaturated fats are protective against CVD, this claim always seems to be stated in the context of: "compared with

saturated, trans or monounsaturated fats". No one ever seems to address the question as to whether a diet with - all else equal - 10% polyunsaturated, is healthier or less healthy than one with 30% polyunsaturated. I suspect Ornish would believe the lower poly diet would be healthier than the higher poly intake.They say lauric, myristic and palmitic all raise cholesterol, with myristic being the worst. Not much new in that. They also say stearic may not be a problem, but also say that 20% of stearic consumed is turned into monos in the liver.They also say that linolenic acid is NOT protective against CVD. I find this quite surprising. But EPA directly added to the diet, they say, provides the greatest protection. About one gram a day of EPA+DHA they seem to regard as appropriate. Both appear to be excellent for heart health, but DHA also has benefits for the brain - also not new information. The increased bleeding times associated with

omega-3s was news to me. It was also notable that one participant said that fish with very low levels of omega-3s (from inland waterways) are also associated with substantially improved heart health. This raises the question as to whether the health benefits seen from fish intake really are a function of the fats, or may be some other characteristic of fish entirely. Although, IIRC, the benefit to telomeres in a recent study was found to result from the ingestion of fish oil capsules, not from consumption of the whole fish.I think Dr. Brown was out by one decimal place when he suggested one gram of these daily would amount to 4% of a 2000 calorie diet. I think it is 0.4%. But it doesn't make any sense to me to suggest that polys should be limited to 10% of caloric intake when talking about a 25% to 35% total fat intake. How is it possible to minimize hydrogenated, saturated and mono fats, if only 10% is to come from polys? !!!!!

Indeed, this line of reasoning very much supports the Pritikin/Ornish hypothesis. If trans, sats and monos need to be minimized, and you do not want too much polys because of possible problems with oxidation, then surely the only logical conclusion has to be a very low fat diet (10% of calories) with most of that coming from polys?Incidentally, among a few fish I checked the data for, salmon, menhaden and sardine had the highest percentage of polys. Of course, if anyone is aware of published *empirical* research which conflicts with all the above - that is studies showing less atherosclerosis in humans or animals consuming monos, compared with those consuming polys - please post it so we can see both sides of the argument ............ if there indeed is another side to it, which I am increasingly becoming convinced there isn't!Rodney.

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