Monday, July 20, 2009

The Diet-Heart Hypothesis: Stuck at the Starting Gate?

The diet-heart hypothesis is the idea that (1) dietary saturated fat, and in some versions, dietary cholesterol, raise blood cholesterol in humans and (2) therefore contribute to the risk of heart attack.

I'm not going to spend a lot of time on the theory in relation to dietary cholesterol because the evidence that typical dietary amounts cause heart disease in humans is weak.  Here's a graph from the Framingham Heart study (via the book
Prevention of Coronary Heart Disease, by Dr. Harumi Okuyama et al.) to drive home the point. Eggs are the main source of cholesterol in the American diet. In this graph, the "low" group ate 0-2 eggs per week, the "medium" group ate 3-7, and the "high" group ate 7-14 eggs per week (click for larger image): The distribution of blood cholesterol levels between the three groups was virtually identical. The study also found no association between egg consumption and heart attack risk. Dietary cholesterol does not have a large impact on serum cholesterol in the long term, perhaps because humans are adapted to eating cholesterol. Most people are able to adjust their own cholesterol metabolism to compensate when the amount in the diet increases. Rabbits don't have that feedback mechanism because their natural diet doesn't include cholesterol, so feeding them dietary cholesterol increases blood cholesterol and causes vascular pathology.

The first half of the diet-heart hypothesis states that eating saturated fat raises blood cholesterol. This has been accepted without much challenge by diet-health authorities for nearly half a century. In 1957, Dr. Ancel Keys proposed a formula (Lancet 2:1959. 1957) to predict changes in total cholesterol based on the amount of saturated and polyunsaturated fat in the diet. This formula, based primarily on short-term trials from the 1950s, stated that saturated fat is the primary dietary influence on blood cholesterol.

According to Keys' interpretation of the trials, saturated fat raised, and to a lesser extent polyunsaturated fat lowered, blood cholesterol.
But there were significant flaws in the data from the very beginning, which were pointed out in this critical 1973 literature review in the American Journal of Clinical Nutrition (free full text).

The main problem is that the controlled trials typically compared saturated fats to omega-6 linoleic acid (LA)-rich vegetable oils, and when serum cholesterol was higher in the saturated fat group, this was most often attributed to the saturated fat raising blood cholesterol rather than the LA lowering it. When a diet high in saturated fat was compared to the basal diet without changing LA, often no significant increase in blood cholesterol was observed. Studies claiming to show a cholesterol-raising effect of saturated fat often introduced it after an induction period rich in LA. Thus, the effect sometimes had more to do with LA lowering blood cholesterol than saturated fat raising it. This is not at all what I was expecting to find when I began looking through these trials.


Reading through the short-term controlled trials, I was surprised by the variability and lack of agreement between them. Some of this was probably due to a lack of control over variables and non-optimal study design. But if saturated fat has a dominant effect on serum cholesterol in the short term, it should be readily and consistently demonstrable.  

The long-term data are not kind to the diet-heart hypothesis. Reducing saturated fat while greatly increasing LA certainly does lower blood cholesterol substantially. This was the finding in the well-controlled Minnesota Coronary Survey trial, for example (14% reduction). But in other cases where LA intake changed less, such as MRFIT, the Women's Health Initiative Diet Modification trial and the Lyon Diet-Heart trial, reducing saturated fat intake had little or no effect on total cholesterol or LDL (0-3% reduction).  The small changes that did occur could have been due to other factors, such as increased fiber and phytosterols, since these were multiple-factor interventions.

Another blow to the idea that saturated fat raises cholesterol in the long term comes from observational studies. Here's a graph of data from the Health Professionals Follow-up study, which followed 43,757 health professionals for 6 years (via the book
Prevention of Coronary Heart Disease by Dr. Harumi Okuyama et al.): What this graph shows is that at a relatively constant LA intake, neither saturated fat intake nor the ratio of LA to saturated fat were related to blood cholesterol in freely living subjects. This was true across a wide range of saturated fat intakes (7-15%). 

There's more. If saturated fat were important in determining the amount of blood cholesterol in the long term, you'd expect populations who eat the most saturated fat to have high blood cholesterol levels. But that's not the case. The Masai traditionally get a high proportion of their calories from milk fat, half of which is saturated. In 1964, Dr. George V. Mann published a paper showing that traditional Masai warriors eating practically nothing but very fatty milk, blood and meat had an average cholesterol of 115 mg/dL in the 20-24 year age group. For comparison, he published values for American men in the same age range: 198 mg/dL (J. Atherosclerosis Res. 4:289. 1964). Apparently, eating three times the saturated animal fat and several times the cholesterol of the average American wasn't enough to elevate their blood cholesterol. What does elevate the cholesterol of a Masai man?
Junk food.

Now let's swim over to the island of Tokelau, where the traditional diet includes nearly 50% of calories from saturated fat from coconut. This is the highest saturated fat intake of any population I'm aware of. How's their cholesterol? Men in the age group 20-24 had a concentration of 168 mg/dL in 1976, which was lower than Americans in the same age group despite a four-fold higher saturated fat intake.
Tokelauans who migrated to New Zealand, eating half the saturated fat of their island relatives, had a total cholesterol of 191 mg/dL in the same age group and time period, and substantially higher LDL (J. Chron. Dis. 34:45. 1981). Sucrose consumption was 2% on Tokelau and 13% in New Zealand. Saturated fat seems to take a backseat to some other diet/lifestyle factor(s).  Body fatness and excess calorie intake are good candidates, since they influence circulating lipoproteins.

Does dietary saturated fat influence total cholesterol and LDL over the long term?  I don't have the answers, but I do think it's interesting that the evidence is much less consistent than it's made out to be.  It may be that if dietary saturated fat influences total cholesterol or LDL concentration in the long term, the effect is is secondary to other factors.  That being said, it's clear that linoleic acid, in large amount, reduces circulating total cholesterol and LDL.

88 comments:

Robert Andrew Brown said...

Well done Stephan.

Another fascinating and excellent blog.

Deb said...

Love your blog Stephan. Do you have a source for the statement that Dr. Ancel Keys ended up not believing his hypothesis? I have someone who suspects everything! It amazes me that the medical community is still pushing low fat high carb.

Jim Purdy said...

I don't discount the possibility of serious harm from saturated fats.

Long-term statistical studies of other people are great, but what really matters to me is how a food affects me in the short term, especially in the hours right after eating a meal.

I've noticed that eating a couple of big greasy bacon double cheeseburgers quickly gives me enough chest pain and tachycardia to send me to an emergency room. I get the same results from overeating biscuits and gravy.

(And also from too much strong coffee or tea, but I suppose the caffeine is the cause there.)

On the other hand, I can eat high-fat avocados all day long, without any problems.

If I were going to guess, I suppose my chest pains are caused by the saturated animal fats in the cheeseburgers, while the avocados' mono-unsaturated fats (and high fiber?) have little or no impact.

Anne said...

Jim, don't overlook the possibility that it is the bun and the biscuits with gravy that is made from wheat that is causing your chest pain. Gluten(wheat intolerance) is very common. I do have CAD and when I stopped eating gluten my, GERD, shortness of breath and pitting edema disappeared. My lipid profile looks good on a low carb diet.

diana said...

Jim
If I had to guess as to the source of your chestpains, it would be the refined hamburger bun, and the refined biscuit,and gravy, most likely thickened with flour or cornstarch (all carbs, which become triglycerides after digestion) and NOT the beef patties / bacon. An avocado also has 12 grams of carb, but 9 grams are fiber, and all natural. Nothing refined.
We have evolved eating saturated animal fat, not refined grains.
Just my take

Jim Purdy said...

Anne and Diana, those are excellent points about the buns and biscuits.

And I agree, I do try to avoid grains. Maybe I was blaming the meat when I should have looked at the grains.

I don't seem to have the same chest pains with a big slab of ham, or a bunch of grilled chicken breasts. Thanks!

Anyway, I still prefer mono-unsaturated fats from avocados, but maybe I won't have any avocado sandwiches.

Mario Renato said...

Stephan,

First post: great blog and what a great mind you have! Congratulations and thank you very much for all information you give us!

I and my wife have started to eat a "Lacto-Paleo" diet, roughly 60% fat (mostly saturated fat), 30% protein and less than 10% carbs. Our blood tests after and before (4 weeks on such a diet):

Me:

LDL 179 -> 148
HDL 42 -> 52
Triglyc 132 -> 60
Lp(a) -- -> <10

My wife:

LDL 188 -> 132
HDL 43 -> 54
Triglyc 127 -> 48
Lp(a) -- -> <10

LDL measured, not calculated. So, If anything, such a diet not only not rised, but on the contrary drop significantly our LDL...

Ps. I'm eating around 4 pastured eggs a day, 28 eggs a week!

Daryl said...

Jim - your problem is that no more than 20 or 30% of your diet should be (wild caught or grass fed) animal protein. The other 70% should be whole, mostly raw, fruits and vegetables.

With this diet, your body will quickly reach homeostasis. Then your chest pains will disappear.

Before I switched to this diet, I had high cholesterol, arthritis in my elbows and occasional kidney stones and hemorrhoids.

No more.

Nice article, Stephan. Thanks for the effort.

Dave said...

The other place where diet-heart is stuck at the starting gate is in identifying any sort of biochemical connection between saturated fat and LDL. You'd think after 50+ years there would be some sort of working hypothesis along the lines "saturated fat causes more of enzyme X to be generated thus raising LDL" etc.

But if you check the textbooks, you'll find a big fat zero. Indeed, the authors generally make this point explicitly, noting something like "Despite half a century of research, the mechanism by which saturated fatty acids affect serum LDL has remained elusive." Note the implicit belief that such a mechanism exists, so strong that few seem to ever turn the thing around and wonder if maybe the reason the mechanism hasn't been found is that there never was one.

Absence of evidence does not imply evidence of absence. But since there was never really any evidence connecting saturated fat and LDL in the first place, the whole business is scientifically ridiculous.

Chris said...

Jim

At the risk of piling on, I think it is also worth pointing out that "overeating" anything is likely to cause an unnecessarily exaggerated inflammatory response from the body.

randy said...

Dave Wrote:
You'd think after 50+ years there would be some sort of working hypothesis along the lines "saturated fat causes more of enzyme X to be generated thus raising LDL" etc.

Reply:
I believe the mechanisms by which certain SFA increase LDL have been worked out.

The basic research was awarded the Nobel prize in medicine in 1985.

Here's Loren Cordain's brief description of the process:

"As consumption of certain saturated fatty acids (12:0, 14:0, 16:0, but not 18:0) increases, the number of hepatic (liver) and peripheral low-density lipoprotein (LDL) receptors decreases which in turn causes serum concentrations of LDL cholesterol to rise (a process called down regulation). Down regulation occurs because internalization of 12:0, 14:0 and 16:0 within cells reduces the expression of genes which code for the LDL receptor protein."

Basically some SFAs turn down LDL receptors in the liver (only?) that reduces the liver's ability to remove LDL particles from the blood.

Regards
Randy

LeenaS said...

To Randy:

As for the 16:0 saturated, your (and maybe even the Nobel laureates) conclusion is at least flawed if not wrong.

The 16:0 will show up in tests for metabolic patients, but... But not because of the consumed 16:0 but because of the excess carbohydrates that the liver tries to get rid of, via transforming thmen to the safest matter that it knows. Which happens to be 16:0 saturated fat.

It is no longer seen in people who do not overeat carbohydrates, in spite of the consumed levels of 16:0 SFA... if measured after fasting.

Life (especially in living creatures and in live processes) are interesting, aren't they?

Dave said...

@Randy,

I don't suppose you have a reference for this? I'm curious as to whether there was any experimental evidence for the effect you cite in vivo, or if it was just a model. The references I've followed from Cordain's papers are generally either observational or unconfirmed models. Indeed, one case (and it may be the one you cite) referred to a model of down-regulation of hepatic LDL in response to serum cholesterol levels, with one mention (in a figure caption, no less) of saturated fatty acids. I remember thinking at the time that it seemed Cordain had over-extrapolated a bit.

If I'm not confusing hypotheses, I believe the mechanism you are referring to, while once the leading candidate, has since been taken off the table.

The textbooks I was referring to were all post 1985, including Lipid Biochemistry (1991), and a couple from the 21st century. I discuss this in more detail here on my blog:

http://sparkofreason.blogspot.com/2008/04/cognitive-dissonance-and-scientific.html

I'd be extremely interested if you had some additional info. Thanks.

Jen said...

@ Jim - it seems everyone has advice for you, and so do I:

You might want to check your blood sugar 1-2 hours after eating a meal with substantial carbohydrate. Postprandial hyperglycemia and hyperinsulinemia can cause tachycardia, shortness of breath and chest pain.

Nancy LC said...

Jim Purdy, I get tachycardia too when I eat a lot of carbs, especially from wheat. Try that double cheeseburger without the bun and see if that doesn't change things.

It turns out I'm gluten intolerant and the fast, pounding heart beat was just another indicator of that.

Robert Andrew Brown said...

LenaS

You said

"transforming them to the safest matter that it knows. Which happens to be 16:0 saturated fat."

Can you expand on this please.

How is the balance between 14 16 and 18 carbon determined?

Grass fed ruminants seem to have a fairly even balance.

Marine animals seem to have significantly more 16 than 18.

Chicken and pheasants have more 16 that 18 but I do not know if that is due to diet (eg grain fed)

I have been puzzling on this.

Thanks

Carl M. said...

A hypothesis: Under some circumstances (say, inflamed arteries or some such) saturated fats are dangerous, (perhaps by making the blood a bit more viscous). Under other circumstances, saturated fats are beneficial (say, by protecting against peroxidation of the more delicate fats.)

If such a hypothesis was true, then single-variate studies of saturate fat would give statistically ambiguous results even though saturated fat might be an important factor (dangerous for Jim, for instance).

Methinks such conditional good/bad hypotheses are the next frontier for diet and exercise research.

Stephan Guyenet said...

Deb,

The dietary cholesterol theory was never really championed by Keys, as far as I know. Here's a reference:

http://circ.ahajournals.org/cgi/reprint/5/1/115.pdf

Jim,

I think your reaction to cheeseburgers and biscuits/gravy is a good reason to avoid those foods. Just keep in mind that saturated fat is a relatively small fraction of the calories in those.

Mario,

Thanks for the anecdote, I think it's common to see results like that.

Carl,

While that's hypothetically possible, I think at some point it becomes splitting hairs unless the effect is large.

randy said...

Dave Wrote:
I'd be extremely interested if you had some additional info.

Reply:
Hi Dave.
My understanding is that the LDL receptor model is considered established.

Brown and Goldstein won the 85 Nobel Prize in Medicine for its discovery.

Here's a couple of links to studies that found the relationship between SFAs and LDL down regulation.

1.
http://www.jlr.org/cgi/content/abstract/38/3/459

Reducing saturated fat intake is associated with increased levels of LDL receptors on mononuclear cells in healthy men and women
VA Mustad, TD Etherton, AD Cooper,

2.
Lipoprotein receptors and the control of plasma LDL cholesterol levels
Goldstein and Brown Eur Heart J.1992;

The earlier quote I provided was from Cordains site here:
http://www.thepaleodiet.com/faqs/

If you'd like a very interestind detailed view of the history of standard Lipid over the last 100 years please check out this:

Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy
http://www.jlr.org/cgi/content/abstract/45/9/1583

Please note there are six papers in this series all available on the web. Agree or disagree its a good primer on what the standard theory is and why its believed.

Thanks
Randy

randy said...

Hey Dave,

A couple more points.

Folks that have a genetic defect such that the LDL receptor is always down regulated have a very large increase in heart attacks, some as early a 2 years old.

Folk that have a genetic advantage such that the ldl receptor is over expressed have a large reduced rate of heart attacks.

Finally another study in healthy humans:

Reducing saturated fat intake is associated with increased levels of LDL receptors on mononuclear cells in healthy men and women

Studies with animal models suggest that saturated fatty acids raise low density lipoprotein (LDL)-cholesterol levels by reducing LDL receptor- mediated clearance. To examine this directly in humans, we studied the effects of lowering dietary saturated fat on LDL-receptor abundance in peripheral mononuclear cells which reflects hepatic LDL-receptor status. Healthy males and females (n = 25) participating in the DELTA (Dietary Effects on Lipoproteins and Thrombogenic Activity) Study consumed three experimental diets in a randomized cross-over design. Diets provided 34% fat, 15% saturated fatty acids (Average American Diet); 29% fat, 9% saturated fatty acids (Step-One Diet); and 25% fat, 6% saturated fatty acids (Low SAT Diet). Peripheral mononuclear cells were isolated from blood samples collected after 6 and 8 wk. An ELISA was used to quantify LDL-receptor protein in total cell membranes. LDL- receptor abundance increased by 10.5% after the Low SAT Diet (P < 0.05). This was associated with an 11.8% decrease in serum LDL- cholesterol (P < 0.05). A linear inverse relationship was observed between the percentage change in LDL-cholesterol and the percentage change in LDL-receptor abundance (r = -0.59; P < 0.01). In addition, LDL-receptor abundance also was correlated inversely (P < 0.001) with serum levels of LDL-cholesterol (r = -0.747) and apoB (r = -0.593). In summary, reducing dietary saturated fat is associated with an increase in LDL-receptor abundance of magnitude similar to the decrease in serum LDL-cholesterol. Thus, an important mechanism by which reductions in dietary saturated fatty acids decrease LDL-cholesterol in humans is through an increase in LDL-receptor

Stephan Guyenet said...

Randy and Dave,

I don't see the purpose of debating the mechanism of an effect that doesn't exist in humans.

Total cholesterol and LDL don't seem to be affected by dietary saturated fat in the long term, at least not to any significant degree.

LeenaS said...

Robert Andrew Brown:

I cut short on the long story of lipids, but there is a difference in lipid ratios that we eat, lipid ratios found in fasting plasma and lipid ratios found in our tissues (which are selective as the double lipid membranes in our cells are veri specific and ingenious). These ratios are dependent partially on what is preferred for fuel (and how much choise we have on using lipids at all) and partially on what liver makes of the excess carbohydrates that cannot be stored as glycogen or used as fuel. So, that is already 3 by 2 variables :)

The only rather constant thing in all these variables with multiple lipids is that liver tends to make only one kind of fat from excess glykogen/carbs/protein and that for us is 16:0 - which it then delivers into liver tissue or as triglyserides, to be stored elsewhere.

Ruminants, on the other hand, have their useful bacteria to provide them also with other short chain SFA's, during digestion. And birds seem to thrive even with grains, which privides them a good selection of lipids for tissue.

(sorry, this is still just a short cut to the lipide...)

Carl M. said...

Hairsplitting?

Consider a single-variate study of sunlight. Such a study might find some nice things about large amounts of sunlight, but the overall mortality might be worse than office worker levels.

However, if you were to look at two variables: sunlight levels and ancestry, you'd get a much less ambiguous picture of optimal sunlight.

Robert Andrew Brown said...

Leena S

Many thanks for responding.

"The only rather constant thing in all these variables with multiple lipids is that liver tends to make only one kind of fat from excess glykogen/carbs/protein and that for us is 16:0 - which it then delivers into liver tissue or as triglyserides, to be stored elsewhere."

Thanks that was really helpful. I did not know that there is some sort of break point in fatty acid synthesis when palmitate C16.o is reached.

I found this on wikipedia which may offer the beginning of an explain why palmitate is preferred - path of least resistance. (-:

http://en.wikipedia.org/wiki/Fatty_acid_synthesis

"After release from the ACP, palmitate is esterified to Coenzyme A, as this is done with all free fatty acids inside cells to prevent lysis of the cell membranes. If further elongation has to happen, the palmitoyl CoA, or any other acyl-CoA from a dietary acid, then moves into the endoplasmic reticulum, where it can be elongated up to a length of 20 to 24 carbons by essentially the same chain of reactions as happens in the cytosolic ACP."

Robert Andrew Brown said...

Randy

"Journal of Lipid Research, Vol. 46, 2037-2051, October 2005"

Thank you very much for the link - some very useful material

randy said...

Stephan,

I've got a number of what I believe are very valid criticism of the Muller el al study.

1. The authors admit their results were an outlier. From the study:

"When we compared our results with those from other studies we observed greater effects *** than in any other study."

2. When they replaced fats by carbs in the low fat group they used Sucrose and Fructose. GAK!

The authors even reference other studies the replaced fats with high fiber/Low GI carbs reported a reduction of LDL with little change in HDL. Other studies that used real food low GI high fiber report the same thing. LDLs go down and HDL go up (with total fat <15%) Refs (1) (2) (3) (4). The Ornish study reported LDL reductions of up to 40% for over 5 years with no or little reduction of HDL levels. Also, its only these very low fat (sat and polys) that have shown artery lesion reduction via imaging studies. I still wait (and hope for, believe or not) higher sat fat diets will show the same thing, but it hasn't happened yet.

3.
A much larger study evaluating 82 metabolic ward studies (much tighter controlled than the Muller study) using complex carbs instead of sucrose and fructose showed a greater response to carb substition for saturated fats for LDL levels. (5)

Refs:
1.
The effect of a low-fat, high-carbohydrate diet on serum high density lipoprotein cholesterol and triglyceride.

2.
Glycaemic index as a determinant of serum HDL-cholesterol concentration.

3.
Intensive lifestyle changes for reversal of coronary heart disease. JAMA. 1998;280:
2001-7. [PMID: 9863851]

4.
Effect of a short-term diet and exercise intervention on oxidative stress, inflammation, MMP-9, and monocyte chemotactic activity in men with metabolic syndrome factors

5.
Meta-Analyses of Plasma Lipoprotein
Responses to Changes in Dietary Fat and Cholesterol

Stephan Guyenet said...

Randy,

You left out part of the quote:

"When we compared our results with those from other studies, where high fat and low fat diets were compared as to their effects on serum lipoproteins, we observed greater effects on LDL/HDL cholesterol and apoB/apoA-I ratios than in any other study"

The quote wasn't referring to the TC and LDL changes they saw, just to the LDL/HDL ratio and the apoB/apoA-I ratio. They went on to describe other studies that came to similar conclusions on TC and LDL changes:

"In the study of Nelson et al., which was also similar to our study, where the effects of a low fat diet (22 E%) and a high fat diet (39 E%) both with P/S 1.0 were compared, no significant differences in plasma total or LDL cholesterol levels between the diets were observed."

I agree with your comment about the difference in sucrose intake, that could definitely be a factor. At the very least, the paper shows that factors besides saturated fat can have an equivalent effect on blood lipids. This makes me wonder why researchers have focused their efforts so tightly on saturated fat, nearly to the exclusion of other dietary factors.

I have very little faith in meta-analyses of this data now that I've seen the primary literature. You can't meta-analyze garbage into good data.

But honestly, let's not spend too much effort debating about these short-term trials. They're water under the bridge, because the long-term data are clear that saturated fat has little or no effect on TC and LDL in the long term.

Stephan Guyenet said...

Randy,

I'm having a hard time seeing the relevance of the LDL receptor study you posted. First of all, it was a short-term trial (8 weeks). Second of all, mononuclear cells don't make a significant contribution to LDL clearance.

If you have a study showing that liver LDL receptors are lower in humans after a year or more of eating a high-saturated fat diet, then that will be more relevant.

Nadia Sam Cyrus said...

I find a lot of important in your blog, Stephan. Thanks your posting.

Bris said...

Jim Purdy
If I were going to guess, I suppose my chest pains are caused by the saturated animal fats in the cheeseburgers, while the avocados' mono-unsaturated fats (and high fiber?) have little or no impact.

More likely it is the carbs in the cheeseburger buns and the biscuits that are causing the problems. Avocados have no carbs.

No naturally occurring food is high in both fat and carbs.

randy said...

Stephan Wrote:
I'm having a hard time seeing the relevance of the LDL receptor study you posted. First of all, it was a short-term trial (8 weeks).

Reply:
Do you have any reason to think that the results revert back after 8 weeks? Also the Muller et al study you referenced was for only 3weeks, doesn't the same critic apply?

Stephan Wrote:
Second of all, mononuclear cells don't make a significant contribution to LDL clearance.

Reply:
Mononuclear cells are used because they are a suragate for liver ldl receptors. It's not easy to take liver samples from subjects so an indicator of these receptors are used (1).

Regards
Randy

1.
Powell, E. E., and P. A. Kroon. 1994. Low density lipoprotein
receptor and 3-hydroxy-Smethylglutaryl coenzyme A
reductase gene expression in human mononuclear leukocytes
is regulated coordinately and parallels gene expression
in human liver. J. Clin. Invest. 93: 2168-2174.

TedHutchinson said...

Statins and Vitamin D The full text is online if you click the PDF link

Starts with the sentence The diet-cholesterol-heart hypothesis dominated medical thinking for the latter half of the 20th century and it still persists. The diet component has so many inconsistencies that it is unsustainable. It continues in popular folklore and government dietary policies but it seems to have been quietly dropped by most cholesterol-heart researchers

Increased Levels of 25 Hydroxyvitamin D and 1,25-Dihydroxyvitamin D After Rosuvastatin Treatment: A Novel Pleiotropic Effect of Statins? again full text online.
This study has shown an effect of rosuvastatin on vitamin D metabolism, with an increase in both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. This may be an important pleiotropic effect whereby rosuvastatin reduces mortality in patients with coronary artery disease. Further studies are needed to clarify the relationship between statins and vitamin D metabolism.
I'm sure this will give impetus to the idea of adding statins but not vitamin D to the drinking water.

Robert Andrew Brown said...

Ted Hutchinson

Thank you for that link

Somebody else brought up Vit D and statins and my uneducated thoughts were the same as summarised in the paper;

"The statin Vit D argument is largely beyond me but my quick skim thoughts / guess are;

According to "Metabolism at a Glance" 7-dehydrocholesterol is a direct downstream product of HMG CoA so why would reducing the HMG CoA increase vitamin D?

Vit D levels could increase because of lower uptake or usage.

Vit D is an antioxidant. This trial and others suggest lovastatin is an antioxidant. Is lovastatin sparing vitamin D.

http://www.springerlink.com/content/x727024h05175620/

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T8P-45NT8SK-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=951729169&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=9ec9367894343f9078aa2e4fc6e5210d

Reduced cholesterol and improved antioxidant status / oxidised cholesterol etc would reduce the risk of coronary events."

Stephan Guyenet said...

Randy,

OK, there does seem to be a good correspondence between LDL receptors on mononuclear cells and hepatocytes.

But I still don't understand why we're debating the mechanism of a phenomenon that's inconsistent in short-term trials and nonexistent in the long term.

Chandler said...

Randy >> Do you have any reason to think that the results revert back after 8 weeks?

Here's the results of two studies (cribbed from the Eades site):

The first lasted 12 months, with the following:

The CHO [conventional carbohydrate] diet reduced serum cholesterol and LDL cholesterol compared with PRO [reduced carbohydrate] (P < 0.01) at 4 mo, but the effect did not remain at 12 mo.

Taken from here.

The second lasted 24 months, with the following:

LDL cholesterol levels (Figure 3C) did not change significantly within groups, and there were no significant differences between the groups in the amount of change.

Also, [t]he P values for the comparison between the low-fat group and the low-carbohydrate group are 0.01 for HDL cholesterol, 0.03 for triglycerides, 0.94 for LDL cholesterol, and 0.01 for the ratio of total cholesterol to HDL cholesterol.

Taken from here.

So unless I'm drastically misinterpreting the data, these two studies provide no indication that LDL is significantly affected by swapping saturated fat for carbohydrates.

Also, provided LDL receptors in the liver play a major role in regulating LDL levels in the blood, is there any reason to suspect that the number/effectiveness of these LDL receptors remains constant over time?

Senta said...

I also wonder what exactly the number of LDL receptors signifies?

For instance, since my husband and I have been eating high fat, low carb, he had a VAP cholesterol test. His cholesterol is not "low" at all but he has pattern A LDL (lots of light, fluffy particles and hardly any small, dense particles). Could liver LDL receptors possibly down-regulate because they are no longer needed?

After all, one of the liver's main functions is to remove "garbage" from the blood. Possibly it doesn't see the light, fluffy LDL as garbage.

Stephan Guyenet said...

Senta,

I think that's a great hypothesis. I've been wondering the same thing lately. PUFA increase the susceptibility of LDL to oxidation in vivo and also lower cholesterol. Coincidence?

Maybe not. If the body wanted to limit LDL serum residence time to counter a tendency toward oxidation, increasing LDL receptors and decreasing serum LDL would be one way to do it.

If the LDL are full of saturated fat and large, they will be less susceptible to oxidation so the body can let them float around for longer.

Kurt G. Harris MD said...

Stephan

I can't speak for Peter but he talks about this some on his blog - a large part of the reason he says not to worry about saturated fat. It's the oxidized (or oxidizable) stuff that need to be cleared.

I for one buy his reasoning.

I have seen some have LDL and total chole go up when first going VLC paleo, then it may go down again at 6 months - maybe it's temporary and related to ketoadaptation and decreased glycolysis with time?

randy said...

Stephan Wrote:
But I still don't understand why we're debating the mechanism of a phenomenon that's inconsistent in short-term trials and nonexistent in the long term.

Reply:
Because very low total fat(<10%), low SFA diets do drastically reduce LDL levels (averate ~40%) and these levels are mantained for over a year. (1) (2)

Randy


I agree that if you put folks on AHA/NCEP diets the results are mild at best (<5% ldl reduction) and these don't last and we don't really know what these folks have been eating.


1.
Intensive lifestyle changes for reversal of coronary heart disease. JAMA. 1998;280:
2001-7. [PMID: 9863851]

2.
Updating a 12-year experience with arrest and reversal therapy for
coronary heart disease (an overdue requiem for palliative cardiology). Am J Cardiol.

randy said...

Its often that one of the benefits of higher SFA consumption is reduce risk of LDL oxidation.

One study that looked at this issue came to the conclusion that lower total fat, lower SFA consumption, contrary to expectations, increased ldl susceptibility to oxidation.

Randy

1.
Full paper here: http://jn.nutrition.org/cgi/reprint/130/9/2228

Lowering Dietary Saturated Fat and Total Fat Reduces the Oxidative
Susceptibility of LDL in Healthy Men and Women1

randy said...

Sorry, I mis-wrote:
Here's what I was intended.

Its often stated that one of the benefits of higher SFA consumption is reduced risk of LDL oxidation.

One study that looked at this issue came to the conclusion that lower total fat, lower SFA consumption, contrary to expectations, Decreased ldl susceptibility to oxidation.

Randy

1.
Full paper here: http://jn.nutrition.org/cgi/reprint/130/9/2228

Lowering Dietary Saturated Fat and Total Fat Reduces the Oxidative
Susceptibility of LDL in Healthy Men and Women1

Stephan Guyenet said...

Randy,

What makes you think it was saturated fat that reduced cholesterol in the Dean Ornish study you cited? It involved major lifestyle and diet changes. We've just cited numerous studies showing that saturated fat doesn't affect total cholesterol or LDL in the long term, so I doubt saturated fat restriction had anything to do with it.

About LDL oxidation, you've got it backwards. You're looking at in vitro results, where they take LDL out of serum and oxidize it with copper. When you simply draw serum and look at LDL oxidation in vivo, it's reduced on high-saturated fat diets and greatly increased with high PUFA. The copper oxidation assay gives results that don't match up with what you see when you actually look directly at human serum. Here's one reference:

http://atvb.ahajournals.org/cgi/content/full/17/10/2088

See the TBARS assay in table 4. That's the only in vivo measure they checked. oxLDL in the sat fat group was barely more than 50% what they saw in the veg oil group. Note that it doesn't line up with the in vitro copper oxidation assay. That assay is therefore highly suspect.

Here's another reference:

http://atvb.ahajournals.org/cgi/content/full/16/11/1347

Take a look at the TBARS assay in table 4. Again, oxLDL is higher in the PUFA group.

And finally, a low-fat, high-PUFA diet rich in fruits and vegetables also increases oxLDL:

http://atvb.ahajournals.org/cgi/content/full/24/3/498

I doubt the increase in oxLDL had anything to do with the fact that it was low-fat. It probably had to do with the PUFA.

When you eat a low-fat diet, your liver takes the carbohydrate and makes it into palmitic acid. Thus, your serum lipids become highly saturated. That's what you see in the Kitavans. That's probably the reason the Bantu had so little atherosclerosis. They had a diet that was very low in PUFA and so their LDL was highly saturated and not prone to oxidation. You can do the same thing by eating beef tallow.

randy said...

Stephan Wrote:
"Here's one reference:

http://atvb.ahajournals.org/cgi/content/full/17/10/2088

See the TBARS assay in table 4. That's the only in vivo measure they checked. oxLDL in the sat fat group was barely more than 50% what they saw in the veg oil group. Note that it doesn't line up with the in vitro copper oxidation assay. That assay is therefore highly suspect."

Reply:
Stephan that's an incorrect (in my view) analysis.

Its improper to take numbers from one test on oxidation (with its own units) and compare to it another test with different units measuring differnt things and say one test is bogus because the numbers have a different linear scale. Thats bogus.

Your arguement would hold more weight if both test (in vivo and in vitro) yielded different significant results, but they don't. They both indicate the same thing. Namely that PUFAs form more oxidants than MUFAs and SFA. It also appears that MUFAs take a little longer to oxidize, but this can only be measured from the in vitro test.

Randy

randy said...

Stephan Wrote:
"What makes you think it was saturated fat that reduced cholesterol in the Dean Ornish study you cited? It involved major lifestyle and diet changes."

Reply,
I think its the very low fat (<10%),low SFA , low GI and high fiber content of the diet thats responsible for their exteme reductions in LDL levels. I don't think the other life style changes had much to do with it. I say this because the same results have been achieved by others using diet alone.

My only point is that this is the only diet that's been shown to reduce arterial lesion via angiogram imaging.

What's a bummer is this diet sucks and I'd much rather eat more paleo style, but I'm not sure its healthy, especially regarding CAD prevention.

Alot of this could be resolved if there was some of the imaging evidence that exist for Ornish style of diets.

Stepan Wrote
"We've just cited numerous studies showing that saturated fat doesn't affect total cholesterol or LDL in the long term, so I doubt saturated fat restriction had anything to do with it. "

Reply:
For one thing I don't think its proper to ignore lots of metabolic ward data that's out there. Asking someone what they been eating over the last year is not very reliable. This has been shown in many studies.

At least in the metabolic ward studies we know exactly what everybody eats.

Also I'm alittle suspect of using coconut oil as the main sourec of SFAs because of the relative lack of palmetic acid not to mention using sucrose and fructose as substitute carbs.

Randy

Stephan Guyenet said...

Randy,

I don't quite understand your argument. We have two types of data here:

1) A direct measurement of the oxidation status of LDL drawn directly from patient blood.

2) A test tube experiment where they take LDL from the blood, expose it to copper (which has nothing to do with how LDL is oxidized in the body), and see how fast it oxidizes.

When you look directly at LDL oxidation straight from human blood, it's lowest in saturated fat-rich diets and highest in PUFA-rich diets. That's a fact and it's consistent across studies.

When you do a test tube experiment using copper as an artificial oxidant, it's lowest in monounsaturated-fat rich diets and higher in PUFA and saturated fat diets.

To me, it's clear which measure is the most relevant.

Ornish's interventions have never been demonstrated to reduce total mortality or cardiovascular mortality. They are essentially untested, apart from some very preliminary imaging studies. He flaps his lips a lot but he doesn't have a shred of convincing data behind him. He advocates a bizarre diet that no human culture in history has eaten.

Winston said...

Stephan, are you saying Willett has changed his mind since this 2004 interview?

LeenaS said...

To Randy:

Finally you said it:
"Reply,
I think its the very low fat (<10%),low SFA , low GI and high fiber content of the diet thats responsible for their exteme reductions in LDL levels. I don't think the other life style changes had much to do with it. I say this because the same results have been achieved by others using diet alone."

What you think/believe is one thing.
What is proved by controlled studies, may be very different.
This "achieved by other studies" I have not seen, although I've been looking for that for years.
But, on the other hand, I have seen that many of the non-nutritious Ornish lifestyle factors have been proven to decrease metabolic syndrome.

Besides, I have clear opposing data for you:
Greetings from a lab animal family. We are high-butter-and-animal-fat eaters, just starting our tenth year on LowCarb. No problems with cholesterol (as a fact, our 20-year-old yangster has the fantastic Maasai figures there - maybe just because of the butter?). And, thank God, even us oldies are relieved from our health problems and symptoms experienced in the bad old times. In our case it is pretty evident that our health problems were linked with diet that was far too low on animal fats and far too-oo high on grain fibres and "good carbs".

Bris said...

Hi Stephan,

I have just read the American Diabetic Association new guidelines"

American Diabetes Association (2008). "Nutrition Recommendations and Interventions for Diabetes". Diabetes Care 31 suppl: S61–78. doi:10.2337/dc08-S061. PMID 18165339.
http://care.diabetesjournals.org/cgi/content/full/31/Supplement_1/S61.

They suggest an upper limit of 130g cabs/day. With a 65g protein intake this requires a 73% fat intake for a 2500/Cal diet. This sounds just like the Atkins "maintenance phase" to me!

Robert Andrew Brown said...

Randy
Thanks for posting this.

Full paper here: http://jn.nutrition.org/cgi/reprint/130/9/2228

Lowering Dietary Saturated Fat and Total Fat Reduces the Oxidative
Susceptibility of LDL in Healthy Men and Women1

Do you know of any other trials that give fat breakdowns of LDL?

Some of the shifts in fat compostion shown in table 3 are thought provoking.

For example why has the Omega 6 content dropped in the low sat group given that the poly-unsaturated intake on all three diets is the same?

Why equally has the Omega 9 content risen?

Chandler said...

Stephan,

2) A test tube experiment where they take LDL from the blood, expose it to copper (which has nothing to do with how LDL is oxidized in the body), and see how fast it oxidizes.

Unfortunately, I'm not familiar enough with the chemistry involved, but when reading this paper I did have a two main questions:

1. Does the provided method of measuring oxidative susceptibility take into account LDL that's already oxidized in the blood sample? I.e., could the oxidation rate have been faster in the baseline diet because there was simply more unoxidized LDL?

What would happen if they reran the oxidation tests on the same in-vitro samples a second time? Wouldn't all samples show a reduced oxidation rate (as a function of the remaining unoxidized LDL)?

2. Since oxidized LDL can be trapped as part of atherosclerosis, wouldn't any attempt to measure oxidized LDL in vitro be misleading?

One could simply claim that the reason these LDL values differ is that although all test subjects had the same amount of susceptible LDL, perhaps the low-sat groups had higher rates of atherosclerosis.

Chandler said...

I was rereading my comment and realized I left out a bit of the direction my mind is going to:

1. Since oxidized LDL is "damaged" in a sense, and the test merely demonstrates how much "undamaged" LDL is free within the bloodstream, it seems to me that it's better to eat the diet that trends towards higher amounts of undamaged LDL free within the blood.

2. Since oxidized LDL seems to bind to arterial walls, of what use is measuring oxidized LDL levels from blood serum?

For all I know, the three diets had little influence on absolute LDL levels in the patients (it was a short term cross-over study...) and the PUFA diets simply resulted in a higher ratio of oxidized LDL becoming trapped in arterial walls (and therefore unmeasurable in-vitro).

homertobias said...

I think that I see the direction of your next post. When I first read this post, what struck me as interesting was PUFA APPEARS TO LOWER LDLC! WHAT! This appears to be a more short term affect. I was wondering if any of the articles looked beyond the friedenwald calculated ldlc and into particle size, oxidation, affect of acute phase reactants. I too like the hepatic ldl receptor theory.
Robert Andrew Brown, pleasefinish your book. I'll read it.

Kurt G. Harris MD said...

Randy

You said:

"My only point is that this is the only diet that's been shown to reduce arterial lesion via angiogram imaging.
"
I would not place too much faith in Ornish's supposed angiographic evidence of plaque regression, which was a miniscule difference and to my knowledge has never been replicated. Angiography does not assess plaque, only stenosis or degree of narrowing. With the phenomenon of positive remodeling, stenosis can improve even while plaque is increasing. Positive remodeling even correlates with plaques being unstable and more likely to rupture. IVUS (intravascular ultrasound) and not conventional angiography or even calcium scoring is the way to prove plaque regression.

I plan to post on Ornish's study soon, as it is so often quoted.

I concur with Stephan's point about the Ornish diet being completely outside our evolutionary experience. Try weaning your child to a radiaclly low fat diet like that without supplementation and see how she develops.

randy said...

Kurt,

I look forward to your comments as you know what these imaging actually mean.

I provided links to all the angiogram studies on diet that I could find. Appreciate all comments. (1,2,3,4,5,6)

Also Kurt, I'd be interested in your view of "calcium scans". Would these tests be a better indicator to use in evaluating a dietary approach?

To Robert,

I don't have any futher data on the points you mentioned and thanks for pointing them out

Here's refs to angiogram studies:

1.
Gould KL, Ornish D, Kirkeeide R, et al. Improved stenosis geometry
by quantitative coronary arteriography after vigorous risk factor
modification. Am J Cardiol 1992;69:845–53.

2.
Ornish DM, Brown SE, Billings JH, et al. Can lifestyle changes
reverse coronary atherosclerosis? Four-year results of the Lifestyle
Heart Trial. JAMA 1998;280:2001–8.

3.
Blankenhorn DH, Johnson RL, Mack WJ, et al. The influence of
diet on the appearance of new lesions in human coronary arteries.
JAMA 1990;263:1646–52.

4.
Watts GF, Lewis B, Brunt JNH, et al. Effects on coronary artery
disease of lipid-lowering diet, or diet plus cholestyramine, in the
St Thomas’ Atherosclerosis Regression Study (STARS). Lancet
1992;339:563–9.

5.
Haskell WL, Alderman EL, Fair JM, et al. The effects of intensive
multiple risk factor reduction on coronary atherosclerosis and clinical
cardiac events: the Stanford Coronary Intervention Project
(SCRIP). Circulation 1994;89:975–90

6.
Quinn TG, Alderman EL, McMillan A, et al. For the SCRIP Investigators.
Development of new coronary atherosclerotic lesions during
a 4-year multifactor risk reduction program: The Stanford Risk
Intervention Project (SCRIP). J Am Coll Cardiol 1994;24:900–8.

Stephan Guyenet said...

Winston,

What I stated in my post is that Willett doesn't believe that dietary cholesterol elevates blood cholesterol in humans. I didn't see anything in that interview to the contrary.

Bris,

Wow. That's unexpected. I guess I can stop bashing the ADA then.

Chandler,

I'm sure some oxLDL does end up sticking to plaque. However, oxLDL in serum associates tightly with the risk of heart attack. That suggests that however much oxLDL plaque is taking out of serum, it doesn't reduce its effectiveness as a marker of heart disease. I'll be writing about oxLDL soon.

Barkeater said...

Stephan - You mention the study in Arterioscler. Thromb. Vasc. Biol. 18:441. 1988., which showed a reduction in LDL with lower sat fat diets. I took the hint you give - mentioning that LDL in that study was calculated by the Friedewald formula -- and recalculated the results using the Iranian formula that is more accurate where trigs are less than 100. I found that the 6% sat fat diet (vs. 15% sat fat) lowered LDL-C by 5% rather than the reported 11%.

I have compared the Iranian method to Friedewald in relation to a few NMR particle counts and found the Iranian method closer to NMR at lower trigs, although this is anecdote and not science.

Studies based on Friedewald may have skewed the results to appear that lowering sat fat in the diet has a greater effect on LDL than is actually the case, given the fact that trigs normally go up as sat fat is reduced.

Barkeater

lightcan said...

Bris,

I'm afraid you got that wrong. The 130 grams of carbs is the minimum amount, not the maximum.
This is the reason for not recommending low-carb!!:
"Low-carbohydrate diets might seem to be a logical approach to lowering postprandial glucose. However, foods that contain carbohydrate are important sources of energy, fiber, vitamins, and minerals and are important in dietary palatability. Therefore, these foods are important components of the diet for individuals with diabetes."

And they say this about sat fat:
"In nondiabetic individuals, reducing saturated and trans fatty acids and cholesterol intakes decreases plasma total and LDL cholesterol. Reducing saturated fatty acids may also reduce HDL cholesterol."
Very funny.

Kurt G. Harris MD said...

Randy

Thanks I will review some of those for sure.

The thing to remember about calcium score is that that you can have a lot of atherosclerosis at a young age and have zero calcium.

I too was shocked to see reference to a new ADA recommendation of 135 g carbs. Lindeberg's group has a new paper out that made mention of that.

The ADA website, however, says:

"How much carb?
A place to start is at about 45-60 grams of carbohydrate at a meal."

That sounds like a floor of 135, not a ceiling!

Stephan Guyenet said...

Barkeater,

Nice work! You did pick up on my little hint. I wasn't going to bother calculating it myself but I appreciate you doing it.

So the effect on LDL is cut in half when you use a more accurate formula.

Kurt,

I think what you're saying about atherosclerosis is very interesting. It's making me think there are at least two types with possibly two different causes-- the fatty type that doesn't necessarily contain calcium, and the calcified type. The fatty kind probably has to do with macrophage scavenging of oxLDL, and the calcification may have to do with a deficiency of vitamin K2.

I'm going to have to take a look back at some of the old UK autopsy studies to refresh my memory, but if I recall, the fatty type has increased along with the CHD epidemic, while the calcified type has stayed the same or even decreased.

I think it's interesting that fatty streaks (sudanophilia) are lowest in Masai arteries when they're at a period of their life when they're restricted to milk, meat and blood (low PUFA).

I look forward to more of your thoughts on this. It would be cool if you wrote a post on the relationship between Ca scans and atherosclerosis at some point.

Winston said...

Stephan, thanks, I misunderstood you. I hope I didn't come across as sarcastic, I was genuinely curious and your reply helps. :-)

Kurt G. Harris MD said...

Stephan

Will post much more on this in the future - need to do some more work on it first.

rahmin said...

Stephen, I'm a bit confused. This post suggests that a diet high in LA (Omega 6s) reduces LDL. One would extrapolate that Omega 6s are good for heart health under the common understanding that reducing LDL reduces risk of CHD mortality (though you do not say this explicitly). But your post on 5/24 suggests that CHD mortality and the occurrence of Omega-6s in tissue are directly related.

http://wholehealthsource.blogspot.com/2009/05/eicosanoids-and-ischemic-heart-disease.html

If a diet high in Omega 6s reduces LDL, but increases CHD mortality, could it be that LDL is not correlated to CHD mortality at all?

Am I missing something?

Much thanks for your work interpreting and sharing this information.

Pinoy White Metal said...

A very enlightening post Stephan, thanks for sharing your thoughts.

"I've noticed that eating a couple of big greasy bacon double cheeseburgers quickly gives me enough chest pain and tachycardia to send me to an emergency room. I get the same results from overeating biscuits and gravy. - Jim Purdy

Jim, eating greasy bacon double cheeseburgers especially if you do it on a regular basis means you are piling up on low-density lipoprotein. And from a layman's point of view, I guess you have to go easy on those kind of food or you'll find yourself in some hospital room later on down the road.

Edwin K.

Stephan Guyenet said...

Rahmin,

I'll be explaining everything in later posts. Here's a preview: industrial vegetable oils increase oxidized LDL, they increase inflammation and oxidative damage, they probably increase blood clotting and they probably increase the likelihood of ventricular fibrillation if omega-3 is insufficient.

Robert Andrew Brown said...
This comment has been removed by the author.
Robert Andrew Brown said...

Rahmin


You can reduce something in the blood stream by making more of something or using less of it.

Healthy people make less LDL.

Omega 6 eaters use more LDL so lowering blood LDL

Omega 6 encourages the body to take LDL up more quickly.

Omega 6 increases oxidisation of LDL in the blood and LDL once trapped in the vascular membrane. I suspect Omega 6 also increases the inflammatory processes in the macrophages.

Because more LDL is taken up I guess Omega 6 eaters get higher levels of LDL trapped in the vascular structure, and higher level of oxidation and damage, so no benefit from increased Omega 6 intake in vascular disease terms which explains the stats.

I suspect healthy people have low LDL because they make less not use more.

Bris said...

Edwin K
Jim, eating greasy bacon double cheeseburgers especially if you do it on a regular basis means you are piling up on low-density lipoprotein. And from a layman's point of view, I guess you have to go easy on those kind of food or you'll find yourself in some hospital room later on down the road.

Do you have any evidence to support this claim?

Saturated fat prevents coronary artery disease? An American paradox.

Robert H Knopp and Barbara M Retzlaff
American Journal of Clinical Nutrition, Vol. 80, No. 5, 1102-1103, November 2004

Dave said...

Nice, discussion, though I think it highlights the over-emphasis on a measurement (LDL) vs. searching for root cause (all the worse in the LDL case, since it often isn't directly measured). Type II diabetes provides an analogous example. You can easily measure fasting blood glucose, but chronically elevated blood glucose is not the cause of Type II diabetes, but a symptom. Idiot doctors treat it as if it were the disease, giving hyperinsulinemic Type II diabetics more insulin, which generally has no effect.

The discussion of observations of in vitro oxidation of LDL highlight a similar hyper-focus on individual measurements, rather than a consideration of all available information. Fundamentally, saturated fat is less-easily oxidized than unsaturated. If presence of saturated fatty acids somehow increase the potential for LDL to be oxidized, one needs to propose a mechanism. It follows from basic and extremely well-established chemistry that presence of PUFA would promote oxidation of LDL: once a free radical is formed, it has the ability to oxidize other molecules. What is the mechanism by which SFA increases LDL susceptibility to oxidize?

It is often said that absence of evidence does not imply evidence of absence, but this adage is often used in an empty context by those clinging to a hypothesis for which the evidence is absent. Rational reasoning demands that the hypothesis with greater evidence receive greater weight. You don't throw out knowledge of basic chemistry because an observation supports some other theory. That's backwards reasoning.

We can throw evolution in the pot as well. The body has evolved to manufacture and store saturated fat. It would be absolutely bizarre to suppose that we evolved a mechanism that would increase oxidative stress, given the considerable effort organisms expend to minimize damage from oxidation. I don't think anyone is going to hypothesize that the chain length of SFA somehow affects the oxidation of LDL (any takers?).

Pinoy White Metal said...

"Do you have any evidence to support this claim? - Bris



Yes. I got buried evidence. My father died from a stroke a few years back.

Dave said...

@Pinoy White Metal,

While I empathize with the loss of your father, I'm afraid your loss, while tragic, doesn't provide any scientifically valid evidence for this discussion.

Stephan Guyenet said...

Dave,

There is one mechanism whereby saturated fat might increase the amount of LDL oxidation in blood: massively increasing LDL concentration. When you feed rabbits or hamsters cholesterol and saturated fat (I don't know how well it works without the sat fat, maybe just as well), their LDL increases by some 10-fold, and oxLDL increases in parallel.

Obviously that bears little resemblance to the human situation, but it does show that if you have enough LDL floating around, it's one way to influence the total amount of serum oxLDL. oxLDL can go up in this way even if the particles themselves are more resistant to oxidation.

Pinoy White Metal said...

"While I empathize with the loss of your father, I'm afraid your loss, while tragic, doesn't provide any scientifically valid evidence for this discussion. - Dave

I'm sorry, I merely replied originally on Jim Purdy's comment about how double cheeseburgers affect him.

I never claimed anything other than he might be harming himself by eating double cheeseburgers.

Do you mean to say I cannot comment on Jim Purdy's choice of food unless I have scientific evidence?

Anyway, I find Stephan's post very informative.

Jim Purdy said...

I hope Pinoy empathizes with my having to give up double bacon greaseburgers.

Dave said...

@Pinoy White Metal,

My fault - looks like I lost track of the thread (though it probably is better to have scientific evidence if you're going to comment on somebody's food choices, at least beyond the effect on their breath :-)

Dave said...

@Jim Purdy

You might try giving up the bread on your double bacon cheeseburgers.

Dave said...

@Stephan

Agreed.

Let's consider some of the hypotheses discussed above in the context of overall metabolic regulation. One hypothesis seems to be the following:

"Saturated fatty acids (SFA) reduce expression of the LDL receptor AND increase susceptibility of LDL to oxidation."

The other would be

"Polyunsaturated fatty acids (PUFA) increase expression of the LDL receptor AND increase susceptibility of LDL to oxidation."

We have many examples where the body attempts to minimize oxidative stress. The PUFA hypothesis is in line with this: PUFA is prone to oxidation, so in response to increased dietary PUFA, the body responds by expressing more LDL receptors to clear LDL before it oxidizes. If SFA did indeed make LDL more susceptible to oxidation, in the SFA hypothesis we'd have the strange situation where the body's response to dietary SFA increases oxidative stress.

SFA has been on the human (and proto-human) menu for a long time. PUFA probably has too, if nothing else from brains. Similar to the situation with glucose, it would appear we've evolved mechanisms to reap the benefits of the PUFA's found in foods while mitigating potential damamge.

The evolutionary diet of rodents is, as far as I know, pretty low fat. It would not surprise if large quantities of fat caused a rat's LDL to go berserk, as they would not have evolved regulatory mechanisms to deal with this case.

LeenaS said...

Dave said:
"The evolutionary diet of rodents is, as far as I know, pretty low fat. It would not surprise if large quantities of fat caused a rat's LDL to go berserk, as they would not have evolved regulatory mechanisms to deal with this case."

Actually, there is rather strong evidence that rodents go for fat, too, if the choice is given to them. See study on wild type (i.e. not lab bred) mice in this peter's post. Given the freew choice the wild mice gorged on saturated fat. And stayed ok.
http://high-fat-nutrition.blogspot.com/2008/09/physiological-insulin-resistance-wild.html

The study above is one of the reasons, why I really don't buy Stephans SFA-cholesterol-hypothesis either. The other big reason is the maasai. And the third is Kwasniewski's OD, which is literally based on continuous, rich supply of SFA's and cholesterol. And which seems to be working very, very nicely, too.

Robert Andrew Brown said...

LlenaS

What is Stephans SFA-cholesterol-hypothesis.

Could you please expand your comment.

Do the Masai not support Stephan's contentions?

Thanks

LeenaS said...

Dear Robert,
Sorry, I was inaccurate in my words. I was referring to one Stephan's response to Dave in this long line of comments, not his general SFA-chol hypothesis:

Stephan wrote: "There is one mechanism whereby saturated fat might increase the amount of LDL oxidation in blood: massively increasing LDL concentration. When you feed rabbits or hamsters cholesterol and saturated fat (I don't know how well it works without the sat fat, maybe just as well), their LDL increases by some 10-fold, and oxLDL increases in parallel."
... and I do doubt that SFA-cholesterol connection in eatable amounts.

The study he here refers to, is pretty awkward, even for rabbits: The rabbits were fed up to 5% of their food as chemical cholesterol dissolved in Wessen oil, which is mostly linoleic acid /ref: peters hyperlipid/. So there was the synthetic cholesterol, worth nearly 100 eggs a day for a human. And there was the processed fat from the Dood old days, with lots of LA, trans fats and dihydro-K...

Robert Andrew Brown said...

LeenaS

Thanks for the clarification.

Ashu said...

@Jim

What causes that pain is quite clearly the amount of grease on the food, wasn't it proved that greasy foods are metabolized differently/slower than regular, non greasy foodstuffs.

All that grease is just going to cause that pain, steaks don't have grease and grilled chicken breasts don't neither.

I highly doubt it's related to the bun, surely you've eaten wheat products without toast and they haven't had nearly the same effect on your body.

Dave said...

@Ashu

"What causes that pain is quite clearly the amount of grease on the food"

Why exactly is that so clear?

Andreboco said...

To Bris, I just read the ADAs diet recommendations. They do not state that the 130 gram carb is an upper limit. It says "not less than 130 grams". Quite a different meaning. There is no upper limit. As a Type 1, I know that 130 is way to high to have normal BS control. Please re read the recomm. The ADA is still way off.

trinkwasser said...

Greatly reducing my carbs doubled my HDL and decimated my trigs. It had little effect on my LDL. Well it increased slightly. but adding more saturated fat brought my HDL from 46.8 to 54.6 and reduced by LDL from 105.3 back to 93.6

Doesn't matter how many papers claim this cannot happen, since this kind of change is common in the Real World (and many people do it much better than me)

"“The deleterious effects of fat have been measured in the presence of high carbohydrate. A high fat diet in the presence of high carbohydrate is different than a high fat diet in the presence of low carbohydrate.” Richard Feinman, PhD "

I think that's the nub of the problem - most dietary research is carried out on the basis that carbs are beneficial or at worst neutral, and they concentrate on the macronutrient changes they *think* are important while ignoring the changes that may actually be having the effect they are studying.

Finally we're seeing papers like Mente

http://www.natap.org/2009/HIV/042209_01.htm

and a couple with Ron Krauss and Frank Hu

http://www.ajcn.org/cgi/content/abstract/ajcn.2009.27725v1

http://www.ajcn.org/cgi/content/abstract/91/3/502

not to mention a whole bunch now looking at the connection between carbohydrate intake, glycemic index and HbA1c vs. cardiovascular disease

Josh Dale said...

Dr. Guyenet,

I just started reading your blog and it's addictive to say the least! Quick question: if PUFA drops LDL but increases the chances of it being oxidized, what percent of the calories do you suggest for it (little as possible?) Thanks in advance!

Josh

Tom Weiss said...

I was wondering if you could provide a rebuttal to this blogger who has criticized your articles on Diet-Heart:

http://healthylongevity.blogspot.com/

Stephan Guyenet said...

Certainly.

1) This person is conflating the effect of PUFA with the effect of SFA. The long-term trials cited in which circulating cholesterol were durably reduced either involved a large increase in linoleic acid intake, or multiple dietary changes besides SFA. There are several long-term trials including the Women's Health Initiative and MRFIT where the expected long-term reduction in circulating cholesterol with SFA reduction was either absent or very small in the absence of a large increase in PUFA (0-3% reduction in TC or LDL).

2) This person refers to the meta-analysis of Siri-Tiriano as "misleading". The reality is that the meta-analysis is the same thing anyone would conclude if they read the primary literature, since very few prospective studies have found a direct association between SFA intake and heart attack risk. The counterargument usually offered for the Siri-Tarino meta-analysis is that some of the studies it was based on adjusted for circulating cholesterol ("overadjustment"). However, Siri-Tarino responded to this critique by re-analyzing the data only including the studies that did not adjust for cholesterol, and found the exact same result (which is what one would expect, considering that little or no association is found between diet and circulating cholesterol in these studies). It is a fact that the best observational studies ever conducted have almost all reported no association between SFA intake and heart attack risk. This is frequently muddled by making PUFA-to-SFA ratios and the like, but I find this sort of argument unconvincing.

3) This person cites the Health Professionals Follow-Up Study as if it supports the diet-heart hypothesis. Here is one of the key findings of the study:

"The results of mutivariate analyses, with or without correction for measurement errors, however, indicated that intake of fiber is more strongly related to risk of coronary disease than intake of saturated fat or cholesterol, and that this largely accounts for the observed association with saturated fat"

"Benefits of reducing intakes of saturated fat and cholesterol are likely to be modest unless accompanied by an increased consumption of foods rich in fiber"

In other words, when you correct for fiber intake, the effect of SFA on heart attack risk basically disappears. Their words, not mine.

They analyzed the data in various ways, and after maximum adjustment, they found that SFA intake was not associated with overall heart attack risk or fatal heart attack, and in fact some of the trends were inverse (which would have suggested a protective association if it had been significant). Rather than acknowledge these findings, this person focuses on one single number, which is the barely significant elevated risk of fatal MI in the highest quintile of SFA intake. However, the association between the two variables was not significant overall (p = 0.09). It is therefore not correct to suggest that this paper supports the idea that SFA is associated with heart attack risk, when nearly all of the data it contains do not support this conclusion.

That's all I want to write about it for now.

Robert said...

I wouldn't use the Massai, who are pastoralists, or hunter/gatherers as examples of how, despite being on high fat/low carb diets have low cholesterol levels. The one thing you do not address is parasitic infestations. All h/g groups have them and our Paleo ancestors most certainly would have. This has the effect of lowering cholesterol levels. Why is this never mentioned?

Saturated fat most definitely raises cholesterol levels. I can raise my cholesterol levels quite easily simply by increasing my intake of saturated fat.

Early on in this thread someone mentioned that they had chest pains after a high-fat meal and other commenters suggested it was wheat or refined buns that accompanied the meal. Are you serious? Its the fat, not the damned muffins/buns/bread etc.

When I was experimenting with a LCHF (Atkins) diet I eventually got to the point where I got chest pains and what I can only describe as a tingling sensation in my neck, hands, arms after a high fat meal. A typical breakfast was 3 eggs, bacon and some other meat plus some non-starchy vegetables like broccoli or green peppers plus a coffee with cream.

I never got such a sensation (chest pains, tingling in the extremities, etc., from high carb meals. In fact, adopting a low-fat/high carb whole foods diet got rid of all those disturbing events permanently.