Butter vs. Margarine

I came across an interesting study the other day, courtesy of Dr. John Briffa's blog. It's titled "Margarine Intake and Subsequent Coronary Heart Disease in Men", by Dr. William P. Castelli's group. It followed participants of the Framingham Heart study for 20 years, and recorded heart attack incidence*. Keep in mind that 20 years is an unusually long follow-up period.

The really cool thing about this study is they also tracked butter consumption.  Here's a graph of the overall results, by teaspoons of butter or margarine eaten per day:

Heart attack incidence increased with increasing margarine consumption (statistically significant) and decreased slightly with increasing butter consumption (not statistically significant). 

It gets more interesting. Let's have a look at some of the participant characteristics, broken down by margarine consumption:

People who ate the least margarine had the highest prevalence of glucose intolerance (pre-diabetes), smoked the most cigarettes, drank the most alcohol, and ate the most saturated fat and butter. These were the people who cared the least about their health. Yet they had the fewest heart attacks. The investigators corrected for the factors listed above in their assessment of the contribution of margarine to disease risk, however, the fact remains that the group eating the least margarine was the least health conscious. This affects disease risk in many ways, measurable or not. I've written about that before, here and here.

The investigators broke down the data into two halves: the first ten years, and the second ten. In the first ten years, there was no significant association between margarine intake and heart attack incidence. In the second ten, the group eating the most margarine had 77% more heart attacks than the group eating none:

So it appears that margarine takes a while to work its magic.

They didn't publish a breakdown of heart attack incidence with butter consumption over the two periods. The Framingham study fits in perfectly with most other observational studies showing that full-fat dairy intake is not associated with heart attack and stroke risk. 

It's worth mentioning that this study was conducted from the late 1960s until the late 1980s. Artificial trans fat labeling laws were still decades away in the U.S., and margarine contained more trans fat than it does today. Currently, margarine can contain up to 0.5 grams of trans fat per serving and still be labeled "0 g trans fat" in the U.S. The high trans fat content of the older margarines probably had something to do with the result of this study.

That does not make today's margarine healthy, however. Margarine remains an industrially processed pseudo-food. I'm just waiting for the next study showing that some ingredient in the new margarines (plant sterols? dihydro vitamin K1?) is the new trans fat.

Butter, Margarine and Heart Disease
The Coronary Heart Disease Epidemic


* More precisely, "coronary heart disease events", which includes infarction, sudden cardiac death, angina, and coronary insufficiency.

A Little Hiatus

I'm going to a conference next week, followed by a little vacation. I've written two posts that will publish automatically while I'm gone. I may or may not respond to comments for the next two weeks. I probably won't respond to e-mails. I'll resume the malocclusion series when I get back.

Malocclusion: Disease of Civilization, Part IV

There are three periods during the development of the face and jaws that are uniquely sensitive to environmental influences such as nutrition and muscle activity patterns.

1: Prenatal Period

The major structures of the human face and jaws develop during the first trimester of pregnancy. The maxilla (upper jaw) takes form between the 7th and 10th week after conception. The mandible (lower jaw) begins two weeks earlier. The nasal septum, which is the piece of cartilage that forms the structure of the nose and divides the nostrils, appears at week seven and grows most rapidly from weeks 8 to 11. Any disturbance of this developmental window can have major consequences for later occlusion.

2: Early Postnatal Period

The largest postnatal increment in face and jaw growth occurs from birth until age 4. During this period, the deciduous (baby) teeth erupt, and the activity patterns of the jaw and tongue influence the size and shape of the maxilla and the mandible as they grow. The relationship of the jaws to one another is mostly determined during this period, although it can still change later in development.

During this period, the dental arch widens from its center, called the midpalatal suture. This ensures that the jaws are the correct size and shape to eventually accept the permanent teeth without crowding them.

3: Adolescence

The third major developmental period occurs between ages 11 and 16, depending on the gender and individual, and happens roughly at the same time as the growth spurt in height. The dental arch continues to widen, reaching its final size and shape. Under ideal circumstances, at the end of this period the arch should be large enough to accommodate all teeth, including the third molars (wisdom teeth), without crowding. Narrow dental arches cause malocclusion and third molar crowding.

Growth of the Dental Arch Over Time

The following graph shows the widening of the dental arch over time*. The dotted line represents arch growth while the solid line represents growth in body height. You can see that arch development slows down after 6 years old, resumes around 11, and finally ends at about 18 years. This graph represents the average of many children, so not all children will see these changes at the age indicated. The numbers are in millimeters per year, but keep in mind that the difference between a narrow arch and a broad one is only a few millimeters.

In the next few posts, I'll describe the factors that I believe influence jaw and face structure during the three critical periods of development.


* These data represent many years of measurements collected by Dr. Arne Bjork, who used metallic implants in the maxilla to make precise measurements of arch growth over time in Danish youths. The graph is reproduced from the book A Synopsis of Craniofacial Growth, by Dr. Don M. Ranly. Data come from Dr. Bjork's findings published in the book Postnatal Growth and Development of the Maxillary Complex. You can see some of Dr. Bjork's data in the paper "Sutural Growth of the Upper Face Studied by the Implant Method" (free full text).

Malocclusion: Disease of Civilization, Part III

Normal Human Occlusion

In 1967, a team of geneticists and anthropologists published an extensive study of a population of Brazilian hunter-gatherers called the Xavante (1). They made a large number of physical measurements, including of the skull and jaws. Of 146 Xavante examined, 95% had "ideal" occlusion, while the 5% with malocclusion had nothing more than mild crowding of the incisors (front teeth). The authors wrote:

Characteristically, the Xavante adults exhibited broad dental arches, almost perfectly aligned teeth, end-to-end bite, and extensive dental attrition [tooth wear].

In the same paper, the author presents occlusion statistics for three other cultures. According to the papers he cites, in Japan, the prevalence of malocclusion was 59%, and in the US (Utah), it was 64%. He also mentions another native group living near the Xavante, part of the Bakairi tribe, living at a government post and presumably eating processed food. The prevalence of malocclusion was 45% in this group.

In 1998, Dr. Brian Palmer (DDS) published a paper describing some of the collections of historical skulls he had examined over the years (2):

...I reviewed an additional twenty prehistoric skulls, some dated at 70,000 years old and stored in the Anthropology Department at the University of Kansas. Those skulls also exhibited positive [good] occlusions, minimal decay, broad hard palates, and "U-shaped" arches.

The final evaluations were of 370 skulls preserved at the Smithsonian Institution in Washington, D.C. The skulls were those of prehistoric North American plains Indians and more contemporary American skulls dating from the 1920s to 1940s. The prehistoric skulls exhibited the same features as mentioned above, whereas a significant destruction and collapse of the oral cavity were evident in the collection of the more recent skulls. Many of these more recent skulls revealed severe periodontal disease, malocclusions, missing teeth, and some dentures. This was not the case in the skulls from the prehistoric periods...

The arch is the part of the upper jaw inside the "U" formed by the teeth. Narrow dental arches are a characteristic feature of malocclusion-prone societies. The importance of arch development is something that I'll be coming back to repeatedly. Dr. Palmer's paper includes the following example of prehistoric (L) and modern (R) arches:


Dr. Palmer used an extreme example of a modern arch to illustrate his point, however, arches of this width are not uncommon today. Milder forms of this narrowing affect the majority of the population in industrial nations.

In 1962, Dr. D.H. Goose published a study of 403 British skulls from four historical periods: Romano-British, Saxon, medieval and modern (3). He found that the arches of modern skulls were less broad than at any previous time in history. This followed an earlier study showing that modern British skulls had more frequent malocclusion than historical skulls (4). Goose stated that:

Although irregularities of the teeth can occur in earlier populations, for example in the Saxon skulls studied by Smyth (1934), the narrowing of the palate seems to have occurred in too short a period to be an evolutionary change. Hooton (1946) thinks it is a speeding up of an already long standing change under conditions of city life.

Dr. Robert Corruccini published several papers documenting narrowed arches in one generation of dietary change, or in genetically similar populations living rural or urban lifestyles (reviewed in reference #5). One was a study of Caucasians in Kentucky, in which a change from a traditional subsistence diet to modern industrial food habits accompanied a marked narrowing of arches and increase in malocclusion in one generation. Another study examined older and younger generations of Pima Native Americans, which again showed a reduction in arch width in one generation. A third compared rural and urban Indians living in the vicinity of Chandigarh, showing marked differences in arch breadth and the prevalence of malocclusion between the two genetically similar populations. Corruccini states:

In Chandigarh, processed food predominates, while in the country coarse millet and locally grown vegetables are staples. Raw sugar cane is widely chewed for enjoyment rurally [interestingly, the rural group had the lowest incidence of tooth decay], and in the country dental care is lacking, being replaced by chewing on acacia boughs which clean the teeth and are considered medicinal.

Dr. Weston Price came to the same conclusion examining prehistoric skulls from South America, Australia and New Zealand, as well as their living counterparts throughout the world that had adhered to traditional cultures and foodways. From Nutrition and Physical Degeneration:

In a study of several hundred skulls taken from the burial mounds of southern Florida, the incidence of tooth decay was so low as to constitute an immunity of apparently one hundred per cent, since in several hundred skulls not a single tooth was found to have been attacked by tooth decay. Dental arch deformity and the typical change in facial form due to an inadequate nutrition were also completely absent, all dental arches having a form and interdental relationship [occlusion] such as to bring them into the classification of normal.

Price found that the modern descendants of this culture, eating processed food, suffered from malocclusion and narrow arches, while another group from the same culture living traditionally did not. Here's one of Dr. Price's images from Nutrition and Physical Degeneration (p. 212). This skull is from a prehistoric New Zealand Maori hunter-gatherer:


Note the well-formed third molars (wisdom teeth) in both of the prehistoric skulls I've posted. These people had ample room for them in their broad arches. Third molar crowding is a mild form of modern face/jaw deformity, and affects the majority of modern populations. It's the reason people have their wisdom teeth removed. Urban Nigerians in Lagos have 10 times more third molar crowding than rural Nigerians in the same state (10.7% of molars vs. 1.1%, reference #6).

Straight teeth and good occlusion are the human evolutionary norm. They're also accompanied by a wide dental arch and ample room for third molars in many traditionally-living cultures. The combination of narrow arches, malocclusion, third molar crowding, small or absent sinuses, and a characteristic underdevelopment of the middle third of the face, are part of a developmental syndrome that predominantly afflicts industrially living cultures.

(1) Am. J. Hum. Genet. 19(4):543. 1967. (free full text)
(2) J. Hum. Lact. 14(2):93. 1998
(3) Arch. Oral Biol. 7:343. 1962
(4) Brash, J.C.: The Aetiology of Irregularity and Malocclusion of the Teeth. Dental Board of the United Kingdom, London, 1929.
(5) Am J. Orthod. 86(5):419
(6) Odonto-Stomatologie Tropicale. 90:25. (free full text)

Malocclusion: Disease of Civilization, Part II

The Nature of the Problem

In 1973, the US Centers for Disease Control and Prevention (CDC) published the results of a National Health Survey in which it examined the dental health of American youths nationwide. The following description was published in a special issue of the journal Pediatric Dentistry (1):

The 1973 National Health Survey reported 75% of children, ages 6 to 11 years, and 89% of youths, ages 12 to 17 years, have some degree of occlusal disharmony [malocclusion]; 8.7% of children and 13% of youth had what was considered a severe handicapping malocclusion for which treatment was highly desirable and 5.5% of children and 16% of youth had a severe handicapping malocclusion that required mandatory treatment.

89% of youths had some degree of malocclusion, and 29% had a severe handicapping malocclusion for which treatment was either highly desirable or mandatory. Fortunately, many of these received orthodontics so the malocclusion didn't persist into adulthood.

This is consistent with another survey conducted in 1977, in which 38% of American youths showed definite or severe malocclusion. 46% had occlusion that the authors deemed "ideal or acceptable" (2).

The trend continues. The CDC National Health and Nutrition Examination Survey III (NHANES III) found in 1988-1991 that approximately three fourths of Americans age 12 to 50 years had some degree of malocclusion (3).

The same holds true for Caucasian-Americans, African-Americans and Native Americans in the US, as well as other industrial nations around the world. Typically, only 1/3 to 1/2 of the population shows good (but not necessarily perfect) occlusion (4- 8).

In the next post, I'll review some of the data from non-industrial and transitioning populations.


Malocclusion: Disease of Civilization


1. Pediatr. Dent. 17(6):1-6. 1995-1996
2. USPHS Vital and Health Statistics Ser. 11, no 162. 1977
3. J. Dent. Res. Special issue. 75:706. 1996. Pubmed link.
4. The Evaluation of Canadian Dental Health. 1959. Describes Canadian occlusion.
5. The Effects of Inbreeding on Japanese Children. 1965. Contains data on Japanese occlusion.
6. J. Dent. Res. 35:115. 1956. Contains data on both industrial and non-industrial cultures (Pukapuka, Fiji, New Guinea, U.S.A. and New Zealand).
7. J. Dent. Res. 44:947. 1965 (free full text). Contains data on Caucasian-Americans and African-Americans living in several U.S. regions, as well as data from two regions of Germany. Only includes data on Angle classifications, not other types of malocclusion such as crossbite and open bite (i.e., the data underestimate the total prevalence of malocclusion).
8. J. Dent. Res. 47:302. 1968 (free full text). Contains data on Chippewa Native Americans in the U.S., whose occlusion was particularly bad, especially when compared to previous generations.

Diabetics on a Low-carbohydrate Diet, Part II

I just found another very interesting study performed in Japan by Dr. Hajime Haimoto and colleagues (free full text). They took severe diabetics with an HbA1c of 10.9% and put them on a low-carbohydrate diet:

The main principle of the CRD [carbohydrate-restricted diet] was to eliminate carbohydrate-rich food twice a day at breakfast and dinner, or eliminate it three times a day at breakfast, lunch and dinner... There were no other restrictions. Patients on the CRD were permitted to eat as much protein and fat as they wanted, including saturated fat.

What happened to their blood lipids after eating all that fat for 6 months, and increasing their saturated fat intake to that of the average American? LDL decreased and HDL increased, both statistically significant. Oops. But that's water under the bridge. What we really care about here is glucose control. The patients' HbA1c (glycated hemoglobin; a measure of average blood glucose over the past several weeks) declined from 10.9 to 7.4%.

Here's a graph showing the improvement in HbA1c. Each line represents one individual:

Every single patient improved, except the "dropout" who stopped following the diet advice after 3 months (the one line that shoots back up at 6 months). And now, an inspirational anecdote from the paper:

One female patient had an increased physical activity level during the study period in spite of our instructions. However, her increase in physical activity was no more than one hour of walking per day, four days a week. She had implemented an 11% carbohydrate diet without any antidiabetic drug, and her HbA1c level decreased from 14.4% at baseline to 6.1% after 3 months and had been maintained at 5.5% after 6 months.

That patient began with the highest HbA1c and ended with the lowest. Complete glucose control using only diet and exercise. It may not work for everyone, but it's effective in some cases. The study's conclusion:

...the 30%-carbohydrate diet over 6 months led to a remarkable reduction in HbA1c levels, even among outpatients with severe type 2 diabetes, without any insulin therapy, hospital care or increase in sulfonylureas. The effectiveness of the diet may be comparable to that of insulin therapy.

Diabetics on a Low-carbohydrate Diet
The Tokelau Island Migrant Study: Diabetes

Diabetics on a Low-carbohydrate Diet

Diabetes is a disorder of glucose intolerance. What happens when a diabetic eats a low-carbohydrate diet? Here's a graph of blood glucose over a 24 hour period, in type II diabetics on their usual diet (blue and grey triangles), and after 5 weeks on a 55% carbohydrate (yellow circles) or 20% carbohydrate (blue circles) diet:


The study in question describes these volunteers as having "mild, untreated diabetes." If 270 mg/dL of blood glucose is mild diabetes, I'd hate to see severe diabetes! In any case, the low-carbohydrate, high-fat diet brought blood glucose down to an acceptable level without requiring medication.

It's interesting to note in the graph above that fasting blood glucose (18-24 hours) also fell dramatically. This could reflect improved insulin sensitivity in the liver. The liver pumps glucose into the bloodstream when it's necessary, and insulin suppresses this. When the liver is insulin resistant, it doesn't respond to the normal signal that there's already sufficient glucose, so it releases more and increases fasting blood glucose. When other tissues are insulin resistant, they don't take up the extra glucose, also contributing to the problem.

Glycated hemoglobin (HbA1c), a measure of average blood glucose concentration over the preceding few weeks, also reflected a profound improvement in blood glucose levels in the low-carbohydrate group:

At 5 weeks, the low-carbohydrate group was still improving and headed toward normal HbA1c, while the high-carbohydrate group remained at a dangerously high level. Total cholesterol, LDL and HDL remained unchanged in both groups, while triglycerides fell dramatically in the low-carbohydrate group.

When glucose is poison, it's better to eat fat.

Graph #1 was reproduced from Volek et al. (2005), which re-plotted data from Gannon et al. (2004). Graph #2 was drawn directly from Gannon et al.

Paleolithic Diet Clinical Trials Part IV

Dr. Staffan Lindeberg has published a new study using the "paleolithic diet" to treat type II diabetics (free full text). Type II diabetes, formerly known as late-onset diabetes until it began appearing in children, is typically thought to develop as a result of insulin resistance (a lowered tissue response to the glucose-clearing function of insulin). This is often followed by a decrease in insulin secretion due to degeneration of the insulin-secreting pancreatic beta cells.

After Dr. Lindeberg's wild success treating patients with type II diabetes or glucose intolerance, in which he normalized the glucose tolerance of all 14 of his volunteers in 12 weeks, he set out to replicate the experiment. This time, he began with 13 men and women who had been diagnosed with type II diabetes for an average of 9 years.

Patients were put on two different diets for 3 months each. The first was a "conventional diabetes diet". I read a previous draft of the paper in which I believe they stated it was based on American Diabetes Association guidelines, but I can't find that statement in the final draft. In any case, here are the guidelines from the methods section:

The information on the Diabetes diet stated that it should aim at evenly distributed meals with increased intake of vegetables, root vegetables, dietary fiber, whole-grain bread and other whole-grain cereal products, fruits and berries, and decreased intake of total fat with more unsaturated fat. The majority of dietary energy should come from carbohydrates from foods naturally rich in carbohydrate and dietary fiber. The concepts of glycemic index and varied meals through meal planning by the Plate Model were explained [18]. Salt intake was recommended to be kept below 6 g per day.

The investigators gave the paleolithic group the following advice:

The information on the Paleolithic diet stated that it should be based on lean meat, fish, fruit, leafy and cruciferous vegetables, root vegetables, eggs and nuts, while excluding dairy products, cereal grains, beans, refined fats, sugar, candy, soft drinks, beer and extra addition of salt. The following items were recommended in limited amounts for the Paleolithic diet: eggs (≤2 per day), nuts (preferentially walnuts), dried fruit, potatoes (≤1 medium-sized per day), rapeseed or olive oil (≤1 tablespoon per day), wine (≤1 glass per day). The intake of other foods was not restricted and no advice was given with regard to proportions of food categories (e.g. animal versus plant foods). The evolutionary rationale for a Paleolithic diet and potential benefits were explained.

Neither diet was restricted in calories. After comparing the effects of the two diets for 3 months, the investigators concluded that the paleolithic diet:

• Reduced HbA1c more than the diabetes diet (a measure of average blood glucose)
• Reduced weight, BMI and waist circumference more than the diabetes diet
• Lowered blood pressure more than the diabetes diet
  
• Reduced triglycerides more than the diabetes diet
• Increased HDL more than the diabetes diet

However, the paleolithic diet was not a cure-all. At the end of the trial, 8 out of 13 patents still had diabetic blood glucose after an oral glucose tolerance test (OGTT). This is compared to 9 out of 13 for the diabetes diet. Still, 5 out of 13 with "normal" OGTT after the paleolithic diet isn't bad. The paleolithic diet also significantly reduced insulin resistance and increased glucose tolerance, although it didn't do so more than the diabetes diet.

As has been reported in other studies, paleolithic dieters ate fewer total calories than the comparison group. This is part of the reason why I believe that something in the modern diet causes hyperphagia, or excessive eating. According to the paleolithic diet studies, this food or combination of foods is neolithic, and probably resides in grains, refined sugar and/or dairy. I have my money on wheat and sugar, with a probable long-term contribution from industrial vegetable oils as well.

Were the improvements on the paleolithic diet simply due to calorie restriction? Maybe, but keep in mind that neither group was told to restrict its caloric intake. The reduction in caloric intake occurred naturally, despite the participants presumably eating to fullness. I suspect that the paleolithic diet reset the dieters' body fat set-point, after which fat began pouring out of their fat tissue. They were supplementing their diets with body fat-- 13 pounds (6 kg) of it over 3 months.

The other notable difference between the two diets, besides food types, was carbohydrate intake. The diabetes diet group ate 56% more carbohydrate than the paleo diet group, with 42% of their calories coming from it. The paleolithic group ate 32% carbohydrate. Could this have been the reason for the better outcome of the paleolithic group? I'd be surprised if it wasn't a factor. Advising a diabetic to eat a high-carbohydrate diet is like asking someone who's allergic to bee stings to fetch you some honey from your bee hive. Diabetes is a disorder of glucose intolerance. Starch is a glucose polymer.

Although to be fair, participants on the diabetes diet did improve in a number of ways. There's something to be said for eating whole foods.

This trial was actually a bit of a disappointment for me. I was hoping for a slam dunk, similar to Lindeberg's previous study that "cured" all 14 patients of glucose intolerance in 3 months. In the current study, the paleolithic diet left 8 out of 13 patients diabetic after 3 months. What was the difference? For one thing, the patients in this study had well-established diabetes with an average duration of 9 years. As Jenny Ruhl explains in her book Blood Sugar 101, type II diabetes often progresses to beta cell loss, after which the pancreas can no longer secrete an adequate amount of insulin.

This may be the critical finding of Dr. Lindeberg's two studies: type II diabetes can be prevented when it's caught at an early stage, such as pre-diabetes, whereas prolonged diabetes may cause damage that cannot be completely reversed though diet. I think this is consistent with the experience of many diabetics who have seen an improvement but not a cure from changes in diet. Please add any relevant experiences to the comments.

Collectively, the evidence from clinical trials on the "paleolithic diet" indicate that it's a very effective treatment for modern metabolic dysfunction, including excess body fat, insulin resistance and glucose intolerance. Another way of saying this is that the modern industrial diet causes metabolic dysfunction.

Paleolithic Diet Clinical Trials
Paleolithic Diet Clinical Trials Part II
One Last Thought
Paleolithic Diet Clinical Trials Part III

Animal Models of Atherosclerosis: LDL

Researchers have developed a number of animal models of atherosclerosis (fatty/fibrous lesions in the arteries that influence heart attack risk) to study the factors that affect its development. In the next two posts, I will argue that these models rely on a massive increase in LDL, up to 10-fold, due to overloading the cholesterol metabolism of herbivorous species with excessive dietary cholesterol. This also greatly increases oxidized LDL, leading to atherosclerosis. I will discuss the role of saturated fat, which often receives the blame, in this process.

A reader recently sent me a reference to an interesting paper titled "Dietary Fat Saturation Effects on Low-density-lipoprotein Concentrations and Metabolism in Various Animal Models". It's a review of animal studies that have looked at the effect of different fats on LDL concentration as of 1997. 

When an investigator wants to study diet-induced atherosclerosis, first he selects a species that's susceptible to it. These are generally herbivorous or nearly herbivorous species such as rabbits, guinea pigs, hamsters, and several species of monkey. Then, he feeds it an "atherogenic diet". This is typically a combination of 0.1 to 1% cholesterol by weight, plus 20-40% of calories as fat. The fat can come from a variety of sources, but animal fats or saturated vegetable fats are typical. The remainder of the diet is processed grains, vitamin and mineral supplements, and often casein for protein.

Let's put that amount of cholesterol into human context. Assuming the average person eats about 2 pounds dry weight of food per day, 0.5% cholesterol would be 4.5 grams. That's the equivalent of:

• 17.5 pounds of beef steak, or
• 3.8 pounds of beef liver, or
• 22.5 eggs

Per day. Now feed that to an herbivore that's not adapted to clearing cholesterol. You can imagine it doesn't do their blood lipids any favors. For example, in one study, compared to a low-fat, low-cholesterol "control diet", a diet of 20% hydrogenated coconut oil plus 0.12% cholesterol caused hamsters' LDL to increase by more than 7-fold. A polyunsaturated fat (PUFA) rich diet caused LDL to increase less. This study is typical, and the interpretation is typical as well: SFA raises LDL. But there's another possible explanation: in the absence of unnatural amounts of dietary cholesterol, PUFA reduces LDL in some species, and SFA has very little effect on it in most.

It's important to remember that the relevance of this hamster experiment to humans is unclear. No one is claiming that reducing saturated fat and cholesterol will reduce a human's LDL by 7-fold.  

But let's get back to the animal models. The hypothesis the paper addresses is that saturated fat raises LDL in animal models. If that is true, it should be able to raise LDL even in the absence of added cholesterol. So let's consider only the studies that didn't add extra cholesterol to the diets. And if saturated fat raises LDL, it should also do it relative to monounsaturated fat (MUFA- like olive oil), rather than only in comparison to PUFA, which has a known cholesterol-lowering effect. So let's narrow the studies further to those that compared SFA-rich fats, MUFA-rich fats and PUFA-rich fats. In Fernandez et al. (1989), investigators fed guinea pigs 35% of calories from corn oil (PUFA), olive oil (MUFA) or lard (MUFA-SFA). Here's what their LDL looked like:
The same investigators published two more studies showing similar results over the next five years. The next study was published by Khosla et al. in 1992. They fed cebus and rhesus monkeys cholesterol-free diets containing 40% of calories from safflower oil (PUFA), high-oleic safflower oil (MUFA) or palm oil (SFA-MUFA). How was their LDL?
None of the differences were statistically significant. Khosla and colleagues published another study with the same result in 1993. This is hardly supportive of the idea that saturated fat raises LDL in animal models. The most you can say is that PUFA lowers LDL in some, but not all, species. There is no indication from these studies that SFA raises LDL in the absence of excessive dietary cholesterol. I didn't cherry pick studies here; this is every study in the review paper that met my two criteria of no added cholesterol and a MUFA comparison group.

The bottom line is that experimental models of atherosclerosis appear to rely on overloading herbivorous species with dietary cholesterol that they are not equipped to clear. SFA does exacerbate the increase in LDL caused by cholesterol overload. But in the absence of excess cholesterol, it does not necessarily raise LDL even in species ill-equipped to digest these types of fats. Dietary cholesterol has a modest effect on LDL cholesterol in humans, and it has even less effect on LDL particle number, a more important measure. So there may not be a cholesterol overload for saturated fat to exacerbate in humans. 

PUFA vegetable oils do lower LDL in humans, and the effect appears to persist for at least a few years (probably indefinitely). But the evidence is not conclusive that lowering cholesterol in this way actually prevents heart attacks.

Dr. Stephan

After a very challenging summer, I've finally turned in my written thesis, so it's official: I have my Ph.D. I'm publishing the abstract below. These findings should all be published in peer-reviewed journals in the next 6 months.


Ataxin-7 Conserved Motifs Determine the Severity of the Neurodegenerative Disorder Spinocerebellar Ataxia Type 7 in Transgenic Mice and Influence Lifespan in Yeast

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant, progressive neurodegenerative disorder whose characteristic features are cerebellar ataxia, dysarthria, and retinal cone-rod dystrophy culminating in blindness. SCA7 is caused by an abnormally long glutamine-coding CAG repeat in the SCA7 gene, which encodes the protein Ataxin-7.

Ataxin-7 contains several conserved motifs that may influence the toxicity of the glutamine tract. Among these are three conserved regions (conserved block I – III), two caspase-7 cleavage sites, a nuclear export signal and two monopartite nuclear localization signals (NLS). Previous investigations have shown that the caspase-7 cleavage site D266 is required for the full toxicity of the Ataxin-7 protein in cell culture. We generated SCA7 transgenic mice expressing a 92 CAG version of the human SCA7 cDNA, with and without a D266N mutation. Mice carrying the D266N mutation were protected from SCA7-like neurodegeneration, behavioral signs and shortened lifespan.

To further characterize the role of conserved motifs in SCA7 pathology, we generated SCA7 transgenic mice carrying point mutations in both C-terminal NLSs (KKRK -> KAAK). Previous work has shown that nuclear localization is an important step in the pathology of CAG repeat disorders. We observed that mice lacking C-terminal NLS activity were substantially protected from degeneration of the retina and cerebellum, SCA7-like behavioral signs and shortened lifespan.

Age is the primary risk factor for neurodegenerative disease. Even in the absence of overt disease, the aging brain shows histopathological and molecular changes reminiscent of neurodegeneration. To explore the link between neurodegenerative disease and aging, we have examined the replicative lifespan of Saccharomyces cerevisiae missing the SCA7 ortholog, SGF73. This strain exhibits an unusually long lifespan, which is dependent on the function of the NAD+-dependent deacetylase SIR2. We present evidence that the extended lifespan of the SGF73 null strain is due to the influence of Sgf73 on the activity of Sir2 and the histone deubiquitinase Ubp8. Furthermore, we show that the level of ubiquitinated H2B is elevated in an SCA7 transgenic mouse line, indicating that an alteration in Ubp8 activity may play a role in SCA7 pathology and that aging and neurodegeneration may share a common mechanism.