## Monday, November 28, 2011

### Triglycerides, VLDL, and industrial carbohydrate-rich foods

Below are the coefficients of association calculated by HealthCorrelator for Excel (HCE) for user John Doe. The coefficients of association are calculated as linear correlations in HCE (). The focus here is on the associations between fasting triglycerides and various other variables. Take a look at the coefficient of association at the top, with VLDL cholesterol, indicated with a red arrow. It is a very high 0.999.

Whoa! What is this – 0.999! Is John Doe a unique case? No, this strong association between fasting triglycerides and VLDL cholesterol is a very common pattern among HCE users. The reason is simple. VLDL cholesterol is not normally measured directly, but typically calculated based on fasting triglycerides, by dividing the fasting triglycerides measurement by 5. And there is an underlying reason for that - fasting triglycerides and VLDL cholesterol are actually very highly correlated, based on direct measurements of these two variables.

But if VLDL cholesterol is calculated based on fasting triglycerides (VLDL cholesterol  = fasting triglycerides / 5), how come the correlation is 0.999, and not a perfect 1? The reason is the rounding error in the measurements. Whenever you see a correlation this high (i.e., 0.999), it is reasonable to suspect that the source is an underlying linear relationship disturbed by rounding error.

Fasting triglycerides are probably the most useful measures on standard lipid panels. For example, fasting triglycerides below 70 mg/dl suggest a pattern of LDL particles that is predominantly of large and buoyant particles. This pattern is associated with a low incidence of cardiovascular disease (). Also, chronically high fasting triglycerides are a well known marker of the metabolic syndrome, and a harbinger of type 2 diabetes.

Where do large and buoyant LDL particles come from? They frequently start as "big" (relatively speaking) blobs of fat, which are actually VLDL particles. The photo is from the excellent book by Elliott & Elliott (); it shows, on the same scale: (a) VLDL particles, (b) chylomicrons, (c) LDL particles, and (d) HDL particles. The dark bar at the bottom of each shot is 1000 A in length, or 100 nm (A = angstrom; nm = nanometer; 1 nm = 10 A).

If you consume an excessive amount of carbohydrates, my theory is that your liver will produce an abnormally large number of small VLDL particles (also shown on the photo above), a proportion of which will end up as small and dense LDL particles. The liver will do that relatively quickly, probably as a short-term compensatory mechanism to avoid glucose toxicity. It will essentially turn excess glucose, from excess carbohydrates, into fat. The VLDL particles carrying that fat in the form of triglycerides will be small because the liver will be in a hurry to clear the excess glucose in circulation, and will have no time to produce large particles, which take longer to produce individually.

This will end up leading to excess triglycerides hanging around in circulation, long after they should have been used as sources of energy. High fasting triglycerides will be a reflection of that. The graphs below, also generated by HCE for John Doe, show how fasting triglycerides and VLDL cholesterol vary in relation to refined carbohydrate consumption. Again, the graphs are not identical in shape because of rounding error; the shapes are almost identical.

Small and dense LDL particles, in the presence of other factors such as systemic inflammation, will contribute to the formation of atherosclerotic plaques. Again, the main source of these particles would be an excessive amount of carbohydrates. What is an excessive amount of carbohydrates? Generally speaking, it is an amount beyond your liver’s capacity to convert the resulting digestion byproducts, fructose and glucose, into liver glycogen. This may come from spaced consumption throughout the day, or acute consumption in an unnatural form (a can of regular coke), or both.

Liver glycogen is sugar stored in the liver. This is the main source of sugar for your brain. If your blood sugar levels become too low, your brain will get angry. Eventually it will go from angry to dead, and you will finally find out what awaits you in the afterlife.

Should you be a healthy athlete who severely depletes liver glycogen stores on a regular basis, you will probably have an above average liver glycogen storage and production capacity. That will be a result of long-term compensatory adaptation to glycogen depleting exercise (). As such, you may be able to consume large amounts of carbohydrates, and you will still not have high fasting triglycerides. You will not carry a lot of body fat either, because the carbohydrates will not be converted to fat and sent into circulation in VLDL particles. They will be used to make liver glycogen.

In fact, if you are a healthy athlete who severely depletes liver glycogen stores on a regular basis, excess calories will be just about the only thing that will contribute to body fat gain. Your threshold for “excess” carbohydrates will be so high that you will feel like the whole low carbohydrate community is not only misguided but also part of a conspiracy against people like you. If you are also an aggressive blog writer, you may feel compelled to tell the world something like this: “Here, I can eat 300 g of carbohydrates per day and maintain single-digit body fat levels! Take that you low carbohydrate idiots!”

Let us say you do not consume an excessive amount of carbohydrates; again, what is excessive or not varies, probably dramatically, from individual to individual. In this case your liver will produce a relatively small number of fat VLDL particles, which will end up as large and buoyant LDL particles. The fat in these large VLDL particles will likely not come primarily from conversion of glucose and/or fructose into fat (i.e., de novo lipogenesis), but from dietary sources of fat.

How do you avoid consuming excess carbohydrates? A good way of achieving that is to avoid man-made carbohydrate-rich foods. Another is adopting a low carbohydrate diet. Yet another is to become a healthy athlete who severely depletes liver glycogen stores on a regular basis; then you can eat a lot of bread, pasta, doughnuts and so on, and keep your fingers crossed for the future.

Either way, fasting triglycerides will be strongly correlated with VLDL cholesterol, because VLDL particles contain both triglycerides (“encapsulated” fat, not to be confused with “free” fatty acids) and cholesterol. If a large number of VLDL particles are produced by one’s liver, the person’s fasting triglycerides reading will be high. If a small number of VLDL particles are produced, even if they are fat particles, the fasting triglycerides reading will be relatively low. Neither VLDL cholesterol nor fasting triglycerides will be zero though.

Now, you may be wondering, how come a small number of fat VLDL particles will eventually lead to low fasting triglycerides? After all, they are fat particles, even though they occur in fewer numbers. My hypothesis is that having a large number of small-dense VLDL particles in circulation is an abnormal, unnatural state, and that our body is not well designed to deal with that state. Use of lipoprotein-bound fat as a source of energy in this state becomes somewhat less efficient, leading to high triglycerides in circulation; and also to hunger, as our mitochondria like fat.

This hypothesis, and the theory outlined above, fit well with the numbers I have been seeing for quite some time from HCE users. Note that it is a bit different from the more popular theory, particularly among low carbohydrate writers, that fat is force-stored in adipocytes (fat cells) by insulin and not released for use as energy, also leading to hunger. What I am saying here, which is compatible with this more popular theory, is that lipoproteins, like adipocytes, also end up holding more fat than they should if you consume excess carbohydrates, and for longer.

Want to improve your health? Consider replacing things like bread and cereal with butter and eggs in your diet (). And also go see you doctor (); if he disagrees with this recommendation, ask him to read this post and explain why he disagrees.

Beth@WeightMaven said...

Ned, if you haven't, you should go check out Todd Becker's hypothalamus hypotheis of obesity (http://gettingstronger.org/2011/11/obesity-starts-in-the-brain-2/). He's got some interesting theories re leptin transport to the brain being inhibited by triglycerides. He also points a finger at fructose as being a bigger contributor to elevated trigs. Would love for you to take a peek and weigh in!

In the meantime, I'm thrilled that my WOE has my trigs around 50!

Pål Jåbekk said...

Good one Ned!

L said...

Why do you only mention liver glycogen? Muscle has a higher storage capacity. Fasting trigs may only elevate when both liver and muscle glycogen are full and glucose consumption continues (no where to go, so liver must convert to fat). You don't have to be an athlete to consume a high percentage of total calories as carb. You can be sendentary and do so, but you can't consume the same total (higher) amount of an athlete and not expect body fat gain and associated lipo profile.

I don't understand "industrial" and "processed" carb fear? Ultimately your cells only know and use glucose. Does it really matter what the original form is (excluding possibly problematic sources like wheat--problem not the carb in wheat but gluten, WGA)? Is dried potato flour bad and whole boiled potato good? "Industrial" and "processed" food is not specific enough. Cassava pounded by hand in jungle hut good, but pounded by large machine press in brick factory surrounded by chain link fence bad?

Not intending to be confrontational, just to get unconfused.

Ned Kock said...

Hi Beth. I’ll take a look. Congrats on the low trigs!

Ned Kock said...

Thanks Pal. You are the man!

Ned Kock said...

Hi L. The reality is that very little of the glucose/fructose from carbs gets past the liver in a health person. Muscle glycogen synthase activity is elevated days after an acute glycolitic event (e.g., an intense weight training session).

The liver is a smaller glycogen tank (about 100 g) that fills up quickly, and that is used to replenish the bigger muscle glycogen tank (about 500 g). That happens over time though, and always after the needs of the brain are met.

Ned Kock said...

On the issue of industrial v. non-industrial carb-rich foods, a big difference is in the glycemic loads:

http://bit.ly/gVqBiv

That is not to say that a non-industrial carb-rich food will always have a lower glycemic load. There are exceptions.

Generally speaking though, the difference is significant.

Industrial foods tend to also be less satiating, which is another way of saying that they are less boring:

http://bit.ly/keEYcB

We humans are smart engineers eh!

Ned Kock said...

Hi Beth, again. Very interesting discussion there. A couple of quotes that are relevant within the context of this post’s discussion are the following:

“Impaired transport of leptin [into the brain] occurs in obesity and accounts for peripheral resistance [...] Leptin transport is [...] inhibited [...] by hypertriglyceridemia. Since hypertriglyceridemia occurs in both starvation and obesity, we have postulated that the peripheral resistance induced by hypertriglyceridemia may have evolved as an adaptive mechanism in response to starvation.” [Note: This is from a study by Banks.]

“In a study on mice, Banks et al. showed that triglycerides, but not free fatty acids, induce leptin resistance. This same study showed that, that fasting for 16 hours reduced triglycerides and increased leptin transport, whereas fasting for 48 hours increased triglycerides and impaired leptin transport.”

The following statement, however, is very speculative:

“Triglyceride levels tend to increase with your degree of adiposity. But what causes them to rise in the first place? The primary culprit seems to be fructose [...]”

Why? Because it seems that fructose per se, probably in natural amounts (from eating natural foods; sorry, I need to simplify things), turns the liver into a sugar sponge:

http://bit.ly/edzA7t

The problem seems to be too much fructose overwhelming the liver and reducing its ability to handle byproducts of carbs.

In other words, if you are healthy: eat a fruit --> your liver will be happy, as glucose/fructose clearance will be enhanced; eat a bagel and drink a bottle of coke --> your liver will not be happy, and will want some extra pay for overtime work.

David Isaak said...

Nice post, Ned.

On the subject of making the liver work overtime, how do you feel about the concept that it might be good for the liver to get some regular exercise in the form of some fructose, some glucose, some alcohol?

Of course, liver "exercise" is more in the nature of keeping enzymes busy--and keeping a full complement of enzymes around--than it is like exercise of skeletal muscles. So the analogy is a poor one.

But I wonder if our bodies aren't designed at all levels for occasional challenges--the key here probably being "occasional."

Some approaches to health, like Volek's TNT Diet, claim that--once one is in the vicinty of a healthy level of body fat--optimal results are obtained by a low-carb diet with an occasional high-carb day. They believe this has a different effect on things like weight loss and muscle building than the same weekly carb intake spread evenly across the week...

Lerner said...

Hi, Ned. You've somehow got (a) and (b) switched in your lipoproteins figure. Chylomicrons should be the largest.

Zorica Vuletic said...

I don't mean to over-simplify or miss the point by my reducing of the problem here, but I find it interesting that after 16 hrs, leptin 'resistance' improved and resulted in increased leptin transport (leptin transport is NOT leptin resistance in my opinion), and yet after 48 hours, leptin transport was impaired again...hmmm. To me that is evidence to support the claim that leptin can be considered to be an anti-starvation hormone.

That is something very important to keep in mind if one is addressing weight-loss and post weight-loss status.

Ned Kock said...

Hi David. The liver will be doing extra work from time to time for various reasons, and it is a big organ with many functions. For example, in a prolonged fast many more ketones are produced by the liver based on FFAs than in the fed state.

What I am not so sure is about providing the liver with an unnatural stimulus as a form of “liver workout”. I think that in this context the idea of hormesis is overused, and frequently used incorrectly.

On a related note, I find it quite reasonable to think that moderate alcohol consumption is healthy because of things other than hormesis – e.g., ketosis itself.

Ned Kock said...

Hi Lerner. You deserve kudos for bringing that up; but there is no mistake there. The chylos on the photo are at the mature and remnant stages. The “gigantic” (relatively speaking) chylos that you see in some illustrations (not so commonly in photos) are at the nascent stage. Those are transitory, after a fatty meal – not the case with this photo, I guess.

Lerner said...

Ned, here is a screenshot of the correct illustration, taken from Amazon:

http://visionals.info/NedCorrectAmazon.jpg

In the version you have, someone has literally switched (a) and (b).

here is the link to see for yourself:
http://www.amazon.com/Biochemistry-Molecular-Biology-William-Elliott/dp/0199226717

page 172

Ned Kock said...

Thanks for the links Lerner. Indeed, what probably happened was that the figure was corrected in a version of the book that is different from the one I scanned it from.

The largest particle looks like it is 200 nm in diameter. Nascent chylos are about 75 to 1,200 nm in diameter; they shrink to about 30 to 50 nm, to become remnants. VLDL particles are about 30 to 80 nm in diameter.

I have made the corrections. Thanks again!

Lerner said...
This comment has been removed by the author.
Lerner said...

Ned, I realize your article is about LDL size as relates to body composition. However, since you are very involved in correlations, I'll point out that pattern A has been claimed to be less atherosclerotic, and even online sometimes falsely claimed to be proven as protective. However, a fairly recent sub analysis of the MESA study says that it is really LDL-P (number) that matters.

http://www.athero.org/commentaries/comm564.pdf

(from Samia Mora, M.D., M.H.S., Brigham and Women’s)

Her analysis is all involved with correlation artifact, so I thought you might be interested.

Lerner said...

...and I'm sure you know well the claims about LDL-size healthwise, but I didn't see the opposing MESA view mentioned here except in the 'skinny fat' thread (which wasn't about LDL size).

Also, wrt to fasting TAG, studies like the Homburg Cream and Sugar study are showing that postprandial TAG is more predictive of CVD in normoglycemics. So pp testing might very well become the standard instead of fasting tests.

http://www.theheart.org/article/1269389.do

Anonymous said...

Ned,

Great post. Your post is refreshing as I find it frustrating to read great "paleo blogs" that now espouse high carbohydrate consumption through a discussion and citation of, say, a culture of African tribesmen who work in the fields 12 hours a day and are very healthy eating 78% carbohydrate.

These studies are totally useless for those of us who work in a cubicle farm and maybe get to a gym 3 times a week.

Ned Kock said...

Hi Lerner. That article by Dr. Mora concludes that: “Small LDL confounded the association of large LDL with IMT because of its strong inverse correlation with large LDL …”

Multivariate data analysis tools, such as WarpPLS, allow one to control for the effect of confounders. This is the reason why I can conclude, in the post linked below, that: “Animal protein and wheat flour consumption are still significantly associated with mortality, even after we control for smoking ...”

http://bit.ly/rXC0k0

Dr. Mora is right. Reaching sweeping conclusions based on univariate correlations (aka “unadjusted correlations”) is unwise. Still, I have a feeling that small-dense LDL particles are a problem, in the presence of other factors, such as systemic inflammation and oxidative agents.

Ned Kock said...

Hi Mark. Exactly!

Zorica Vuletic said...

That's a good point you say about animal protein. Of course it's not good to get too much even from 'natural' sources. It's just wise to eat a moderate amount, as proposed by Jan Kwasnieski. Interesting how he was so correct in many things without having provided full range of 'evidence' at all times. (I'm no the only one to point this out of course, as Peter and Stan have both continually pointed out such observations regarding JK).

Also, for some people eating TOO much protein actually induces anxiety-like responses. This even in the presence of an individual who may be lacking enough dopamine too.

I don't have scientific evidence to back it up, just anecdotal evidence. If you care to dig up some supporting articles, feel free, although I kind of realize the fallacy in post hoc analysis, but still it could at least provide supporting evidence none the less, and generate hypothesis to investigate further.

Also, I am frustrated at the fad-like approach people take with 'paleo'. I agree with other frustrated commentors that 'paleo' should not define what is 'healthy' per se. It is merely an estimation of how our ancestors MAY have eaten, which certainly did not include processed junk, food which is cropped in an entirely nutrient-depleted soil etc.

The key to healthy eating is moderate ketogenic diet which is supported through high fat, moderate protein and low carb. People use this type of diet for more than 'weight-loss' as it has neuro-protective effects for which some people actually need. It is palliative in many cases (as we all know the effects on seizure control). When it becomes palliative, you know it is necessary, just as using a wheelchair for someone who cannot walk is necessary.

Keenan said...

How do you explain the 811 diet? I did the diet for 8 months and was the lowest weight I've ever been in my adult life. This was all while consuming ~1000 grams of carbs daily and maybe doing a couple miles of walking.

I could see two factors that influence this weightloss, the fiber and the very low fat aspect.

I do something similar now with zero fiber juice and milk that is much higher in fat and protein(and slightly higher cals) but I also am way more athletic. I have yet to gain anything but lean mass on my current regimen for the most part despite eating 150 grams of fat and 700 grams of carbs daily.

Ned Kock said...

Hi Gladina. Here is a post on a study of the OD (JK’s diet), if you haven’t seen already:

http://bit.ly/rW065a

I don’t think this study truly reflects a “pure” OD following, but it is a good study in many respects. If one’s HDL is going up a lot, with trigs going down, LDL numbers should not matter much for an otherwise healthy person.

Having said that, I am not sure about some aspects of the OD. One example is the “protein only in small amounts” idea.

Seafood consumption is almost universally found to be health-promoting, and yet seafood has a much higher protein-to-fat ratio than muscle meat from ruminants, as well as other sources of animal protein.

So I doubt that protein from natural sources, per se, could be the problem. Protein in unnatural forms, such as protein powders; that is a different story.

The reality seems to be that, as body fat mass goes up beyond a certain level (which varies from person to person), so do health problems.

So the problem with too much protein may be that, when it is taken together with a lot of fat, it drives body fat mass up. Protein is also insulinogenic, but not as much as engineered carb-rich foods:

http://bit.ly/grde0g

Energy balance, body fat gain, muscle gain etc. – they are all fundamentally number games. Eating natural, high nutrient-calorie ratio foods helps your body reach optimal levels. Crunching numbers helps too.

Ned Kock said...

A 190-lb reasonably fit man once told me that he lost 40 lbs of body fat consuming 4,000 calories per day, 60 percent of which were carbohydrates. He wanted to know how. After he answered a few questions, it was clear to me that he grossly overestimated his caloric intake. This is not as common as underestimating caloric intake, but happens a lot too.

A colleague who couldn’t lose weight told me that she had adopted the diet that I have been following (see “My transformation” post, linked at the top of this blog). I asked her if she was avoiding industrial foods. She said yes, with exception of: (a) “cheesecake”, which she ate with “healthy fruits at night”; and (b) “healthy cereal in the morning, but no bread”, together with eggs and bacon.

These two examples illustrate patterns of behavior that are unfortunately very, very common.

Keenan said...

I was neurotic about getting enough calories and weighed my food so my estimations were very close. I was eating mostly dates so it made it pretty easy to accurately measure calories. If you check out the 30bananasaday forum you'll see the trend of people eating ridiculous amounts of calories but looking anorexic skinny. They have done studies on rats and they feed them almost pure sucrose diets, the rats stay very lean. Obviously there is some sort of catalyst that makes carbohydrates fattening, my guess is PUFAs with there beta cell damaging properties.

steve said...

Interesting post. I would point out several things: for some of us, we have low trgs- less than 70, and still have small LDL as a high proportion of total LDL. Weight normal,etc.
Not as simple as you make it out to be. I eat no wheat, or grains except some rice/potatoes, little to no fruit, and no sugar. My trigs are 40, and small LDL still far higher % of total LDL than i would like.
Also, research from Atvos seems to show what Lerner said: total amount of particles first; then small LDL

Lerner said...

Here is a page on genetic predisposition and particle size:

http://www.lbl.gov/Science-Articles/Archive/extremediet-patternb.html

It's from the same place, Lawrence Berkely Lab, where Ned's particle photos originally came from - but from the year 2000 when lo-fat was the fad instead of lo-carb.

"For patients who started out with the pattern B cholesterol profile, the study by Krauss and his research group showed that an extreme low-fat/high-carbohydrate diet can reduce the number of circulating small LDL particles which in turn reduces the risk of heart disease."

But OTOH:

"For patients who started out with the pattern A cholesterol profile, however, Krauss and his research group found that an extreme low- fat/high-carbohydrate diet worked to reduce the cholesterol content of the LDL particles circulating in the blood. This depletion in the composition of the LDL particles resulted in a downsizing that in turn led to a conversion from the pattern A to the pattern B profile."

So yes, as steve says, it's not simple on how Pattern B arises.

Btw, here's a very quick animation I'd made showing the principle of how starting out with less cholesterol per particle (as presumably after a hi-carb meal) can typically result in a smaller particle:

http://visionals.info/LDLsize.php

Lerner said...

also fwiw, I can eat carbs all day (bread, potatoes, noodles, peanut butter, barbecue cheese puffs, etc.) and that does not change my body composition unless I eat too many calories - which I don't do. For me anyway, it's all about the calories and not at all about macronutrient ratios. (I am also not an aerobics afficionado.)

steve said...

Lerner: Thanks for the URL. I am aware of the research of Krauss. The question for me is how low to take the starch carbs in my diet in order to have an LDL particle profile- what % small LDL of total LDL- consistent with minimizing further CAD. At age 61 I want to manage this as best possible.
Regards,
Steve

Lerner said...

@Steve: at age 57 I'm also interested in these things, but the internet isn't exactly overflowing with it.

I did run across this, not what you want but still interesting:

it would be incorrect to generalize ... that all VLF diets inevitably lead to an increased number of small, dense LDL particles ... Indeed, at the Pritikin Center we found that the LDL status of 6 of 22 subjects actually changed from pattern B to pattern A ... while consuming a VLF diet, which is the exact opposite of the trend observed by Dreon et al (6).

http://www.ajcn.org/content/70/3/423.full

Btw, did niacin do anything helpful for you?

Pem said...

When I first went low carb my triglycerides tested as 27, which was below the reference range used by the lab at the time. I tried to find out if there was any danger from low triglycerides but concluded probably not. I'm genetically lucky--HDL over 70 and triglycerides under 50 with not very careful low carb and only a few hours of real exercise a week. My LDL is higher than my doctor likes, in the 130s, but I refuse to consider it a problem with my other numbers so good.

My triglycerides were under 100 even before I went low carb, but I was going into diabetes as shown by blood glucose spikes after meals and gaining weight.

So what is the liver doing to result in high LDL and low triglycerices?

Zorica Vuletic said...

@ Pem:

It looks like with your higher LDL, you still have some inflammation at the liver level. (But it's great you have a good HDL and low triglycerides. Congrats!)

Two things you can consider for optimal hs crp (that's better than just regular crp and this is for liver inflammation level). 1. You can supplement with curcumin and 2. You can use the cold thermogenisis as described by Dr. Jack Kruse. If you have any indicators of high blood sugars, CT will certainly crush those, along with correcting systemic inflammation. It's truly remarkable and I highly suggest you check the CT out! :-)

tallie said...