So I’ve had a go at writing up tonight’s paper in a way that I normally wouldn’t do… by drafting it over several days.  I’m generally the type that settles in for the long haul and aims to get a post out in one hit.  That’s just how I roll.  But with a couple of special projects on the go recently, my attentions have been distracted away from undertaking a concerted blogging effort.

As the incremental blogging approach wasn’t working, this paper was going to get the full intravenous-coffee, write-it-all-night-if-I-have-to, treatment – determined as I was to get it written.  Fortunately for everyone who may have to deal with my sleep-deprived self over the coming days, I discovered that much of this paper, or certainly the concepts contained within it, have already been blogged.  And by the lead author of the paper itself, no less.  So between free access to the full paper, and her blog, I’m simply going to point to it as an interesting piece in the jigsaw puzzle, and pull out a few quotes which resonated with me.  That way it looks like I’ve still sort of done a post, even though I haven’t really.

Is the metabolic syndrome caused by a high fructose, and relatively low-fat, low cholesterol diet?

The metabolic syndrome (MetS) is manifested by a lipid triad which includes elevated serum triglycerides, small LDL particles, and low high-density lipoprotein (HDL) cholesterol, by central obesity (central adiposity), insulin resistance, glucose intolerance and elevated blood pressure, and it is associated with an increased risk of type 2 diabetes and coronary heart disease.

We have developed a new hypothesis regarding MetS as a consequence of a high intake in carbohydrates and food with a high glycemic index, particularly fructose, and relatively low intake of cholesterol and saturated fat. We support our arguments through animal studies which have shown that exposure of the liver to increased quantities of fructose leads to rapid stimulation of lipogenesis and accumulation of triglycerides.

The adipocytes store triglycerides in lipid droplets, leading to adipocyte hypertrophy. Adipocyte hypertrophy is associated with macrophage accumulation in adipose tissue. An important modulator of obesity-associated macrophage responses in white adipose tissue is the death of adipocytes. Excess exposure to fructose intake determines the liver to metabolize high doses of fructose, producing increased levels of fructose end products, like glyceraldehyde and dihydroxyacetone phosphate, that can converge with the glycolytic pathway.

Fructose also leads to increased levels of advanced glycation end products. The macrophages exposed to advanced glycation end products become dysfunctional and, on entry into the artery wall, contribute to plaque formation and thrombosis.

The authors here are suggesting that a high fructose intake, in the presence of a low-fat (specifically a low saturated fat) diet, which in turn leads to a state of cholesterol depletion, and throwing in a bit of vitamin D deficiency, perhaps drives what we have come to know as the Metabolic Syndrome.

Over the last several decades, medical advice, particularly in the United States, has emphasized the concept that a low-fat diet is a healthy diet, and this has likely led to a shift towards an increased dietary intake in carbohydrates.

However, recent studies have demonstrated that a low-carbohydrate diet leads to improvements on a number of measures related to heart disease and diabetes risks.

As a consequence of these contradictions, considerable confusion exists as to what constitutes healthy eating. A case in point is the recent review article on recommended lifestyle changes to improve cardiovascular risk factors, which recommended reduced fat intake twice and recommended reduced carbohydrate intake twice, while suggesting that protein intake should remain under 20% of total calories…

In this paper, we developed a theory accounting for all the features of MetS, which involves a cascade of events brought on by gross dietary imbalances.

We argue that this syndrome has reached epidemic proportions due to misguided advice regarding a “healthy” lifestyle, leading to reduced dietary intake of fats and cholesterol and excessive sun avoidance.

The increasingly widespread availability of highly processed foods, particularly the practice of substituting fructose for glucose as a sweetener due to economic considerations, has been an equally damaging contributing factor.

Calcium and vitamin D deficiency play a role as well.

To understand the hypothesised mechanisms which these authors feel are at play, a diagram for us visual-types might be in order.

1. Serum LDL (L) cholesterol becomes glycated due to exposure to glucose and fructose
2. Adipocytes (fat cells) depend upon apolipoprotein-E [apoE] (E) to scavenge the glycated and damaged LDL-C and transport it into HDL cholesterol (for return to the liver) (H)
3. ApoE itself becomes damaged and the fat cell begins to accumulate fat droplets (F) and excess cholesterol (C) in its endoplasmic reticulum (ER).  Meanwhile, the plasma membrane of the fat cell (dashed line) becomes cholesterol depleted.  Stressed fat cells release the hormone angiotensin-II (AT-II) which leads to sodium-hoarding and hypertension.
4. Macrophages enter the fat tissue to engulf the cell debris from dead fat cells, forming multi-nucleated giant cells.
5. Due to insufficient HDL-C cholesterol, fatty deposits accumulate ectopically to buffer cholesterol supplies to the major organs (visceral fat accumulates on and around the organs).

Got that? Good.

Let’s wind back to the start and see if we can’t simplify this further (and in doing so, I realise I’ll lose some fidelity to the information).  With fructose entering the liver, where, when it is consumed in excess (>50g/day), it is rapidly converted to fat.  From the liver it should be transported away, via the bloodstream, for use elsewhere.  But for this transport to occur, cholesterol is required.

To get our head around what might be going on, I direct you to the blog of the lead author, Stephanie Seneff (more background and publications here).  Stephanie writes a good summary in her blog post titled “LDL, HDL, and Fructose” (and I would encourage you to read through her whole March 2011 series).

We have been trained by our physicians to worry about elevated serum levels of low density lipoprotein (LDL), with respect to heart disease. LDL is not a type of cholesterol, but rather can be viewed as a container that transports fats, cholesterol, vitamin D, and fat-soluble anti-oxidants to all the tissues of the body. Because they are not water-soluble, these nutrients must be packaged up and transported inside LDL particles in the blood stream. If you interfere with the production of LDL, you will reduce the bioavailability of all these nutrients to your body’s cells.

The outer shell of an LDL particle is made up mainly of lipoproteins and cholesterol. The lipoproteins contain proteins on the outside of the shell and lipids (fats) in the interior layer. If the outer shell is deficient in cholesterol, the fats in the lipoproteins become more vulnerable to attack by oxygen, ever-present in the blood stream. LDL particles also contain a special protein called “apoB” which enables LDL to deliver its goods to cells in need. ApoB is vulnerable to attack by glucose and other blood sugars, especially fructose. Diabetes results in an increased concentration of sugar in the blood, which further compromises the LDL particles, by gumming up apoB. Oxidized and glycated LDL particles become less efficient in delivering their contents to the cells. Thus, they stick around longer in the bloodstream, and the measured serum LDL level goes up.

Worse than that, once LDL particles have finally delivered their contents, they become “small dense LDL particles,” remnants that would ordinarily be returned to the liver to be broken down and recycled. But the attached sugars interfere with this process as well, so the task of breaking them down is assumed instead by macrophages in the artery wall and elsewhere in the body, through a unique scavenger operation. The macrophages are especially skilled to extract cholesterol from damaged LDL particles and insert it into HDL particles. Small dense LDL particles become trapped in the artery wall so that the macrophages can salvage and recycle their contents, and this is the basic source of atherosclerosis. HDL particles are the so-called “good cholesterol,” and the amount of cholesterol in HDL particles is the lipid metric with the strongest correlation with heart disease, where less cholesterol is associated with increased risk. So the macrophages in the plaque are actually performing a very useful role in increasing the amount of HDL cholesterol and reducing the amount of small dense LDL.

The LDL particles are produced by the liver, which synthesizes cholesterol to insert into their shells, as well as into their contents. The liver is also responsible for breaking down fructose and converting it into fat (Collison et al., 2009). Fructose is ten times more active than glucose at glycating proteins, and is therefore very dangerous in the blood serum (Seneff1 et al., 2011).

When you eat a lot of fructose (such as the high fructose corn syrup present in lots of processed foods and carbonated beverages), the liver is burdened with getting the fructose out of the blood and converting it to fat, and it therefore can not keep up with cholesterol supply. As I said before, the fats can not be safely transported if there is not enough cholesterol. The liver has to ship out all that fat produced from the fructose, so it produces low quality LDL particles, containing insufficient protective cholesterol. So you end up with a really bad situation where the LDL particles are especially vulnerable to attack, and attacking sugars are readily available to do their damage.

This inability of the liver to keep up with cholesterol supply has consequences for fat cells that are trying to store ever-increasing amounts of fat inside them.  You see, the outer plasma membrane of all cells requires cholesterol to make it.  Make the cell bigger (by storing more fat inside it), and you are going to need a bigger plasma membrane, thus requiring more cholesterol.  Yet cholesterol, ironically, is in short supply.  If fat cells keep getting fatter, well, something is just going to have to give.

These cells, facing imminent disintegration, send out a final SOS (via cytokines) to macrophages which come along and gobble up several of these cells at a time, forming giant cells (protecting the heavily damaged cells from even further glycation and oxidation).  But it is not only the fat cells that are suffering with a lack of good quality cholesterol to integrate into plasma membranes.  The cells of the pancreas, liver, heart, kidneys, and skeletal muscle, for example, also become vulnerable to attack by sugar and oxygen as they are unable to maintain a strong plasma membrane.

In order to try to circumvent some of these cholesterol supply issues, the body begins to accumulate ectopic deposits of fat and cholesterol, on-site, at some of these organs in order to supply vital nutrients to them.  As the pancreas is damaged, glucose and fructose circulate in increasing amounts, and due to the damage to heart and skeletal muscle (damaged plasma membrane), they become unable to utilise these sugars as fuel.

From the main Seneff paper;

In our view, MetS arises out of a dietary imbalance with an overabundance of refined, high-glycemic index carbohydrates, most notably, fructose, and a relative dietary deficiency in cholesterol…For people exhibiting insulin resistance, cholesterol synthesis was upregulated and cholesterol absorption [by the liver] was downregulated, independent of obesity level. This suggests that a dietary deficiency in cholesterol, or an impaired ability to absorb it, may be associated with insulin resistance…

…Fructose is especially damaging because it is highly reactive as a reducing agent, and the liver must remove it aggressively from the blood serum to prevent it from damaging serum lipids and proteins via fructation. With a high-carbohydrate, low-fat diet, postprandial fructose and glucose enter the bloodstream very rapidly due both to the abundance of refined carbohydrates and to the lack of buffering in the gut by dietary fats. The tissues are reluctant to utilize fructose as fuel, likely because it is ten times as reactive as a reducing agent as glucose.

With all the focus on low glycaemic index carbohydrates, where the lack of carbohydrate or the presence of fibre reduce the speed at which the glucose/fructose appears in the bloodstream, one of the things that gets conveniently ignored is that the presence of fat in the gut is the single biggest factor that will slow the speed of carbohydrate entry into the bloodstream.  So if you are really that panicked by the glycaemic impact of your sweet potato, FFS, drown them in fat when you cook them (in Vanuatu, they eat a mountain of root vegetables at every meal – all cooked in an equally large mountain of coconut cream).

How is it possible that we can suffer cholesterol deficiency?  Isn’t this something we can readily make from fat and typically have too much rather than not enough?

It is commonly believed that the body can synthesize all the cholesterol and fats that it needs, but this may not be true, because the liver becomes overburdened with its many tasks when the diet is so skewed. Furthermore, cholesterol synthesis in the liver, a complex 25- to 30-step process, may be relatively suppressed when insulin is present. The liver has to take up excess fructose as quickly as possible to prevent it from damaging serum proteins. After a meal, the liver rapidly processes the fructose to basic building blocks that can later be converted to fat, but it can neither safely store the fat nor release it within newly synthesized lipoproteins. This is the key factor that leads to both fatty liver and liver insulin resistance, early indicators of the metabolic syndrome.

Typically, the liver would release the fats and cholesterol it has made as very low-density lipoprotein (VLDL) particles, which deliver fat, cholesterol, and antioxidants to all the tissues.  At the end of this delivery process, we are left with VLDL remnants.  The liver is responsible, in the normal run of things, for recycling these remnants through bile secretion, with the benefit of this aiding in the digestion of dietary fats.  This becomes especially important when the VLDL remnants have been damaged by glucose, fructose, and oxygen.

However, when the are relatively few fats in the diet – such as when you are trying to live off Chop Chop Chicken in spring water and salad – less bile is needed, and the damaged VLDL remnants can’t be as readily recycled.  The liver can’t do much to help as it is too busy dealing with the fructose and glucose being supplied by all the healthy fruit you are eating (or more likely, the litre of “Immunobooster” you have bought at the Juice Bar and are now sucking back through a straw).  The already overworked fat cells have to pick up the slack.

Over time, the adipocyte [fat cell] accumulates AGE products due to its chronic exposure to both glucose and damaged VLDL remnants. ApoE is especially susceptible to AGE damage, and, eventually, it can no longer function. This leads to the accumulation of excess free cholesterol within the adipocyte, ironically while it is suffering from cholesterol deficiency in its outer wall. The adipocytes are required to store the excess cholesterol. However, the increased size requires a corresponding expansion in the surface area. Without sufficient cholesterol in the plasma membrane, the cell becomes first permeable to outward sodium leaks but ultimately unable to keep calcium out, at which point the cell literally disintegrates.

Seneff et al discuss the issue of vitamin D deficiency within the metabolically obese and how this becomes an aggravating factor…

Calcium and vitamin D deficiency in the obese has been attributed to excessive storage of 25-hydroxyvitamin D in adipose tissue. Zemel et al. claim that low calcium diets promote excess storage of fats in fat cells…In our view, their abundant oversized adipocytes are hoarding vitamin D along with calcium because vitamin D catalyzes calcium transport…

…Pancreatic β cells are the sole producers of insulin. Beta cells have stringent nutrient requirements before they will release insulin into the bloodstream. In particular, there must be sufficient amounts of cholesterol, vitamin D, calcium and fats available in the cytoplasm, as well as an abundant supply of glucose to fuel the synthesis and release of insulin…

…This situation is further aggravated by poor calcium absorption in the gut. Fats promote calcium absorption, and dietary fibre interferes with it.So a high-fibre diet, if associated with a stringent low-fat diet may compound the problem of insulin resistance and β cell dysfunction.

And that, ladies and gentlemen, is why our health guidelines encourage people to eat a high-fat, low-grain fibre diet, and to get plenty of sunlight exposure, in order to prevent metabolic syndrome and diabetes…