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. A recently published paper [24
] demonstrated an intriguing relationship between fasting glucose level and cholesterol metabolism. For people exhibiting insulin resistance, cholesterol synthesis was upregulated and cholesterol absorption 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.
A study of the relationship between dietary cholesterol and serum cholesterol in rats, undertaken in the mid 1970s, uncovered some surprising results [25
]. Most notably, a cholesterol-free diet resulted in greater accumulation of cholesterol in adipose tissue than a diet enriched with 0.05 or 0.1% cholesterol. Furthermore, even up to a 5% cholesterol diet, serum cholesterol concentration was inversely related to dietary supply after a two-month interval. These authors also demonstrated compellingly that the amount of cholesterol stored in adipose tissue is proportional to the amount of triglycerides stored. Leptin-deficient (ob/ob) mice, (a model of type 2 diabetes with relatively mild hyperglycaemia and obesity) had five times the adipose mass of controls, and 1.2- to 2-fold differences in fat cell diameter, yet the cholesterol to triglyceride ratios were identical between the two groups.
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 [26
]. 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 [26
An excess of fructose and glucose in the bloodstream causes extensive glycation damage to vulnerable proteins [27
]. A glycated (whether fructated or glucated) protein is typically both impaired in its function and more susceptible to oxidation damage. It is also resistant to degradation through lysosomal breakdown. Over time, a collection of glycated protein debris accumulates in the blood serum and along arterial walls. These damaged proteins are referred to collectively as advanced glycation end products (AGEs) [29
], and they play a critical role in aging, in atherosclerosis, and in the health issues associated with long-term diabetes. Collagen, haemoglobin, LDL, and albumen are all susceptible to AGE damage. In particular, the lysine residues of apo-B in LDL are susceptible to glycation and, once they are glycated, LDL is only poorly recognized by lipoprotein receptors and scavenger receptors [30
]. A schematic of the receptor-mediated uptake of cholesterol and fatty acids from LDL is illustrated in Figure and an illustration of impairment of this process through glycation is given in Figure .
Figure 2 Endocytosis of normal LDL. This schematic represents the normal binding of the apolipoprotein (A) and absorption of an LDL particle (L), which has attached to the receptor (R). The activated receptor has caused the formation of a caveolus for absorption (more ...)
Figure 3 Failed Endocytosis of glycated LDL. In this schematic the lysine in apoB or E (A) has become damaged by glycation (D). Consequently, the receptor (R) is unable to recognize the LDL particle (L). The cell endocytosis via the cell membrane (M) does not (more ...)
Glycation of LDL also causes it to be more susceptible to oxidation damage. A study of the potential effects of lipoprotein glycation on the oxidation of contained cholesteryl esters was conducted by Ravandi et al
]. In controlled in vitro
experiments, the presence of a synthesized glucosylated lipid, phosphatidylethanolamine (Glc PtdEtn) resulted in a 4- to 5-fold increase in the generation of oxidation products such as hydroperoxides and aldehydes. Furthermore, when this AGE product was included in the LDL lipid monolayer, it resulted in rapid loss of cholesteryl esters from the interior. The authors concluded that the presence of glucosylated phospholipids in the membrane may promote oxidation of both the membrane phospholipids and cholesteryl esters in the interior of the particle.
Cholesterol and fats that are delivered to the cells from food sources arrive in the form of a chylomicron, a spherical particle that is also encased in a lipoprotein shell, but is at least an order of magnitude larger than LDL. Lipoproteins range in diameter from 8 Angstroms for HDL [32
] to around 250 Angstroms for LDL [12
] whereas the chylomicron can be as large as 5000 Angstroms [32
]. This large size offers superior protection of its contents from oxidation. Indeed, given the choice, the heart will preferentially take up fats and cholesterol from the chylomicron rather than from LDL [33
]. Simple geometry tells us that a sphere whose radius is ten times larger than that of another sphere contains 1000 times as much content with only 100 times as much surface area. Thus, it would take 1000 LDL particles to contain the equivalent content of a single chylomicron ten times as large in diameter, and it would require ten times as much cholesterol and lipoprotein to encase those contents.
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.
The liver releases its synthesized fats and cholesterol as VLDL particles, which deliver fat, cholesterol, and antioxidants to all the tissues, while becoming steadily smaller as they migrate through stages of IDL, LDL, and, finally, VLDL remnants, also known as small dense LDL: small lipoprotein shells with minimal content but damaged by exposure to glucose, fructose, and oxygen. The liver is responsible for recycling these remnants through bile excretion to aid in the digestion of fats (and to be reconstituted as free cholesterol in the membrane and esterified cholesterol in the contents of the chylomicron). When there are relatively few fats in the diet, less bile is needed, and the liver, being burdened by fructose and glucose metabolism, falls behind on the task of providing cholesterol to the bile salts.
Meanwhile, the task of cleaning up damaged VLDL remnants is delegated to the adipocytes. In particular, they synthesize substantial amounts of apoE to reconstitute damaged cholesterol and orchestrate its transport to PM so that it can be utilized both by the adipocyte itself and by many other cells in the body (after it is taken up by HDL particles in the bloodstream). Over time, the adipocyte accumulates AGE products due to its chronic exposure to both glucose and damaged VLDL remnants. ApoE is especially susceptible to AGE damage [34
], 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 PM, the cell becomes first permeable to outward sodium leaks but ultimately unable to keep calcium out, at which point the cell literally disintegrates.
Macrophages are responsible for engulfing lipids that are exposed to the interstitial spaces, so they rush in to clean up the cell debris left behind by dead adipocytes. In fact, so-called giant cells accumulate in unhealthy adipose tissue: a single cell encasing multiple cell nuclei and lipid droplets [35
]. Such a cell is likely taking advantage of the same principle as that used by the chylomicron. A single PM surrounding multiple cell nuclei requires significantly less cholesterol to protect the contents from damage than would several individual cell walls. The macrophages secrete various inflammatory agents such as interleukin (IL)-6 and tumour necrosis factor-α (TNF-α).
Over time, more and more adipocytes swell in size to the point of cell death to accommodate cholesterol that they cannot discharge, and the subcutaneous adipocytes become increasingly unable to deliver refurbished cholesterol to the tissues. Cholesterol deficiency becomes a problem for cells throughout the body, with dire consequences. One consequence will be the increased susceptibility of the fats in cell membranes to oxidation [36
]. This problem can be partially ameliorated through the accumulation of fat storage in non-adipocyte cells in and among the viscera, including the heart, i.e., ectopic fat. Epicardial fatty deposits (and ectopic fat in general) serve as a private source of fats and cholesterol to replenish supply to repair damaged membranes when blood serum levels are insufficient.
Initially, it is only the liver that is resistant to insulin, but the skeletal muscles and adipocytes also show signs of insulin resistance as they become exposed to accumulated AGE damage. The resulting excess of glucose in the blood leads to a sharply increased demand for insulin, which imposes excess energy requirements on the β cells in the pancreas, leaving them susceptible to glycation and oxidation damage as well. β cells require glucose, calcium, fats, vitamin D and cholesterol to all be present at adequate levels in the cytoplasm before they will release insulin. Due to deficiencies in these nutrients, the β cells eventually become dysfunctional leading to diabetes.