Dr. Oz Five Food Felons

---the other 200 posts---

Biofilms on intestine microvilli

The medical industry is slowly pulling away from diet advice that has contributed significantly to disease in America.  It promoted or at least tolerated, the shift from butter to margarine and polyunsaturated vegetable oils, and from saturated fats in meats to starches and grains.  The medical emissary, Dr. Oz, still supports medical advice that is not based on medical research.

Dr. Oz's Five Food Felons and Why His Choices Are Unhealthy:

"1) Trans fats raise lousy LDL cholesterol and triglyceride levels, lower your healthy HDL cholesterol level and fuel disease-triggering inflammation."  Trans fats are inflammatory and should not be eaten.  New labeling has permitted substantial amounts of trans fats to be added to processed foods and still be labelled "No trans fats."  LDL blood levels reflect inflammation, but artificially lowering the LDL with statins has no impact on heart disease.  Lowering LDL, by lowering inflammation with fish oil and/or repair of gut flora, diet and exercise is effective.

"2) Saturated fat in red meats, poultry skin, full-fat dairy products and palm and coconut oils fuels cancer risk, coronary artery disease, dementia, obesity and diabetes."  Linking saturated fats with heart disease, etc. was never supported by medical research.  Elimination of red meat, removing skin from chicken, avoiding egg yolks, etc. and replacing them with omega-6 polyunsatured vegetable oils has been a major contributor to inflammation and disease.  Full fat milk is the healthful choice, especially for children.  The change was dangerous and is being reversed with new emphasis placed on omega-3 fish oils.

"3) Added sugars and 4) sugar syrups cause the proteins in your body to be less functional and age your immune and cardiovascular systems and your joints. Plus, they disrupt your metabolism and contribute to almost every lifestyle-related malady, including some cancers."  Oz got this right even though they initially promoted high fructose corn syrup (half glucose/oligos) and its evil and even higher fructose sister agave nectar (all fructose/oligos.)  Equally bad, however, are the hyperglycemic starch in breads (including whole grain!) and over cooked pasta.

Gut flora

"5) Refined and processed grains don't contain the fiber or nutrients (contained in 100 percent whole grains) that you need to keep the bacteria in your guts happy, glucose levels regulated, immune system strong and digestion running smoothly."  Dr. Oz and company fail to understand the basics of vitamins, soluble fiber and gut flora.  Grains are not healthy for most people, because of the toxicity of gluten and hyperglycemic starch.  Ultra fine milling and fast commercial bread making eliminate the resistant starch.  "Whole grain" processed foods just add back the insoluble fiber that is considered toxic, because of its phytic acid content.  Grains should just be replaced with whole foods, such as vegetables that contain the soluble fiber that feeds the gut flora that provide all of the needed vitamins and are required for immune system development.

Why Does Dr. Oz Make Health Mistakes?

Dr. Oz has been criticized for promoting foods, supplements, medical treatments, etc. that are not supported by medical research.  While that is true, I think that he is just following the general views of the medical industry and simply doesn't know any better.  Sadly, most doctors don't have the background to read scientific research papers, let alone their own biomedical literature that is rife with scandals of nonreproducibility and inappropriate industry influence.  Doctors find it hard to give valid dietary advice, because nutritionists have false information and celebrity doctors, and their research teams, don't do their homework.  The result is the mix of ancient orthodoxy, industry promotion, alternative medicine and unscientific fads that appears in the media.  Doctors need a scientific background sufficient to answer the essential question posed to health claims, "Does it make sense?"

Aricept: dementia treatment

Aromatic Binding to Enzymes -- 

Aricept, an acetylcholine esterase inhibitor used to treat Alzheimer’s disease and other conditions that benefit from enhanced accumulation of acetylcholine, is an example of a molecule with multiple hydrophobic rings that binds to an enzyme.

I want to discuss aricept as an arbitrary example that I just looked up to illustrate the lack of specificity of statins that I will characterize in another article as little more than molecular skeleton keys that work on many different enzymes.

I have presented two diagrams of the structure of Aricept. It has two isolated rings on the left and then a fused pair of rings on the right. The major chemical feature here is the inability of the rings to hydrogen bond with water. The result is that water next to the faces of the rings is highly structured in a high energy configuration. Two rings will be at a much lower energy if they are stacked together, because two of the surfaces will no longer be exposed to water.

Typical low energy, noncovalent bonds in water, such as ionic bonds are readily broken by the thermal, kinetic energy of water -- they get knocked apart. The energy of these bonds is only 1-2 kcal/mol. In contrast, the stacked hydrophobic rings are quite stable, because it takes ten times the energy to separate them, 20 kcal/mol.

Aricept binds to acetylcholine esterase, the enzyme that degrades the neurotransmitter acetylcholine by at least three stacked rings. These ring structures are shown in the close up of the tunnel leading to the enzymes active site near the yellow tryptophan on the left. Part of the enzyme shown by the white, ribbon-like twists of the amino acid backbone have been removed over the tope of the grey-red and blue aricept molecule, to make it easier to see.

I also showed the aricept in the tunnel with the surface of the protein shown to indicate how the aricept slips and sticks in the enzyme and blocks its activity.

The aricept is bound to yellow tryptophans at both ends and the middle ring is bound to the hydrophobic ring of orange tyrosine. The geometry of the interaction is important, but many other molecules with fewer rings would also bind to the same hydrophobic, aromatic ring amino acids. Acetylcholine, which can form hydrogen bonds with the paired electons of the acetyl oxygens, will just slip across the surface of the hydrophobic rings on its way into the enzymatic tunnel.

Statins were found by testing fungal extracts for molecules that would inhibit an enzyme (HMG-CoA reductase) in lipid metabolism. The normal lipid substrates for that enzyme would also be expected to bind to the surface of rings in the acetylcholine esterase enzyme. In fact, I would expect to find molecules from fungal extracts that would inhibit acetylcholine esterase.

I demonstrated the nonspecificity of all of these binding events with the aromatic rings in the active sites of enzymes by having one of my students check for the binding of a flat hydrophobic molecule, metformin, one of the common drugs for treating type II diabetes, to a common bacterial enzyme, beta galactosidase. Kinetic studies demonstrated competitive inhibition of typical beta galactosidase substrates, which indicates that the metformin binds the aromatic amino acids that are known to be involved in binding of the sugar substrates, e.g. lactose, of the enzyme. I would not be surprised if the statins are transported into cells by the same organic cationic transporter that transports metformin.

I am setting the stage for a discussion in a future article of what kind of activities would be expected from fungal molecules that were identified by the statin screening. It is not surprising that the statins have many activities other than reducing LDL. The only statins that are effective in treating cardiovascular disease are those that also lower inflammation. It is also not surprising that statins have many side-effects.

Niacin Flush

Niacin is a B vitamin that is cheap and highly effective at raising HDL and lowering LDL. HDL and LDL were previously called good and bad cholesterol, resp., but since the data from numerous studies show that they don’t have a big impact on health, it is probably easier to just call them heavy and light reflecting less and more lipid content. If you still want to adjust your blood lipids, then niacin is more effective than the costly statins. Unfortunately, niacin also causes an uncomfortable (itchy and hot) flush.

The niacin flush is part of the inflammatory process that includes the classic tetrad of symptoms: rubor (redness), calor (increased heat), tumor (swelling), dolor (pain). Flushing in response to niacin shows that the immune cells in the skin respond to ingested niacin that is flowing through the capillaries. Mast cells in the skin have receptors that bind niacin and the cells secrete inflammatory prostaglandins. The prostaglandins act on the capillaries to cause dilation and flushing. Mast cells have secretory granules that fuse to the cytoplasmic membrane and release their contents outside. The granules contain histamine, heparin and tryptase. The histamine stimulates histamine receptors on pain/itch nerves and the tryptase stimulates receptors on a second set of pain/itch nerves.

Prostaglandins are produced by membrane bound enzymes on the surface of mast cells. When the mast cells are stimulated, additional enzymes are added to the surface through fusion of the secretory granules. The combined enzyme complex produces prostaglandins by releasing arachidonic acid (ARA) from phospholipids of the membrane (phospholipase A2, PLA2), converting the ARA to an epoxide prostaglandin (cyclooxygenase, COX-1) and stepwise producing additional prostaglandins. These prostaglandins cause the dilation of capillaries that is seen as flushing.

Niacin also binds to receptors on fat cells, adipocytes, and blocks release of fatty acids from the triglycerides stored in these cells. It is this action that is responsible for the increase in HDL and the lowering of LDL in blood serum.

An extension of the niacin skin flushing reaction is the use of this response to demonstrate the presence of arachidonic acid and a functional immune system in the skin. A recent study used topical application of niacin and skin reddening to test the idea that schizophrenia exhausts ARA as a result of inflammatory processes in the brain. Tests showed a tendency for schizophrenic episodes to be accompanied by a diminished flushing response to niacin. This result also suggests that a lowered system-wide ARA level should show up in a predisposition to gut problems.

It would be very interesting to test the interplay between inflammatory provocations, e.g. infection, serum omega-6/omega-3 fatty acids, and measures of inflammation, e.g. C-reactive protein on niacin flushing. Inflammatory depletion of ARA may be important in the decline in the integrity of tissues that is observed in inflammatory diseases of the gut (Helicobacter-based ulcers, IBD, Crohn’s disease, celiac), autoimmune diseases (arthritis, atherosclerosis), skin diseases (vitiligo), etc. It would also be interesting to test the impact of helminth infections to reverse ARA depletion.

reference:
Benyó Z, Gille A, Kero J, Csiky M, Suchánková MC, Nüsing RM, Moers A, Pfeffer K, Offermanns S. 2005. GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. J Clin Invest. 2005 Dec;115(12):3634-40.

Statins and Atherosclerosis

A recent study (JUPITER) on the statin Crestor was ended prematurely when the drug was shown to dramatically reduce vascular events. The statin was tested on patients with chronic inflammation as judged by elevated C-reactive protein, but with low LDL. These patients would not normally be treated with statins and therefore represent an immense new market for statins.

Statins are supposed to act by interfering with the synthesis of cholesterol and thereby lowering the serum concentration of the lipid carrier LDL. Lowered LDL is supposed to decrease vascular disease that is aggravated by accumulation of cholesterol at sites of inflammation on the surface of blood vessels.

Unfortunately the data linking cholesterol production, LDL levels and vascular disease is weak. Thus, it is possible to lower LDL and have no impact on cardiovacular disease statistics. The recent study on Crestor was interpreted as being support for the link between LDL levels and vascular disease, but I think it shows something very different.

There is increasing evidence that vascular disease is based on diet-based chronic inflammation and that statins have a mild impact on reducing inflammation. It follows then that statins will reduce inflammation enough to have an impact on vascular disease, independent of effects on LDL levels. The Crestor study actually showed that patients with low levels of LDL but chronic inflammation benefited from lowering of inflammation. The LDL levels were unimportant. Reducing inflammation was the point and using statins to reduce inflammation is unnecessarily expensive and ineffective. Adjusting diet makes a lot more sense.

Drug companies are already pushing for increased use of statins on larger segments of the US population to provide prevention from atherosclerosis, stroke and heart disease. This would be immensely expensive with marginal returns. It is also just treating the symptoms without addressing the cause.

The solution to cardiovascular disease is dietary. Omega-6 oils and low availability of omega-3 fish oils is the major cause of the chronic inflammation that is the major risk factor for cardiovascular disease. The major US vegetable oils, corn, soybean, cottonseed, safflower, need to be drastically restricted and olive oil needs to be encouraged. We need to recognize that saturated fats are safer than the omega-6 polyunsaturated fats that have replaced them. Elimination of omega-6 vegetable oils and use of fish oil supplements are cheap and effective ways of lowering chronic inflammation.

Cardiovascular disease is also based on decreasing muscle mass, sarcopenia, which is also the basis for increasing chronic inflammation inappropriately attributed to aging. People get less physical exercise as couch potatoes or with decreasing activity as they age. The result is replacement of muscle by fat, and fat is inflammatory. Obesity is an extreme of this trend that leads to high chronic inflammation identified as metabolic syndrome, the prelude to a suite of nasty degenerative diseases: diabetes, atherosclerosis, allergies, cancer, Alzheimer’s, etc.

The obvious bottom line is to avoid all of these problems with an anti-inflammatory diet and lifestyle.

Palmitoleate: omega-7 lipokine

Palmitoleic acid is responsible for keeping people healthy (lipokine) and for the smell of old people (nonenal). Overproduction of this lipid by blocking uptake of fats results in resistance to type II diabetes and atherosclerosis.

If you listen to the commercials on television, you know that there are two sources of fats/cholesterol; you either make it in your cells or take from your diet. Recent research shows that mice that have been genetically modified to lack cytoplasmic lipid carriers, can’t store dietary fat, so they make more of their own lipids. Specifically, they make more palmitoleic acid (C16:1n7). By U.S. standards, those defective mice are very healthy. It turns out that palmitoleic acid acts as a lipid hormone that communicates between fat tissue and other organs, and maintains a healthy metabolic balance.

Lipids are hydrophobic and require protein carriers to be moved from their source, such as the intestines, through the blood and to be offloaded into tissues. Most of the lipids enter the diet as triglycerides, i.e. a three carbon glycerol with three fatty acids attached. Those fats are extracted from food with bile, which is a mixture of modified cholesterol salts that acts as a detergent to dissolve fats. The dissolved fats, in the form of chylomicrons (big fat droplets coated with a lipid layer and proteins) are produced by intestinal cells and released into the blood stream. During transit, a lipase removes the fatty acids from the triglycerides. As in all of the lipid transport systems, the protein carriers determine how the lipid contents are distributed.

If a fatty acid or triglyceride is added to a cell membrane, the lipid would get stuck in the membrane's double layer of phospholipids. Fat droplets in cells are nothing more than fats that are loaded into the membrane of a cellular vesicle until a droplet covered by a half membrane forms. The alternatives for lipid transport are the HDL and LDL (protein coated lipids of the blood), and the intracellular fatty acid-binding proteins. The proteins bound to the surface of LDLs and HDLs bind to receptors on cell surfaces and control transfer of lipids to and from cells. One example is apolipoprotein E4. This protein is intimately involved in determining risk for athersclerosis and Alzheimer’s. ApoE4 binds to its cell surface receptor via heparin. Note the blue basic amino acids that form a massive heparin-binding domain down one side of the protein.

Fatty acid-binding proteins (FABPs) are just globular proteins, with hydrophobic amino acids arranged in the center and hydrophilic, water-bonding, amino acids on the surface. I have drawn the structure of a FABP using a graphics program called Chimera to visualize X-ray crystallographic data in the National Center for Biomedical Information (NCBI) database. The continuous chain of amino acids is shown as a white ribbon and the surface of the protein is shown as a transparent overlay. The protein chain makes a cage with the hydrophobic parts of the protein pointing toward the center to make a hydrophobic-lined container for the trapped fatty acid (pink). The two ends of the protein vessel are held closed by interdigitation of tryptophans (yellow) and basic amino acids (arginine and lysine, dark and light blue). The FABP also has a nuclear translocation signal, a group of four basic amino acids and other concentrations of basic amino acids displayed linearly across the surface of the cage (not shown), that probably are involved in transport of the trapped fatty acid from the cell surface to the surface of the nuclear envelope, which is involved in phospholipid assembly.

Mice engineered to have the human ApoE4 gene develop atherosclerosis and type II diabetes. If the FABPs of the fat cells of these mutant mice have also been removed, then the mice are essentially normal. Removal of the FABPs blocks the uptake of dietary fatty acids and stimulates the production of endogenous lipids, including the omega-7 fatty acid palmitoleic acid. This fatty acid is a lipid hormone, lipokine that stimulates normal metabolism and provides protection against several inflammation-based diseases. Interestingly, palmitoleic acid accumulates abundantly in the skin of old people and is converted to nonenal that has the smell of old books.

Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS. 2008. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism.Cell. 134(6):933-44.