Atherosclerosis

Pathogenesis of atherosclerosis. (a) In the first stage, low density lipoprotein-cholesterol (LDL) is deposited in the endothelium and undergoes oxidative modification, resulting in oxidized LDL (oxLDL). OxLDL stimulates endothelial cells to express adhesion molecules (vascular cell adhesion molecule-1 (VCAM-1), P-Selectin) and various chemokines (e.g., Monocyte Chemoattractant Protein-1 (MCP-1), Interleukin 8 (IL-8)). This leads to a recruitment of monocytes, which transmigrate into the intima and differentiate to pro-atherogenic macrophages; (b) Macrophages harvest residual oxLDL via their scavenger receptors and add to the endothelial activation and, subsequently, leukocyte recruitment with the secretion of Tumor Necrosis Factor α (TNF-α) and IL-6; (c) The increasing plaque volume promotes neovascularization. Proliferating smooth muscle cells (SMCs) stabilize the nascent fibrous plaque. With deposition of fibrin and activated platelets on the dysfunctional endothelium that expresses tissue factor (TF) and von Willebrand factor (vWF), a pro-thrombotic milieu is formed; (d) Foam cells can undergo apoptosis and release cell-debris and lipids, which will result in the formation of a necrotic core. In addition, proteases secreted from foam cells can destabilize the plaque. This can lead to plaque rupture, in which case extracellular matrix molecules (e.g., collagens, elastin, TF, vWF) catalyze thrombotic events.
(PMC full text: Int J Mol Sci. 2015 May; 16(5): 9749–9769. Published online 2015 )

Pathogenic Bacteria Mediate Inflammatory Effects of Meat

A recent study from Harvard university concluded that, in genetically susceptible mice, dietary saturated fatty acids (SFAs) led to increased pathogens in the gut. (See Rob Wolf's critique of the study.)  The implication appears to be that dietary SFAs feed harmful microbes.  A similar conclusion was also reported for choline...

Researchers have theorized that the evolutionary pressure from pathogenic gut bacteria has led to the link between SFAs and a prophylactic inflammation: our bodies ramp up a defense response to SFAs because these fats feed harmful bacteria.  In contrast, monounsaturated fats (MUFAs) and polyunsaturated fats (PUFAs) are actually antimicrobial.  

However, it appears that pathogenic species are not being stimulated directly by dietary fats, but rather by cholesterol in our own bile.  This makes sense, because most fats should be absorbed before they reach the large colon, but bile is one of the largest inputs to our large intestines.  If this is true, than dietary fats are not the culprit so much as our own bodies' reaction to SFAs.

Even so, the association between saturated fat intake and inflammation has been repeated numerous times.  For example, one study of obese women on a high-fat low-carb diet noted 25% increase in C-reactive protein (CRP, a marker of inflammation) compared to a 43 decrease on a low-fat high-carb diet.  But when I searched for studies confirming this, I found a 2008 study from the University of Aukland, New Zealand, found that in healthy men, a single high-fat (71% of calories) meal did not lead to changes in tumor necrosis factor-α (TNF-α), and CRP.  Also, a 2004 study looking at the acute effect of a high-fat (50% of calories) meal in young healthy men noted no significant changes in CRP.

Jeff Leach at the Human Food Project lays out an interesting theory to explain these divergent results:

"Multiple studies have shown that a high fat diet produces low-grade inflammation, which in turn promotes metabolic disease such as diabetes. Interestingly, the low-grade inflammation correlates with circulating levels of a plasma endotoxin known as lipopolysaccharide (LPS). LPS is the primary structural component of the outer membrane of Gram-negative bacteria. Importantly, LPS only originate in the gut."

He concludes that intestinal permeability and the translocation of inflammatory toxins occurs only in the absence of Bifidobacteria, a type of beneficial bacteria found in mother's milk and fermented dairy products.  Importantly, stimulation of these species with fiber prebiotics like FOS and inulin has been shown to block inflammation from saturated fats.  Indeed, higher dietary intake of fiber has been repeatedly associated with lower markers of inflammation.

Take home message: always eat enough fiber with higher-fat meals.

A Disturbing History of Nutrition Science

What is the biggest mistake scientists have ever made?  Nina Teicholz's The Big Fat Surprise, a wonderful history of the awful state of nutrition science, suggests that science's worst mistake may well be the idea that saturated fat is unhealthy.  She makes a convincing case that nutritional guidelines over the last half century, by focusing on fats rather than sugars, have resulted in the premature deaths of millions of Americans and others around the world.

Even more interesting than turning conventional wisdom on its head, this book is an eye-opening journey into how an entire field of science can be hijacked by special interests and strong personalities. Moreover, this book holds important lessons about how the process of science is still susceptible to the same biases and group-think as the rest of society.

Nina Teicholz sums up the story of how nutrition science went wrong:

"Well-intentioned experts, hastening to address growing epidemics of chronic disease, simply overinterpreted the data. Scientists hypothesized that dietary fat was to blame...  This hypothesis became accepted as truth before it was properly tested.  Public health bureaucracies adopted and enshrined this unproven dogma.  The hypothesis became immortalized in the mammoth institutions of public health.  And the normally self-corrected mechanism of science, which involves constantly challenging one's own beliefs, was disabled.  While good science should be ruled by skepticism and self-doubt, the field of nutrition has instead been shaped by passions verging on zealotry. ...Once ideas about fat and cholesterol became adopted by official institutions, even prominent experts in the field found it nearly impossible to challenge them."  

"What I found, incredibly, was not only that it was a mistake to restrict fat but also that our fear of the saturated fats...has never been based in solid science.  A bias against these foods developed early on and became entrenched, but the evidence mustered in its support never amounted to a convincing case and has since crumbled away."

Let the sorry story of nutrition science be a lesson for the scientists and promoters of scientists in other fields.  We like to think that science is independently and objectively building a tower of knowledge for the ages, one rock at a time, but the reality is that our science is a product of our society, our beliefs, our biases, and our assumptions.

Don't Spike Your Blood Sugar

There have been a number of scientific papers in the last couple years, and now a number of high-profile articles (like last week's Time Magazine article "Ending the War on Fat") that have found no correlation between fat -- even saturated fat -- and Alzheimer's, diabetes, cancer, or heart disease. The idea that cholesterol and saturated fat are the cause of heart disease is no longer supported by the best available science.

However, there is still broad consensus among health professionals that we need to avoid processed, sugary, and high-glycemic foods. High-glycemic foods are energizing for an hour or two but then cause sleepiness and craving for more (usually high-glycemic) snack foods. These foods are dangerous because they raise blood sugar, leading to a crash afterwards, a "roller-coaster" blood sugar dynamic that promotes over-eating and a variety of diseases.

Gary Taubes, in Good Caloreis Bad Calories, explains how sugar metabolism makes you fat:

"Glycerol phosphate is produced from glucose when it is used for fuel in the fat calls and the liver, and it, too, can be burned as fuel in the cells. But glycerol phosphate is also an essential component of the process that binds three fatty acids into a triglyceride. It provides the glycerol molecule that links the fatty acids together. In other words, a product of carbohydrate metabolism --i.e. burning glucose for fuel-- is an essential component in the regulation of fat metabolism: storing fat in the fat tissue. In fact, the rate at which fatty acids are assembled into triglycerides, and so the rate at which fat accumulates in the fat tissue, depend primarily on the availability of glycerol phosphate. The more glucose that is transported into the fat cells and used to generate energy, the more glycerol phosphate will be produced. The the more glycerol phosphate produced, the more fatty acids will be assembled into triglycerides. Thus, anything that works to transport more glucose in the fat cells -- insulin, for example or rising blood sugar, will lead to the conversion of more fatty acids into triglycerides, and the storage of more calories as fat."

"So yes, dietary fat is responsible for fat accumulation, but it is carbohydrates that mediate the accumulation, and the energy balance of the body as a whole. Don't spike your blood sugar, and your body will continue burning fat, not storing it."