February 27th, 2023

The hypothesis: cholesterol and lipoproteins like LDL are inherently good and necessary unless they become unbalanced either through genetics and most definitely lifestyle choices.

From last week: It turns out that the carrier lipoproteins like LDL and HDL cholesterol are an ancient part of our innate immune system that have an important function in fighting infection. We have always used these lipoproteins to clear infectious material before they can do damage.

Remember that the carrier lipoprotein cars are known as chylomicrons, VLDL, IDL, LDL, and HDL. They have a primary role to carry fats/energy around the body. While they serve the fat carrying primary role dutifully, these same little cars float around in your blood stream looking for disturbed infectious particles or pathogens to throw in their trunk in order to transport them back for elimination in the liver. (Harris et. al. 1993) (Vreugdenhil et. al. 2003)

Let us say that these lipoprotein, either LDL or HDL type, cars are waiting for bacterial cell wall debris to enter the bloodstream from somewhere in the body where they are trying to grow and establish residence, aka infection. The HDL particle may pick up the bacterial cell wall debris and begin to carry it back to the liver for filtration and destruction. Let us also say that the volume of bacteria and bacterial cell wall debris floating around are elevated to a point that they cause an increase in the number of lipoprotein cars being produced to handle the burden. Interesting!

Genetically, there is evidence that certain groups of humans have genetic mutations, like APOE4 and PCSK9 variants, that increase the circulation of the lipoprotein cars in order to play a large part in our ancient rapid reaction force called the innate immune system that may have been highly protective in a pre-antibiotic world. Remember from earlier discussions that these types of mutations exist for a reason and are not mistakes. There must have been an evolutionary pressure in society for the mutation to persist. My hypothesis is that these mutations that are now associated with heart disease because of our current lifestyle choices used to be greatly beneficial when infection was our greatest risk of death. Infection was our greatest risk of death throughout human existence until the advent of sanitation, vaccination and antibiotics. This is relatively recent in the human existence spectrum.

Now that you have indulged me to lay out this hypothetical scenario, we now need to switch gears and look at the intestinal microbiome for clues to the heart disease story. It is clear to me that these metaphorical cars can bind to and eliminate viruses, bacterial cell wall debris and parasites throughout the body as a first line of defense, innate immunity. The gut microbiome harbors trillions of good and bad bacteria and their respective cell wall components like LPS/lipopolysaccharides. We know from the amazing work of Patrice Cani and Alessio Fasano that the bacterial cell wall debris from a dysfunctional intestinal microbiome can translocate into the bloodstream and circulate around the body causing inflammation, called low level endotoxemia. (Amar J. et. al. 2008) (Cani P. et. al. 2008) The lipoprotein cars have binding sites, "trunks", to grab the LPS and other pathogenic bacterial endotoxins and transport them back to the liver for excretion in bile and therefore your stool. (Harris et. al. 1990) This is a very advantageous mechanism for survival, if you are in a highly infectious environment like a third world country. (Read et. al. 1993)

Let us look at this infection fighting reality in study. Let us say that we have two sets of rats and infect them both with a deadly dose of a bacteria called E. coli while simultaneously giving one group an infusion of these protective lipoproteins. In the end, you will have most of the lipoprotein infused group relaxed and alive while the other group has died from the infection. (Harris et. al. 1993) It turns out that HDL cholesterol gets used up trying to clear the acute inflammation and infection. As the HDL level drops, LDL cholesterol and triglyceride levels rise as the next line of defense. As the infection clears, we would expect the HDL and LDL levels to flip flop back to normal. This appears to happen and is an amazing reality.

Let's pause here.

The mammalian system was set up to provide a molecule with multiple roles that would already be floating all around the body to deliver energy but also to engage a pathogen immediately. Let us imagine a warrior in the middle ages getting cut by a dirty sword or a modern American with an intestinal overgrowth of pathologic bacteria. The availability of these lipoproteins to grab bacterial particles and remove them rapidly is lifesaving and is a thing of beauty.

It would therefore be nice to have the genetic ability to have more of these lipoproteins floating around and protecting us against infectious disease if the environment dictated it's need. Scientifically, it would make sense then that if you had an elevated cholesterol level, you may be suffering from an infection causing the body to mobilize more cholesterol to clear the systemic pathogens. The big question now is, if it exists is this an acute or a chronic problem?

Let us look at the acute scenario. There is a deadly disease called bacterial meningococcal sepsis that is fatal for many infected patients. As a pediatrician, this disease scares me because it kills quickly. When researchers evaluated the death rate in relation to the cholesterol level, they found an inverse relationship. In other words, at the time of infection, if you have higher levels of lipoproteins, you had a higher survival rate! The deceased group had much lower levels of LDL. (Vermont et. al. 2005) To me the rational behind the why is that the removal of the LPS and other pathogenic debris reduces the inflammatory response to the LPS by the immune system leading to improved immunometabolic survival.

After years of studying the various human microbiomes, it would stand to reason that one major risk factor for human disease of all kinds is intestinal dysbiosis, or poor quality gut bacteria. This is true and there are a litany of studies showing this fact to be true for chronic disease. (DeGruttola A. et. al. 2016) A chronic gut dysbiosis or abnormal microbiome, that is primarily driven by dietary influences, that does not kill you would be expected to force the body to mobilize lipoproteins from the liver to clear the translocated bacterial LPS endotoxin that has made its way into the bloodstream. (Manco et. al. 2010) The increased levels would be a response to infection and not just a cause of CVD. Thus, the elevated levels of cholesterol in the genetically susceptible individuals is a response to this burden. This is exactly what I believe happens in the cardiovascular disease world when individuals have elevated lipoprotein levels and have disease.

This is not to say that we do not need to worry about the higher levels because we do as they directly correlate with negative CVD outcomes.

Based on the data as provided, it is clear to me that an elevated cholesterol is not the only and maybe not even the most significant upstream issue with coronary artery disease but a marker of intestinal dysbiotic or other chronic infection, inflammatory disease and systemic inflammation in response. Thus, I believe that the bigger antecedent player in the game is inflammation (Feingold et. al. 2015), gut dysbiosis and ultimately dietary influences over a lifetime starting at birth. For example, there is a 2X higher risk of CVD in patients that have autoimmune disease. (Onuora et. al. 2022) Later, we will look at the Tsimane Indians as an example of the opposite scenario.

Now that we have a basic understanding of the immune function of cholesterol, it is highly possible and frankly likely only a marker of underlying chronic infection in the gut and oral cavity, systemic inflammation and an activated cholesterol hepatic synthesis byproduct response in genetically susceptible individuals. In certain individuals that have genetic single nucleotide polymorphisms for lipoprotein receptor function or intestinal reabsorption, the elevated cholesterol does not get appropriately cleared by the liver and intestines after it is upregulated and then the cholesterol volume is likely to cause a concentration gradient pushing the lipoprotein into the heart vessel wall leading to atherosclerotic events to take place over time via immune system sensing, engulfment and deposition in the arterial wall. The model proposed by most cardiologists comes to life and is legitimized at this point.

More on this topic later. For now, let us go to the heart vessels. If we have high concentrations of lipoproteins in the blood stream that are going through the coronary heart arteries, how does the disease begin.

Next up: what to do to improve your heart attack risk.

 

Be Alive,

 

Dr. M

 

Manco Endocrine Reviews Article
Ridker Circulation Article
Houston Article
Read Infection and Immunity Article
Harris J Clinical Investigation Article
Vreugdenhil J of Immunology Article
Harris J Clinical Investigation 1993 Article
Vermont Critical Care Medicine Article
Lanter American Society for Microbiology Article
Cani Diabetes Article
Amar Amercian J of Clinical Nutrition Article
DeGruttola Inflammatory Bowel Diseases Article
Feingold Endotext Paper
Creasey Opinions in Lipidology
Onuora Nature Reviews Rheumatology