Chris Kresser and Chris Masterjohn On Cholesterol: Part 1

Chris Kresser and Chris Masterjohn on Cholesterol Part 1

A reader pointed me in the direction of this podcast on Chris Kresser’s show where he interviews Chris Masterjohn about cholesterol, and I have to say, this is perhaps one of the most informative things I’ve read on the subject.

Chris Kresser is the author of Your Personal Paleo Code and Chris Masterjohn is the author of

If you want to listen to the whole podcast, you can listen here.

These are my notes from Part 1 (there are three parts in total):

Saturated fat can actually protect against oxidative stress because they are not vulnerable to oxidative degeneration.

It’s the polyunsaturated fats that are delicate. When you have an over-abundance of these, they are very vulnerable to oxidation and can actually promote oxidative stress.

With regard to lipoprotein particles, we are primarily concerned with the oxidation of LDL. There are 4 basic factors affecting this:

  1. Vulnerability of the LDL particle – this is related to how many delicate fatty acids it carries that are vulnerable to oxidation
  2. Antioxidants – The amount of antioxidants that the liver packages into the LDL particles as they are released
  3. Oxidants – When the LDL is in the blood, they are exposed to oxidants like metabolic byproducts, toxins, inflammation, etc. which will deplete the antioxidants within the particles
  4. Time – The amount of time the particles are exposed to oxidants. The longer particles are exposed to oxidants, the higher likelihood they become oxidized
    1. LDL receptor activity is the primary regulator of how long LDL particles spend in the blood
      1. LDL receptors are what bind to the LDL particles in the blood, removing them from the blood stream, bringing them into the cells.
      2. People with genetic defects causing decreased LDL receptor activity have an increased risk of heart disease
      3. People with genetic defects causing increased LDL receptor have a decreased risk of heart disease

What happens when LDL particles spend too long in the blood because of poor LDL receptor activity?

The LDL particle is exposed to enzymes that remove their triglycerides, making them smaller and denser

The LDL particle also starts to oxidize. When the polyunsaturated fatty acids in the LDL membrane oxidize, they get cleaved off from the membrane and transferred onto lipoprotein A or Lp(a), which further makes the LDL smaller and denser.

The LDL particle also exchanges triglycerides with HDL particles, further making the LDL smaller and denser.

The markers of total cholesterol to HDL cholesterol ratio AS WELL AS the LDL particle size, both indicate that the LDL particle is spending too long of a time in the blood, and are markers of poor LDL receptor activity.

Chris says that in his view, knowing all this, it’s not the TC:HDL or the LDL particle size that cause atherosclerosis because they’re simply markers for LDL receptor activity, but that it’s actually the oxidative degeneration of the LDL resulting from the poor LDL receptor activity that causes atherosclerosis.

There are theories out there about the causal role of TC:HDL and LDL particle size and atherosclerosis which go something like this:

  • TC:HDL ratio reflects reverse cholesterol transport which is how much the HDL is removing cholesterol out of vascular plaques to bring back to the liver.
    • Chris’ main issue with this was with the trials of the drug Torcetrapib, a cholesterylester transfer protein (CETP) inhibitor. This drug, despite raising HDL and decreasing LDL, killed people left and right.
  • Small dense LDL is more likely to fit through the endothelium, to get through the lining of the blood vessel, and get into area where it can easily oxidize and create an atherosclerotic plaque.
    • Chris is skeptical of this theory because when you remove small dense LDL from blood, before it’s even close to passing through the endothelium, it’s already partially oxidized. It’s already oxidized because of the amount of time it spent floating around in the blood.

Eating cholesterol improves LDL particle size, and decreasing carbohydrate intake also improves LDL particle size, because when VLDL is secreted with more cholesterol and less triglycerides, it’s ultimately metabolized to a large, fluffy pattern of LDL instead of the small dense pattern.

So right now the name of the game is to support healthy LDL receptor site function, lessening the amount of time that LDL spends in the blood, therefore reducing the chance that the LDL will oxidize.


LDL receptors are expressed on many cells including the adrenal glands and sex organs. This allows these cells to pull cholesterol out of LDL particles for the production the adrenal steroid hormones and sex hormones.

Despite being expressed throughout the body, the primary site of LDL receptor activity is in the liver. The liver is the site of bile acid production, which is the body’s main method of excreting cholesterol.

This is how the liver affects blood cholesterol levels. It’s not by the amount of cholesterol it synthesizes (all cells in the body can synthesize cholesterol), but how much LDL receptor activity the liver expresses, to bind to LDL particles, making bile acids, and excreting the bile acids into the intestines.

How does the liver know how many LDL receptors to express?

This depends on how much cholesterol the liver itself as well as the rest of the body needs.

The needs of the body are primarily communicated via thyroid hormone.

The hormone that regulates thyroid hormone is leptin, which is the master governing signal about whether our bodies are in a state of abundance or not.

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The Leptin Receptor Gene

There are two regulatory elements, dedicated pieces of DNA that are made for communicating the needs of the cell and the body.

One of these communicates the levels of cholesterol in the cell.

The other binds to thyroid hormone.

So when the cell needs more cholesterol or when the body is telling the liver, adrenal glands, and sex organs that life is abundant, LDL receptor activity gets upregulated.

Since as a population, we are currently suffering an epidemic of leptin resistance, which obesity is closely tied to, we can presume that this leptin resistance is basically a failure of the body to communicate the signal that there is abundance.

We are living in an environment of abundance, that this signal is not getting to where it needs to go, and this is the major factor in disrupted LDL receptor activity.

They then address a listener question about familial hypercholesterolemia, although the principles seem to be universally applicable

Giving Thyroid Hormone

Chris discusses some experiments in the 20th century where cholesterol levels were normalized after administration of thyroid hormone even though they had normal thyroid levels. Success was seen with titrating small doses of thyroid hormone… and then some overzealous people went off and gave huge doses of thyroid hormone leading to patient deaths, which caused this research to be abandoned.

He still thinks we need some very cautious experimentation with this using low doses of thyroid hormone as a way to treat high cholesterol.

Some people have also experimenting with using iodine supplementation which caused similar improvements in thyroid hormone and preventing atherosclerosis.

But again, he cautions about doing any of this without proper supervision.

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So what can be done?

Minimize the oxidation of the LDL particle and prevent the inflammation and pro-clotting environment from the atherosclerotic lesions.

Vitamin C prevents LDL oxidation and stimulates collagen synthesis which encourages plaque stability.

Low LDL receptor activity will promote LDL oxidation no matter how little polyunsaturated fat you eat or how many antioxidants you take.

Provide enough antioxidants in the diet to decrease oxidative stress.   Eat nutrient dense foods and whole foods from plants and animals and animal organs while minimizing refined foods and vegetable oils.

  • Wide spectrum of antioxidants found in fresh, whole animal and plant foods
  • CoQ10 – primarily found in beef and buffalo heart, and to a lesser extent in red meats
  • B Vitamins and Lipoic Acid – liver is a great source
  • Polyphenols – Plants, fruits, and vegetables.
  • Vitamin C – Raw fruits and vegetables

Masterjohn has an interesting interchange in the comments section and lets loose this great analogy:

The LDL particle is a cargo ship. It is supposed to land at various docks to deliver over the goods. However, it is also supposed to protect the goods so that they are in good shape when the ship gets to the dock.

However, there are often pirates at sea, and they may attack both the people at shore as well as the cargo ships. If they block entry to the dock, the ship cannot refuel or purchase more ammunition for defense.

If the ship is thus left at sea, it runs out of ammunition and the pirates are then able to effectively sabotage it, ruin its goods, and purposefully plant explosives and release infectious diseases on the boat.

Then, when it does get near shoreline, the folks at the dock catch illnesses and are caught in terrorist explosions.

Thus, the immune system, like a navy and national guard, rescues the cargo ships that have been attacked (oxidized LDL), and quarantines them and any toxic factors released from them in something like a superfund site, where the surrounding community is protected as best as possible.


Stay tuned for parts 2 and 3.  Things get more interesting I promise… especially in regard to the relationship between a low carb diet, thyroid hormone, and high cholesterol.

2 Responses to Chris Kresser and Chris Masterjohn On Cholesterol: Part 1

  1. schmolch says:

    This is gold. Thx for the notes, you rock 🙂

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