For those who don’t know, LMHR stands for Lean Mass Hyper Responder and refers to the lipid profile of people who achieve high LDL cholesterol, high HDL cholesterol and low triglycerides. Hyper responder refers to the high LDL that is achieved and lean mass because most of these people appear to have low body fat.
- LDL of 200 mg/dL (5.17 mmol/L) or higher
- HDL of 80 mg/dL (2.07 mmol/L) or higher
- Triglycerides of 70 mg/dL (0.79 mmol/L) or lower
I have written about LDL cholesterol before (r/ketoscience LDL wiki ; cholesterol or BHB) and why it raises for these people. In a recent article on the liver buffers I touched upon the mechanisms but I want to take a more extensive dive with a specific focus for these LMHRs and why they are able to go that high on LDL.
I will not provide references to scientific publications unless I found something new. If you would like to check on the concepts explained for which there is no reference then please refer to the previous articles mentioned.
The main reason to do this dive is because the high LDL is the effect of how things change over time and under which conditions. This is usually the most difficult thing to grasp for people compared to a simple on/off result. As already shown in the article on the liver buffers, there are different situations leading to different results.
So what ticks the boxes for the LMHR?
I’ve come to conclude that the main aspects that drive the levels are:
- The production of ApoB100 lipoprotein by the liver
- The clearance of ApoB100 lipoprotein by the liver
It seems obvious but there are plenty of other factors that contribute to the exact level but these 2 are the major ones. The control of these 2 elements is done via the hormones glucagon and insulin.
Let’s first explain what insulin does for LDL cholesterol and also why tests in humans may derail people to the wrong conclusions.
ApoB100 is produced in the liver. It loads up fatty acids and cholesterol and leaves the liver in the range of VLDL to LDL. Under high insulin stimulation, ApoB100 is broken down and cholesterol production is up.
As insulin starts to lower, it allows the ApoB100 production to go up. This is what has led researchers to state that with dropping insulin you get a faster ApoB100 production and this is true for a while.
However, the ApoB100 production is not only depending on low insulin. It is also depending primarily on fatty acid access under this low insulin situation. The low insulin will cause a clearance of the stored fatty acids but as the level of this storage goes down, so will the ApoB100 production.
So although lean, healthy subjects on a high carb diet have a higher ApoB100 production.. LMHR’s are on a ketogenic diet. They don’t stimulate insulin nearly as high as on a high carb diet which causes less of the fat being backed up in the liver.
LMHR’s have low hepatic fatty acid availability and low ApoB100 production.
If there are not sufficient fatty acids, ApoB100 gets broken down again until sufficient fatty acids are collected. With a cleared fatty acid buffer, the main source of fatty acids will have to come from the circulation.
In that case there are 3 sources of lipids for the liver. 1) Dietary fatty acids ; 2) albumin-bound fatty acids ; 3) ApoB100 lipoprotein uptake containing fatty acids.
We’ll look at dietary fatty acids later on. Albumin will be ignored for now so let’s check out the uptake of ApoB100.
The way that LDL cholesterol gets cleared by the liver is through the LDL receptor. This receptor is expressed depending on PCSK9. PCSK9 binds to the receptor and degrades it, lowering the LDL cholesterol clearance. This is also how PCSK9 inhibitors work and they do that very efficiently.
Yet the role that insulin plays on PCSK9 expression needs to be clarified. We find increased expression by insulin and reduced up to 80% by fasting. With reduced PCSK9 under low insulin we get a higher clearance. But PCSK9 is not the dominant factor.
“The Role of Insulin in the Regulation of PCSK9” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484737/
The LDL receptor goes down under fasting and causes the LDL cholesterol level to go up.
Furthermore, plasma LDL cholesterol increased from 24 h onwards preceded by a decrease of liver LDL receptor mRNA which in turn is related to serum T3 (r = 0.55, p < 0.05, n = 19).
“The decrease of liver LDL receptor mRNA during fasting is related to the decrease in serum T3.” https://www.ncbi.nlm.nih.gov/pubmed/9608674
If anything, insulin is at its lowest under fasting conditions so what is causing the LDL receptor to go down and is that applicable to our LMHR profile who are not fasting?
Free T3 (fT3) entering to the scene… It is anecdotal but many of the LMHR’s report hypothyroid symptoms. Good indicators are easily feeling cold at hands and feet and a dry skin.
We find a very good study showing correlation between fat mass and circulating T3 in 941 non-obese healthy men, cleared from any known underlying confounders.
Leptin is a stimulator of the thyroid and leptin production depends on the available fat mass. With 15kg of fat mass in the lowest quartile, these individuals are not yet as lean as in our LMHR. For me personally, at 75kg and +/- 12% body fat I have about 9kg body fat, 40% less than that lowest group. Notice the increasing drop in fat mass as you go from the highest to lowest FT3 quartile with an equal but stronger drop in leptin.
“Body composition and metabolic parameters are associated with variation in thyroid hormone levels among euthyroid young men.” https://www.ncbi.nlm.nih.gov/pubmed/22956557
Also note that lean mass is inversely correlated (see article). Our body is able to sense energy availability according to energy demand. Lean mass = energy demand ; fat mass = energy availability. The balance between the 2 determines energy conservation or wasting via fT3 regulation.
Taking this information together, the LDL receptor is expressed according to the following situation:
NOTE about the graph: Insulin represents the effect of a meal intake. It is much more amplified due to meal ingestion. fT3 has a slower change and the line here represents fasting levels across a longer time frame in which you get leaner.
We can expect insulin to be the most dominant at all levels to ensure storage. Energy storage/conservation has the highest priority. Reducing the LDL receptor to avoid losing energy via hepatic clearance fits into this narative.
As insulin clears and does not dominate anymore, your T3 state becomes the dominant factor in LDL receptor expression.
“Decreased Expression of Hepatic Low-Density Lipoprotein Receptor–Related Protein 1 in Hypothyroidism: A Novel Mechanism of Atherogenic Dyslipidemia in Hypothyroidism” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770248/
LMHR’s have low insulin and low fT3 (resulting from the balance between fat mass & lean mass).
Not only does fT3 influence the LDL receptor expression, it also influences the binding affinity of LDL to the LDL receptor. High ft3 results in a stronger binding and uptake thus we see in the LMHR a reduction in binding affinity resulting in an additive lowered clearance.
“Interactions of triiodothyronine, insulin and dexamethasone on the binding of human LDL to rat hepatocytes in monolayer culture.” https://www.ncbi.nlm.nih.gov/pubmed/3288226
Circulating fatty acids
We addressed point 3 (1. Dietary fatty acids ; 2. albumin-bound fatty acids ; 3. ApoB100 lipoprotein uptake containing fatty acids) with the LDL receptor. Now let’s have a look at point 2.
As mentioned, fT3 is the regulator for energy expenditure. With low fT3 the body wants to conserve energery. fT3 influences lipolysis. A reduction of fT3 will lead to lowered lipolysis and with lowered lipolysis we have a reduction in non-esterified fatty acids or free fatty acids.
A determining effect is the low fT3 but this has further reaching consequences. fT3 also influences the lipolysis in the fat cells.
Normally with dropping glucose and insulin, there will be a higher rate of lipolysis leading to the liberation of more fat, shifting energy metabolism from glucose to fat. Yet, also here we have a similar effect as with the LDL receptor. Insulin is the storage agent, as insulin goes down, lipolysis will go up. fT3 however determines the rate of lipolysis when insulin is down. As such, becoming more and more lean, fT3 will go down and so will lipolysis.
“Effects of thyroid hormone on regulation of lipolysis and adenosine 3′,5′-monophosphate metabolism in 3T3-L1 adipocytes.” https://www.ncbi.nlm.nih.gov/pubmed/2410243
To further showcase fT3’s action on energy, the reduction in heat generation when having low fT3 status is in part because fT3 is involved in the UCP1 mediated heat generation. This is the uncoupled metabolism which essentially means wasting energy to generate heat. fT3 amplifies this effect around 4-fold in rats. With a reduction in ft3 there is less heat generated.
“Triiodothyronine amplifies norepinephrine stimulation of uncoupling protein gene transcription by a mechanism not requiring protein synthesis.” https://www.ncbi.nlm.nih.gov/pubmed/3192531/
So another conclusin that we can make..
LMHR’s have lower circulating fatty acids due to lower lipolysis (versus non-lean mass subjects on a low-carb diet)
This already makes it difficult to generate cholesterol but also to generate ketones.
With point 2 and 3 covered we can now look at point 1 (1. Dietary fatty acids ; 2. albumin-bound fatty acids ; 3. ApoB100 lipoprotein uptake containing fatty acids)
So far we have looked at the state of our LMHR. We’ve identified low ApoB100 production and low clearance. So how do we get high LDL numbers out of it?
This comes down to the effect of a pulsatile production without an equal compensation in clearance. With each meal, the stimulation of production is greater than the stimulation in clearance.
On a low-carb diet, the stimulation in insulin is much lower than a high carb diet. Yet enough to load up the liver with fatty acids resulting from the left-over chylomicrons that are circulating from the fatty meal.
Keep in mind now that we are looking at a profile with low fT3 thus already lowered LDL receptors. Insulin, stimulated by the meal, will also clear the LDL receptors. Now as insulin weans off, the LDL receptors increase again in expression but not as much as for a person with higher ft3.
The production however is depending on that time frame in which fatty acid availability was increased post-absorption. Due to the high fat content of the meal, more fat is obtained in the liver for subsequent ApoB100 release into circulation.
This production is greater than the clearance.
Anecdotally we hear from LMHR’s that when they go on a carnivore diet, they see their LDL cholesterol go even higher. This is where you have to understand the role of incretins.
You can go through the following video to understand the effects (skip the first 30 minutes because it is static image):
The carnivore diet for most people will result in a higher intake of protein. This protein contains amino acids which both increase glucagon and insulin secretion. The increase in glucagon will stimulate more GNG. Normally this would lead to elevating glucose levels but that doesn’t happen because insulin increases as well to maintain homeostasis and storage.
When you watched the above video you’ll understand why that is. The effect won’t be as strong as when you combine carbohydrates with the meal but the level of protein intake does make a difference.
So a carnivore diet will result in a higher insulin stimulation. This results in more fat storage from the diet in the liver. As a consequence, post-absorption and with insulin going down, we’ll have more fat stored in the liver to generate and release more ApoB100 lipoprotein.
So the pulsation on a carnivore diet is stronger the more you take in protein with fat. There will be a maximum point because you can’t keep the fat intake high while continuing to increase protein intake and it’s the fat availability that will lead to higher LDL cholesterol.
Other clearance factors
If there were no other clearance factors then we would be facing an ever increasing level of LDL.
I won’t go into detail here as I mainly wanted to focus on the liver side but note that the skeletal muscle is also a great clearing site of LDL lipoprotein.
With that I hope you enjoyed reading this article and gained some more insights into why the LDL cholesterol goes up on a low carb diet for people who are lean.
Let me know what you think about it!
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