I wanted to know the relationship between and what drives production of cholesterol versus ketones. The simple reason being that 3-hydroxy-3-methylglutaryl Coa or HMG-Coa (HMG) is either reduced by HMG-Coa reductase (HMGr) into the pathway towards cholesterol or HMG-Coa lyase (HMGl) sets it on the pathway towards Acetoacetate. So 2 enzymes work on the same substance.
How are these enzymes regulated? Does one go up when the other goes down? Are both regulated linearly by the same or different triggers?
Ketones are crucial for longer term survival, for example under starvation to avoid muscle breakdown by serving as an alternative to glucose. Without ketones, your skeletal muscle would waste away much quicker being a substrate for gluconeogenesis.
So shouldn’t HMG be diverted towards ketones much more to support ketone production, at the expense of cholesterol production? And if this goes at the expense of cholesterol production, what would be the effect on our sex hormones for which cholesterol is a precursor? It seems that the HMGl must dominate. But is this domination at the expense of reductase, and does it therefor lower cholesterol production or is there simply ample HMG availability to accommodate both?
The feed into HMG can come from Acetyl-Coa which is build up in the mitochondria due to a slower running citric acid cycle thanks to low oxaloacetate which is due to the lower glucose availability due to lower glycogen levels in the liver as we understand it. The Acetyl-Coa comes from the fatty acids that reach the liver and enter the mitochondria where the acyls are cut up to form Acetyl-Coa.
Then there is the LMHR phenotype. Low carb, low body fat and high LDL cholesterol. Likely too low in body fat to have a sufficient continuous supply of fat leading to low ketone levels. It is only n=1 but I noticed for myself, also being LMHR, I had to drastically up my fat intake in order to generate sufficient ketones and see a suppression of glucose caused by the ketones.
Maybe there is a threshold of HMG availability required for ketone production. Perhaps until a certain level, most of HMG goes towards cholesterol and when this level is reached, there is a spill-over towards ketones? But it seems to conflict with my original idea of ketones being so important. They are, but thinking further, if ketones are not high enough the body will try and release more fat and also starts to break down skeletal muscle (low ketone -> low protection against catabolism) through catecholamines. So there must be a priority mechanism towards ketones. We need to hang on to our skeletal muscle as long as possible to increase our chances for survival.
But this is all guess work. What can I find in the studies?
HMG reductase (cholesterol production)
We do find that reductase is inhibited by the re-absorption of LDL. It seems to say stop producing cholesterol when more is returning from the circulation.
According to this study, insulin has an increasing effect on both mRNA and protein production. Glucagon and fasting causes a drop in HMGr activity affecting both protein levels and mRNA. This effectively means that going low carb slows down cholesterol production. This reduction in HMGr is new to me but a confirmation of the reduced ApoB production I wrote about: https://www.reddit.com/r/ketoscience/wiki/ldl
“Insulin and glucagon modulate hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity by affecting immunoreactive protein levels.” – https://www.ncbi.nlm.nih.gov/pubmed/7961882
A further support for why cholesterol could be lower under high carb is that the LDL receptor in the liver seems to correlate with HMGr. Thus, the higher the cholesterol production (faster output), the higher the level of LDL receptors to (faster) reabsorb cholesterol. And keep in mind, cholesterol absorption via the LDL receptors will lower reductase activity thus creating an overall trend to lower circulating LDL-c levels. This mechanism could contribute to the reason why dietary cholesterol does not affect plasma cholesterol. There simply is a negative feedback loop when insulin is up.
“Low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression in human mononuclear leukocytes is regulated coordinately and parallels gene expression in human liver.” https://www.jci.org/articles/view/117213
Insulin is not the only stimulator of HMGr. Thyroid hormone and estrogen both have a similar stimulating effect.
“Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity.” https://www.ncbi.nlm.nih.gov/pubmed/10782041
Update 2021-03-02: Added the section below about AMPK
Further studies show us that when AMPK is activated, it causes a signaling cascade whereby HMGr is inhibited by ACC deactivation thus effectively blocking cholesterol synthesis.
“AMPK and cell proliferation – AMPK as a therapeutic target for atherosclerosis and cancer – Regulation of cholesterol synthesis pathway by AMPK” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1817805/#__sec6title
“Liver AMP-activated protein kinase and acetyl-CoA carboxylase during and after exercise” https://journals.physiology.org/doi/full/10.1152/jappl.19126.96.36.1999
AMPK is an important signal as it is also responsible for stimulating ketogenesis in the liver. And this article is about individuals on a ketogenic diet so we see here that AMPK itself stimulates ketogenesis and inhibits cholesterol production.
HMG lyase (ketone production)
There is surprisingly little to find on lyase except for a deficiency leading to hypoketotic issues. I could not find info on increase or decrease in expression of protein or mRNA. At best guess it is the reverse of HMGr, meaning HMGl would be down regulated under insulin and/or upregulated under glucagon. One thing I did find is that glucagon also increases HMG synthase thus increasing HMG supply and, as you could read above, in our low carb state this means that cholesterol production is down so we increase HMG availability for ketones not only by lowering reductase activity but also by increasing HMG availability itself through inhibition of the succinylation.
“Glucagon activates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in vivo by decreasing the extent of succinylation of the enzyme.” https://www.ncbi.nlm.nih.gov/pubmed/1967579
“Treatment of rats with glucagon or mannoheptulose increases mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase activity and decreases succinyl-CoA content in liver” https://portlandpress.com/biochemj/article-abstract/262/1/159/26061/Treatment-of-rats-with-glucagon-or-mannoheptulose?redirectedFrom=fulltext
What does this tell us about LMHR profiles?
Putting all the sourced material together, including from the wiki, in a situation where insulin is reduced to its minimum due to a low carb diet, it seems that the way to get very high LDL-cholesterol exists out of the following components. The more you tick, the higher you go and the increase is not due to an increase in production, rather due to a reduction in clearance. See the section on carnivore further down to understand the increase plasma levels:
- Very low insulin
- High to very high glucagon
- Low free T3 (usually associated with high reverse T3)
- Low fat mass
- Very low estrogen
Insulin you can measure via blood test. Typical very low values would be 1 or 2 mIU/L.
Glucagon is not standard but you can ask for it. It is not straightforward to suggest a proxy. I’d go by being lean and have high ketone production but this can be confounded by having a high fat intake. Yet being very lean we usually end up having low ketones despite a possible naturally high glucagon level. Consider a blood test to be sure.
Thyroid hormone, free T3, can also be measured but doctors don’t always want to do this. Alternatively you can go by symptoms such as cold hand and feed, dry skin, irregular or missing menstruation. T3 is partially responsible for lipolysis. A reduction will lead to lower basal lipid availability, hence the lower ketones.
“Action of Thyroid Hormones, T3 and T2, on Hepatic Fatty Acids: Differences in Metabolic Effects and Molecular Mechanisms.” https://www.ncbi.nlm.nih.gov/pubmed/28362337
Everybody has a fat mass, even lean people so when are you up for elevated cholesterol? There is no clear cut-off point but my guess is that for males it starts to be noticeable as of 15% body fat and for females probably around 20%.
Estrogen can also be measured in a blood test. I have no experience with this but if you are on the low side or lower than the reference values it will certainly be an additional checkbox.
! IMPORTANT !
If you fit the LMHR profile and don’t get high ketone levels then consider the following.
You have low body fat to begin with. Reaching high ketones requires sufficient fat availability for the liver. If you don’t get ketones in the range of >1, preferably >1.5mmol then you may not have sufficient protective effect against skeletal muscle breakdown. I’m basing this range on the glucose suppressive effect. Only when ketones are high enough to suppress glucose output from the liver, will it provide protection against muscle atrophy.
You should not be in a situation where you loose muscle mass or you are literally in starvation mode in my honest opinion.
If you decide to change something about this, consider a higher protein intake or higher fat intake. Higher fat will lead to higher ketones, helping to replace the need for glucose. Higher protein will lead to more glucose availability, also protecting against atrophy but potentially at the cost of ketones. You can also increase both.
There is a possible combination with temporarily giving up exercise but I don’t think that is sensible and desired. I prefer energy intake to match with what the body needs.
Why the increase in cholesterol when moving on to carnivore?
When leaving out plant food by replacing it with meat, more protein is absorbed. There are specific amino acids which stimulate glucagon production. HMGr, thus the pathway to cholesterol, is reduced by glucagon or at least associated with it. There are also insulin-stimulating amino acids.
I have to guess here because we need to look at things on a time scale. The slight increase in insulin, post-prandial, will increase cholesterol production a little bit more than a similar meal where part of the protein is replaced with plant foods.
At the same time, glucagon is stimulated more strongly due to the higher content of glucagon-stimulating amino acids in the meal. Insulin seems to dominate at all other levels so I suspect that it is also the case here so cholesterol production goes up.
There is the problem of the LDL receptor which is upregulated by insulin which could counteract the increased production. I think producing and translocating it to the cell membrane takes more time. It therefor may be insufficient to prevent a rise in cholesterol.
This mechanism of temporarily increasing production is what leads to higher cholesterol levels in general. So it is the combined effect of getting a very low clearance with temporarily increased production.
The more stronger the cholesterol clearance via the LDL receptor is reduced, the stronger the increasing effect of plasma LDL-c will be when you take a meal which temporarily increases production.
And all this is to prioritize our ketone production !
How can you experiment with your LDL-c levels? Reduce glucagon and increase insulin (without insulin resistance). I haven’t tried this out myself but I would go for high starch, fiber and no meat. Starch to increase insulin, no meat to reduce its glucagon stimulating effect, fiber to help capture and clear the cholesterol and avoid re-absorption. Do this for 3 to 4 days and you should have the lowest LDL. Do the opposite and LDL goes up again.
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