Hi Robb, thank you for taking the time to add your commentary for the Lipid Energy Model.
I'd like to recap from our LEM paper the general outline we propose:
1) Reduction in dietary carbohydrates and depletion of hepatic glycogen stores results in a greater demand for fat as a metabolic fuel, to compensate for reduced glucose availability.
2) Decreased insulin, leptin, and other changes to the hormonal milieu, result in increased hormone-sensitive lipase (HSL)-mediated lipolysis in adipocytes and greater secretion of non-esterified fatty acids (NEFAs) into the bloodstream.
3) In addition to heightened use by tissues in the periphery, there is a greater rate of uptake of NEFAs by the liver. Under these conditions, there is a greater rate of synthesis of TGs from the increased fatty acid pool within hepatocytes.
4) Increased rates of TG synthesis in the liver leads to increased rates of hepatic assembly and secretion of TG-rich VLDL.
5) The increased VLDL secretion rates, in concert with greater LPL-mediated turnover of VLDL in peripheral tissues, and greater transfer of VLDL surface components (including free cholesterol) to HDL, result in higher plasma levels of LDL-C and HDL-C.
- While there are summations, they strongly outline the key components of the Lipid Energy Model and the case for the "lipid triad" of high LDL cholesterol, high HDL cholesterol, and low triglycerides.
From the VA: "But simply stated, this model centers on the high turnover of triglyceride rich lipoproteins, particularly VLDL. This high VLDL turnover results in three major outcomes – more remodeling of VLDL to LDL as it donates lipids, more fat fuel taken up by peripheral tissues, and more surface remnants of VLDL, including cholesterol, taken up by acceptor HDL particles."
- Again, I'm a fan of your work and appreciate your interest in the LEM. The crucial core of this model is VLDL-TG secretion and its rapid turnover resulting increased LDL-C/ApoB – not delivery of fatty acids directly from LDL particles. This is a key starting point for unpacking the model and its implications on whole body fatty acid turnover.
Sorry for replication of the comment, maybe this way it reaches Dave as well..
Hi, maybe reintroducing insulin in the context of ketodiet, increases the liver ldl uptake. Insulin seems to attrack more reseptors, analoguous to glut4 with glucose. This would nicely explain what Dave exprerienced, but both of you have yet to consider this. The genetics could be combined to receptor numbers in general...
"Insulin and triiodothyronine (T3) increase the binding of LDL to liver cells, whereas glucocorticoids (e.g., dexamethasone) have the opposite effect. The precise mechanism for these effects is unclear but may be mediated through the regulation of apoB degradation. The effects of insulin and T3 on hepatic LDL binding may explain the hypercholesterolemia and increased risk of atherosclerosis that have been shown to be associated with uncontrolled diabetes or hypothyroidism"
I think the flaw in your analysis here is a significant one. Attempting to measure energy flux by counting (or weighing) LDL is like measuring how much food is sold in a supermarket by looking at the empty shopping bags.
Chylomicrons and VLDL are of course the main energy conveyers (along with albumin) and one would have to look at those to determine how much energy is being conveyed along with the lipoproteins.
So in order to do a valid accounting for energy flow, you would have to measure the fat that's being conveyed in VLDL, and as far as I know that's not possible to do.
The most interesting thing for me about the LEM and lean mass hyper-responders to a ketogenic diet is that it was first described in 1977 in a paper looking at sled dogs on keto diets. They even used the term hyperrespondive, and noted a clear genetic component.
Four dogs developed serum cholesterol levels that were 4 to 17 SD higher than the means for the other members in each group (Fig. 3).”
"Three of the four hyperresponsive dogs were closely related, as described in the caption to Figure 3 . The fourth of these dogs has two hyperresponsive daughters..."
So LMHR is a compensatory reaction to a high fat diet that exists in two divergent species, suggesting it's highly conserved, or the product of convergent evolution.
Kronfeld, D. S., Hammel, E. P., Ramberg, C. F., & Dunlap, H. L. (1977). Hematological and Metabolic Responses to Training in Racing Sled Dogs Fed Diets Containing Medium, Low, or Zero Carbohydrate. The American Journal of Clinical Nutrition, 30(3), 419–430. https://doi.org/10.1093/ajcn/30.3.419
Over a day when I'm eating and for a period thereafter, I'll have a net increased adipocyte TG deposition, outside of this anabolic state, I round over to the catabolic where there's the net release of NEFA. There's just no easy way to feel confident I know what that flux delta is in this newer keto, fat adapted context. Believe me, I've thought a lot about this because if I could prove it inexpensively, I'd have done that by now at least in an N=1.
We'll ultimately have tracer studies that should help us move the needle more, but they are definitely very expensive.
After doing keto, carnivore, slow carb etc for about 8 years, my doctor was concerned about my high cholesterol. I also keep up with Ivor Cummins' research (and diet suggestions "meat and veg"). I wasn't surprised but the doctor was very concerned (which made me anxious). However... he ordered a CAC scan for me (instead of writing statin rx), which I was excited to get and at least have a baseline (I'm 45 yo). I was happy to get a zero score. I really appreciate all the research done on LMHR Thanks!
Hi, maybe reintroducing insulin in the context of ketodiet, increases the liver ldl uptake. Insulin seems to attrack more reseptors, analoguous to glut4 with glucose. This would nicely explain what Dave exprerienced, but both of you have yet to consider this. The genetics could be combined to reseptor numbers in general...
"Insulin and triiodothyronine (T3) increase the binding of LDL to liver cells, whereas glucocorticoids (e.g., dexamethasone) have the opposite effect. The precise mechanism for these effects is unclear but may be mediated through the regulation of apoB degradation. The effects of insulin and T3 on hepatic LDL binding may explain the hypercholesterolemia and increased risk of atherosclerosis that have been shown to be associated with uncontrolled diabetes or hypothyroidism"
Out of interest, how did they increase monounsaturated fats and decrease saturated fats? Did they use more olive oil, nuts, seeds, avocados in place of animal foods? That could introduce confounders.
Plant fats can contain substantial quantities of ergosterols which lower blood cholesterol. Ask Zoë Harcombe about how. I’m vague about the details. But in my head, the ergosterols are substituting for cholesterol but not being measured as cholesterol. I could be way off.
Also, many plant fats also contain salicylates and polyphenols, which may, for some people, have anti-inflammatory effects through cyclooxygenase inhibition. So potentially you could have lipid-lowering effects from reduced inflammation.
But even so, it’s a tightrope act because salicylates can deplete your coenzyme A, carnitine and glycine. Reduced coenzyme A and carnitine could result in reduced cholesterol and triglyceride synthesis. But would also negatively impact your metabolism.
I think clearing out glycine might affect your nitrogen balance (urea cycle) and also your propensity to form endogenous oxalates from glycine.
The urea cycle needs biotin, zinc, manganese and arginine/citrulline/ornithine. On an animal-based diet, manganese may be limiting. While oxalate-dumping, biotin is limiting. So sparing manganese by possibly reducing glycine might overall improve metabolism.
Additionally, nuts, seeds, and grains (even Oreo cookies) are a source of manganese. So what you might be seeing is improved fat and cholesterol metabolism along with better mitochondrial antioxidant status from superoxide dismutase. Better glycosylation of proteoglycans might even improve LDL synthesis and uptake. The LDL receptor is another glycoprotein.
I’m sure there’s other stuff I’m missing. But you just said you wanted ideas. So here you go.
A lot of similarities here as to when I wrote "to carb or not to carb" covering glycogen conversion, expenditure, and 5,000 calorie training days. To throw another money wrench into this equation, let's look at prevalence of rhabo among LMHRs (with and without Oreo interventions)!
Hi Robb, thank you for taking the time to add your commentary for the Lipid Energy Model.
I'd like to recap from our LEM paper the general outline we propose:
1) Reduction in dietary carbohydrates and depletion of hepatic glycogen stores results in a greater demand for fat as a metabolic fuel, to compensate for reduced glucose availability.
2) Decreased insulin, leptin, and other changes to the hormonal milieu, result in increased hormone-sensitive lipase (HSL)-mediated lipolysis in adipocytes and greater secretion of non-esterified fatty acids (NEFAs) into the bloodstream.
3) In addition to heightened use by tissues in the periphery, there is a greater rate of uptake of NEFAs by the liver. Under these conditions, there is a greater rate of synthesis of TGs from the increased fatty acid pool within hepatocytes.
4) Increased rates of TG synthesis in the liver leads to increased rates of hepatic assembly and secretion of TG-rich VLDL.
5) The increased VLDL secretion rates, in concert with greater LPL-mediated turnover of VLDL in peripheral tissues, and greater transfer of VLDL surface components (including free cholesterol) to HDL, result in higher plasma levels of LDL-C and HDL-C.
- While there are summations, they strongly outline the key components of the Lipid Energy Model and the case for the "lipid triad" of high LDL cholesterol, high HDL cholesterol, and low triglycerides.
We have a great video abstract on this (just 5 min): https://www.youtube.com/watch?v=AkzxESsTJyM
From the VA: "But simply stated, this model centers on the high turnover of triglyceride rich lipoproteins, particularly VLDL. This high VLDL turnover results in three major outcomes – more remodeling of VLDL to LDL as it donates lipids, more fat fuel taken up by peripheral tissues, and more surface remnants of VLDL, including cholesterol, taken up by acceptor HDL particles."
- Again, I'm a fan of your work and appreciate your interest in the LEM. The crucial core of this model is VLDL-TG secretion and its rapid turnover resulting increased LDL-C/ApoB – not delivery of fatty acids directly from LDL particles. This is a key starting point for unpacking the model and its implications on whole body fatty acid turnover.
Sorry for replication of the comment, maybe this way it reaches Dave as well..
Hi, maybe reintroducing insulin in the context of ketodiet, increases the liver ldl uptake. Insulin seems to attrack more reseptors, analoguous to glut4 with glucose. This would nicely explain what Dave exprerienced, but both of you have yet to consider this. The genetics could be combined to receptor numbers in general...
"Insulin and triiodothyronine (T3) increase the binding of LDL to liver cells, whereas glucocorticoids (e.g., dexamethasone) have the opposite effect. The precise mechanism for these effects is unclear but may be mediated through the regulation of apoB degradation. The effects of insulin and T3 on hepatic LDL binding may explain the hypercholesterolemia and increased risk of atherosclerosis that have been shown to be associated with uncontrolled diabetes or hypothyroidism"
https://themedicalbiochemistrypage.org/lipoproteins-blood-lipids-and-lipoprotein-metabolism/#:~:text=Insulin%20and%C2%A0triiodothyronine,uncontrolled%20diabetes%20or%20hypothyroidism
In the sane old world, high cholesterol suggested problems with thyroid. Now it suggests statin deficiency.
I think the flaw in your analysis here is a significant one. Attempting to measure energy flux by counting (or weighing) LDL is like measuring how much food is sold in a supermarket by looking at the empty shopping bags.
Chylomicrons and VLDL are of course the main energy conveyers (along with albumin) and one would have to look at those to determine how much energy is being conveyed along with the lipoproteins.
So in order to do a valid accounting for energy flow, you would have to measure the fat that's being conveyed in VLDL, and as far as I know that's not possible to do.
The most interesting thing for me about the LEM and lean mass hyper-responders to a ketogenic diet is that it was first described in 1977 in a paper looking at sled dogs on keto diets. They even used the term hyperrespondive, and noted a clear genetic component.
Four dogs developed serum cholesterol levels that were 4 to 17 SD higher than the means for the other members in each group (Fig. 3).”
"Three of the four hyperresponsive dogs were closely related, as described in the caption to Figure 3 . The fourth of these dogs has two hyperresponsive daughters..."
So LMHR is a compensatory reaction to a high fat diet that exists in two divergent species, suggesting it's highly conserved, or the product of convergent evolution.
Kronfeld, D. S., Hammel, E. P., Ramberg, C. F., & Dunlap, H. L. (1977). Hematological and Metabolic Responses to Training in Racing Sled Dogs Fed Diets Containing Medium, Low, or Zero Carbohydrate. The American Journal of Clinical Nutrition, 30(3), 419–430. https://doi.org/10.1093/ajcn/30.3.419
But it's even harder to measure than that.
Over a day when I'm eating and for a period thereafter, I'll have a net increased adipocyte TG deposition, outside of this anabolic state, I round over to the catabolic where there's the net release of NEFA. There's just no easy way to feel confident I know what that flux delta is in this newer keto, fat adapted context. Believe me, I've thought a lot about this because if I could prove it inexpensively, I'd have done that by now at least in an N=1.
We'll ultimately have tracer studies that should help us move the needle more, but they are definitely very expensive.
After doing keto, carnivore, slow carb etc for about 8 years, my doctor was concerned about my high cholesterol. I also keep up with Ivor Cummins' research (and diet suggestions "meat and veg"). I wasn't surprised but the doctor was very concerned (which made me anxious). However... he ordered a CAC scan for me (instead of writing statin rx), which I was excited to get and at least have a baseline (I'm 45 yo). I was happy to get a zero score. I really appreciate all the research done on LMHR Thanks!
Hi, maybe reintroducing insulin in the context of ketodiet, increases the liver ldl uptake. Insulin seems to attrack more reseptors, analoguous to glut4 with glucose. This would nicely explain what Dave exprerienced, but both of you have yet to consider this. The genetics could be combined to reseptor numbers in general...
"Insulin and triiodothyronine (T3) increase the binding of LDL to liver cells, whereas glucocorticoids (e.g., dexamethasone) have the opposite effect. The precise mechanism for these effects is unclear but may be mediated through the regulation of apoB degradation. The effects of insulin and T3 on hepatic LDL binding may explain the hypercholesterolemia and increased risk of atherosclerosis that have been shown to be associated with uncontrolled diabetes or hypothyroidism"
https://themedicalbiochemistrypage.org/lipoproteins-blood-lipids-and-lipoprotein-metabolism/#:~:text=Insulin%20and%C2%A0triiodothyronine,uncontrolled%20diabetes%20or%20hypothyroidism
In the sane old world, high cholesterol suggested problems with thyroid. Now it suggests statin deficiency.
JR
Very interesting. You’re probably right.
Out of interest, how did they increase monounsaturated fats and decrease saturated fats? Did they use more olive oil, nuts, seeds, avocados in place of animal foods? That could introduce confounders.
Plant fats can contain substantial quantities of ergosterols which lower blood cholesterol. Ask Zoë Harcombe about how. I’m vague about the details. But in my head, the ergosterols are substituting for cholesterol but not being measured as cholesterol. I could be way off.
Also, many plant fats also contain salicylates and polyphenols, which may, for some people, have anti-inflammatory effects through cyclooxygenase inhibition. So potentially you could have lipid-lowering effects from reduced inflammation.
But even so, it’s a tightrope act because salicylates can deplete your coenzyme A, carnitine and glycine. Reduced coenzyme A and carnitine could result in reduced cholesterol and triglyceride synthesis. But would also negatively impact your metabolism.
I think clearing out glycine might affect your nitrogen balance (urea cycle) and also your propensity to form endogenous oxalates from glycine.
The urea cycle needs biotin, zinc, manganese and arginine/citrulline/ornithine. On an animal-based diet, manganese may be limiting. While oxalate-dumping, biotin is limiting. So sparing manganese by possibly reducing glycine might overall improve metabolism.
Additionally, nuts, seeds, and grains (even Oreo cookies) are a source of manganese. So what you might be seeing is improved fat and cholesterol metabolism along with better mitochondrial antioxidant status from superoxide dismutase. Better glycosylation of proteoglycans might even improve LDL synthesis and uptake. The LDL receptor is another glycoprotein.
I’m sure there’s other stuff I’m missing. But you just said you wanted ideas. So here you go.
A lot of similarities here as to when I wrote "to carb or not to carb" covering glycogen conversion, expenditure, and 5,000 calorie training days. To throw another money wrench into this equation, let's look at prevalence of rhabo among LMHRs (with and without Oreo interventions)!