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I find Internet Archive: Digital Library of Free Books, Movies, Music & Wayback Machine website also good when searching for certain books.How do you find these things?
That’s unusual, there are studies that estimate 85% of the population has some combination of homozygous/heterozygous of either or both of the C677T mutation or A1298C mutation of MTHFR.i had DNA analysis I don't have any mutations (including MTFR)
The decarboxylated carbon skeleton of leucine is reminiscent of isoprene—the cholesterol building block monomer—and studies using ¹⁴C‐leucine have shown it to be incorporated directly into the steroid ring. The body can apparently bypass many steps of cholesterol biosynthesis by using spare leucine directly.
This is exactly how I perceived it after thinking about how leucine could do anything. I had taken a look at leucine − CO₂ and saw it as a 'saturated isoprene,' which could perhaps be used for cholesterol and heme synthesis. This has actually been shown to be true, and we do have a leucine sensor. Leucine first appears to be decarboxylated to isopenylamine, then hyrolyzed to isoamyl alcohol. If this is then phosphorylated, you have isopentenyl pyrophosphate—circumventing the entire mevalonate pathway. This must occur, to a degree, since ¹⁴C‐leucine has been shown incorporated into cholesterol (see Pellagra thread).That's interesting because in digging further why whole eggs stimulated protein synthesis to a greater degree then egg whites I found this
"We are seeing greater movement of mTORC1 to the cell periphery (the hub for dietary amino acids into the muscle) in the whole egg condition vs. egg white condition (preliminary/unpublished results). "
[Digging...]
“In his own laboratory, Roberto recently discovered that mTORC1 senses cholesterol through a pathway that also controls its translocation to lysosomes (77), extending the range of nutrients these organelles sense beyond the amino acids and glucose we have focused on.”
Sabatini, D. M. (2017). Twenty-five years of mTOR: Uncovering the link from nutrients to growth. Proc Natl Acad Sci U S A, 114(45), 11818-11825. doi:10.1073/pnas.1716173114
["77"]
Castellano, B. M., Thelen, A. M., Moldavski, O., Feltes, M., van der Welle, R. E., Mydock-McGrane, L., . . . Zoncu, R. (2017). Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. Science, 355(6331), 1306-1311. doi:10.1126/science.aag1417
'The role of leucine as a precursor of body cholesterol in the rat was first demonstrated by Bloch in 1944 (4). More recently, incorporation of leucine-³H into serum cholesterol in both rats and humans has been reported (26, 27). Miettinen and Penttila (26, 27) have suggested that muscle may be the major extrahepatic site where leucine is converted into cholesterol prior to release into the circulation. However, the data reported here (Table 5) indicate that the adipose organ may be just as active a site of sterol synthesis as muscle. Obesity in humans is associated with an increased rate of cholesterol production (29) which can be decreased by weight reduction (25). Since the proportion of body weight represented by fat tissue in obesity may greatly exceed the normal 15% (21, 28), the adipose organ must be viewed as a potential source of this cholesterol. The role of leucine as a precursor must now be considered in light of the preliminary data in Table 9, which suggest that human adipose tissue can utilize leucine for sterol synthesis and the fact that plasma leucine and insulin levels are elevated in obese man (11). Whether leucine conversion to sterols contributes significantly to the increased cholesterol production rate observed in obese man awaits further experimentation.' ―Rosenthal
I am quite a subject lol, i don't have some pretty common things, like for example I'm Rh negative.That’s unusual, there are studies that estimate 85% of the population has some combination of homozygous/heterozygous of either or both of the C677T mutation or A1298C mutation of MTHFR.
The drop you saw in homocysteine could be a result of more creatine and choline in your diet. Do you think that is the case?
About 40-45% of methylation is used to make creatine, and another 40-45% is used to make phosphatidylcholine. So if either creatine or choline is low in your diet then you have to make it which requires methylation which generates homocysteine.
Yes that one has the least effect of them all.I have heterozygous A1298C mutation.
The drop you saw in homocysteine could be a result of more creatine and choline in your diet. Do you think that is the case?
From my notes:The Pearson correlation coefficient of cobalamin vs homocysteine in vegans was measured to be only −.42 (Krajčovičová-Kudláčková, 2000).
Do you have any of these?In my case twice increase in B12 serum concentration correlated with twice decrease in Homocysteine.
B6 was not measured with any of my blood work, but i suspect that the levels should have been normal or high, considering that even kale is a better source or B6 than egg yolk.Pyroxidal (B₆) is measured because it is the cofactor for the enzymes which convert homocysteine into the much safer cysteine. The vegans consumed more niacin (B₃) which removes methyl groups. These methylation trends appear somewhat predictable, so keeping the homocysteine/methionine ratio to a minimum is mostly a matter of consuming the proper vitamins: cobalamin (B₁₂), pyroxidal (B₆), and folate (B₉)—the ones with subscripts divisible by three. Also thought to play a role are methyl donors (i.e. betaine; choline; creatine; methylene blue).
Yep:
Yes but it’s not necessarily mostly B12, B6, and folate (in your case it probably was) because you can also completely bypass the folate/b12 homocysteine recycling path and use only the BHMT path which is mostly about choline which converts to betaine. You can also probably significantly drop homocysteine without either the b vitamin path or BHMT paths by adding lots of creatine to your diet.For me the point is (yes no paradox):
there is a nonlinear relationship between methionine and homocysteine:
you may have high homocysteine consuming very little methionine
and
you may have low homocysteine consuming a lot of methionine
and
that depends on several thing
mostly on B12,B6 and Folate.
This is true. We did look into this on another thread. I think it had been estimated that over 50% of endogenous SAM‐derived methyl groups go to biosynthesize creatine. Some people see creatine more as a molecule which 'spares' methyl groups than a molecule which 'donates' them.Yes but it’s not necessarily mostly B12, B6, and folate (in your case it probably was) because you can also completely bypass the folate/b12 homocysteine recycling path and use only the BHMT path which is mostly about choline which converts to betaine. You can also probably significantly drop homocysteine without either the b vitamin path or BHMT paths by adding lots of creatine to your diet.
Another interesting find.Reminded me of this
J Physiol. 2017 Dec 19. doi: 10.1113/JP275075. [Epub ahead of print]
Restoration of metabolic health by decreased consumption of branched-chain amino acids.
Cummings NE1,2,3, Williams EM1,2, Kasza I4, Konon EN1,2, Schaid MD1,2,5, Schmidt BA1,2, Poudel C1,2, Sherman DS1,2, Yu D1,2,6, Arriola Apelo SI1,2,7, Cottrell SE1,2,8, Geiger G1,2, Barnes ME1,2, Wisinski JA1,2, Fenske RJ1,2,5, Matkowskyj KA2,9,10, Kimple ME1,2,3,5,11, Alexander CM4, Merrins MJ1,2,12, Lamming DW1,2,3,5,6,9.
KEY POINTS:
We recently found that feeding healthy mice a diet with reduced levels of branched-chain amino acids (BCAAs), which are associated with insulin resistance in both humans and rodents, modestly improves glucose tolerance and slows fat mass gain. In the present study, we show that a reduced BCAA diet promotes rapid fat mass loss without calorie restriction in obese mice. Selective reduction of dietary BCAAs also restores glucose tolerance and insulin sensitivity to obese mice, even as they continue to consume a high-fat, high-sugar diet. A low BCAA diet transiently induces FGF21 (fibroblast growth factor 21) and increases energy expenditure. We suggest that dietary protein quality (i.e. the precise macronutrient composition of dietary protein) may impact the effectiveness of weight loss diets.
ABSTRACT:
Obesity and diabetes are increasing problems around the world, and although even moderate weight loss can improve metabolic health, reduced calorie diets are notoriously difficult to sustain. Branched-chain amino acids (BCAAs; leucine, isoleucine and valine) are elevated in the blood of obese, insulin-resistant humans and rodents. We recently demonstrated that specifically reducing dietary levels of BCAAs has beneficial effects on the metabolic health of young, growing mice, improving glucose tolerance and modestly slowing fat mass gain. In the present study, we examine the hypothesis that reducing dietary BCAAs will promote weight loss, reduce adiposity, and improve blood glucose control in diet-induced obese mice with pre-existing metabolic syndrome. We find that specifically reducing dietary BCAAs rapidly reverses diet-induced obesity and improves glucoregulatory control in diet-induced obese mice. Most dramatically, mice eating an otherwise unhealthy high-calorie, high-sugar Western diet with reduced levels of BCAAs lost weight and fat mass rapidly until regaining a normal weight. Importantly, this normalization of weight was mediated not by caloric restriction or increased activity, but by increased energy expenditure, and was accompanied by a transient induction of the energy balance regulating hormone FGF21 (fibroblast growth factor 21). Consumption of a Western diet reduced in BCAAs was also accompanied by a dramatic improvement in glucose tolerance and insulin resistance. Our results link dietary BCAAs with the regulation of metabolic health and energy balance in obese animals, and suggest that specifically reducing dietary BCAAs may represent a highly translatable option for the treatment of obesity and insulin resistance.
Yes yes yes, more on this please! would be very informative and interestingExcess methionine greatly shortens the lifespans of rats by ~44% and causes weight gain, ostensibly through forming polyamines (I don't think homocysteine can explain the weight gain). Arginine is the nitric oxide precursor, and excess threonine can become methylgloxal (which can adduct with arginine.)
There's been at least three old studies on this. One of them, and I think it was Richie's, had a lifespan reduction of 44% with just a small increase in methionine. I believe this was replicated shortly afterwords by Orentriech, and then again shortly later by someone else. The reductions in lifespan noted in the follow‐up studies were less dramatic, yet still shocking (20–35%). These rats had also gained weight; in fact, you could no longer see their little legs: All you could see were a few claws projecting out of these soft and nearly spherical balls of hair formerly known as the 'test rats.' (lol, kidding!)Yes yes yes, more on this please! would be very informative and interesting
Do you mean as a substrate? Although I know MET is factor in polyamine synthesis (SAM decarboxylase + other), I've never heard anyone say it was that close to ODC. But we don't read all the same articles and I never got deep into polyamines.Although polyamines can be made from lysine and arginine, the enzyme ornithine decarboxylse has the greatest affinity for methionine; so much so in fact, that polyamine synthesis from lysine and arginine are considered minor pathways. Lysine, for instance, has been shown in vitro to have a much lower affinity for ornithine decarboxylase.
Reminded me of this
J Physiol. 2017 Dec 19. doi: 10.1113/JP275075. [Epub ahead of print]
Restoration of metabolic health by decreased consumption of branched-chain amino acids.
Cummings NE1,2,3, Williams EM1,2, Kasza I4, Konon EN1,2, Schaid MD1,2,5, Schmidt BA1,2, Poudel C1,2, Sherman DS1,2, Yu D1,2,6, Arriola Apelo SI1,2,7, Cottrell SE1,2,8, Geiger G1,2, Barnes ME1,2, Wisinski JA1,2, Fenske RJ1,2,5, Matkowskyj KA2,9,10, Kimple ME1,2,3,5,11, Alexander CM4, Merrins MJ1,2,12, Lamming DW1,2,3,5,6,9.
KEY POINTS:
We recently found that feeding healthy mice a diet with reduced levels of branched-chain amino acids (BCAAs), which are associated with insulin resistance in both humans and rodents, modestly improves glucose tolerance and slows fat mass gain. In the present study, we show that a reduced BCAA diet promotes rapid fat mass loss without calorie restriction in obese mice. Selective reduction of dietary BCAAs also restores glucose tolerance and insulin sensitivity to obese mice, even as they continue to consume a high-fat, high-sugar diet. A low BCAA diet transiently induces FGF21 (fibroblast growth factor 21) and increases energy expenditure. We suggest that dietary protein quality (i.e. the precise macronutrient composition of dietary protein) may impact the effectiveness of weight loss diets.
ABSTRACT:
Obesity and diabetes are increasing problems around the world, and although even moderate weight loss can improve metabolic health, reduced calorie diets are notoriously difficult to sustain. Branched-chain amino acids (BCAAs; leucine, isoleucine and valine) are elevated in the blood of obese, insulin-resistant humans and rodents. We recently demonstrated that specifically reducing dietary levels of BCAAs has beneficial effects on the metabolic health of young, growing mice, improving glucose tolerance and modestly slowing fat mass gain. In the present study, we examine the hypothesis that reducing dietary BCAAs will promote weight loss, reduce adiposity, and improve blood glucose control in diet-induced obese mice with pre-existing metabolic syndrome. We find that specifically reducing dietary BCAAs rapidly reverses diet-induced obesity and improves glucoregulatory control in diet-induced obese mice. Most dramatically, mice eating an otherwise unhealthy high-calorie, high-sugar Western diet with reduced levels of BCAAs lost weight and fat mass rapidly until regaining a normal weight. Importantly, this normalization of weight was mediated not by caloric restriction or increased activity, but by increased energy expenditure, and was accompanied by a transient induction of the energy balance regulating hormone FGF21 (fibroblast growth factor 21). Consumption of a Western diet reduced in BCAAs was also accompanied by a dramatic improvement in glucose tolerance and insulin resistance. Our results link dietary BCAAs with the regulation of metabolic health and energy balance in obese animals, and suggest that specifically reducing dietary BCAAs may represent a highly translatable option for the treatment of obesity and insulin resistance.
You got me. I was thinking about ornithine being a better substrate than lysine, not methionine:(sorry if I didn't reply to older posts, it's in the past now)
Do you mean as a substrate? Although I know MET is factor in polyamine synthesis (SAM decarboxylase + other), I've never heard anyone say it was that close to ODC. But we don't read all the same articles and I never got deep into polyamines.
The methionine restriction also jumped out at me about lowering fat mass, but I had no idea about which mechanism is biggest contributor to this.
This is great, Dec 2017, thank you. Alternative hypothesis for issues caused by leucine (& others): mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis