@Kvothe, I'm going by trust in the accounts of reliable people.
Posts made by Amazoniac
-
RE: Conditional problems with vitamin A: a place for sane discussions
-
Contextualizing D-lactate
Selected points:
- L-LDH is cytosolic, whereas D-LDH is mitochondrial, but distributed close to the surface
- D-LDH: highest concentrations in liver and kidneys (3× the tissue activity of the liver), and lowest in brain
- D-lactate is oxidized to pyruvate at low concentrations, but (unlike L-lactate) it tends to be excreted intact in urine as its plasma concentration rises
- Normal, low concentration: 0.01 mmol/L
- Recovery starts to saturate at 1 mmol/L and it's almost completely saturated at 5 mmol/L
- The tubules of kidneys are permeable to unionized (or non-charged) molecules (such as lactic acid)
- Acidosis unionizes part of the circulating D-lactate to D-lactic acid, promoting its passive recovery from filtrate when it would otherwise be lost, decreasing the clearance rate
- Baking soda should counteract the effect, serving to ionize it and promote excretion, regulating D-lactate level as drugs
- In contrast, fast intestinal fermentation of carbohydrates can increase the acidity, changing part of D-lactate to D-lactic acid
- D-lactic acid when crossing compartments drags an additional proton along (beyond those incorporated), which contributes to acidemia and a vicious cycle
- D-lactate can be formed endogenously from methylglyoxal (primary source)
- The average consumption of propylene glycol (as food additive) is about 2.5 g/day and half of it may yield D-lactate after metabolism
- If you're on Windows, it's possible to open a symbols panel with 'Win key + period', and there must be something similar in superior OSs
- The clearance rate of D-lactate is 50% of L-lactate in normal subjects
↳ L-lactate: 1.89 L/min to 0.72 L/min
↳ D-lactate: 0.71 L/min to 0.43 L/min (going from plasma 0.115 mmol/L to 5.24 mmol/L) - D-lactate concentrations found in sauerkraut: 80 mmol/l
- D-lactate concentrations found in unstrained yogurts: 29 to 122 mmol/l
- Lactulose given at 160 g/day resulted in fecal concentrations of 43 mmol/L and ⅓ being D-lactate
Their estimate in short bowel syndrome:
Carbohydrates:
-
277 g/day ingested
↳ 17%: 47 g/day excreted
↳ 83%: 230 g/day retained -
230 g/day retained
↳ 40%: 92 g/day absorbed
↳ 60%: 138 g/day fermented to D-lactate
Molecular weight of monosaccharides:
180 g per 1 mol; or 1 g per 1/180 mol
- 138 g/day fermented to D-lactate
↳ 138 g/day × 1/180 mol = 0.77 mol D-lactate
As in the other thread, the yield is two pyruvates or lactates per toasted monosaccharide:
- 0.77 mol × 2 = 1.54 mol or 1540 mmol D-lactate
Around 500 mmol in each of 3 meals a day, with simulated peaks of 6 or 4 mmol/L, depending on faster or slower absorptions. As the amount of carbohydrates increases, it gets worse.
But the effect was subtle when healthy people were stuffed with yogurt. Not all yogurts are rich in D-lactate, yet they picked one that was, proving 40 mmol or 75 mmol D-lactate per meal, from 800-1600 g of unstrained yogurt that they had to ingest.
In these conditions, the plasma peak after the consumption of what corresponds to an entire large container was 0.2 mmol/L.
↱ [40] Postprandial plasma D-lactate concentrations after yogurt ingestion
- ○ 1.1 mmol D-lactate/kg bw* -- as DL-lactate with water
- ⬤ 1.1 mmol D-lactate/kg bw* (7 g/victim) -- from yogurt
- ■ 0.6 mmol D-lactate/kg bw (4 g/victim) -- from yogurt
*Total absorption was similar, only smoothed out in the case of yogurt.
"Since only a minor fraction of intravenously administered D-lactate is excreted intact in the urine,[10]** the bulk of D-lactate elimination from the plasma requires oxidation to pyruvate.** Following the description of D-lactic acidosis, biochemists searched for a D-lactate oxidizing enzyme with the characteristics of L-LDH (ie, cytoplasmic location, reversible reaction with pyruvate, NAD+ cofactor, etc.). When no such enzyme was identified, it was thought that humans lack D-LDH; rather D-lactate catabolism was attributed to a multipurpose mitochondrial enzyme termed D-alpha-carboxy acid dehydrogenase.[11] Recently, however, it was demonstrated that humans have a gene that molecular biologists term D-LDH because of its ability to code for a protein that catalyzes the oxidation of D-lactate to pyruvate in fungi and prokaryotes.[12,13] When humans with inactivating mutations of this gene were observed to have elevated plasma D lactate concentrations, it was concluded that the human wild-type gene coded for a protein with D-lactate oxidizing ability. Thus, it appears that the mitochondrial D-LDH of the molecular biologist is the D-alpha carboxy acid dehydrogenase of the biochemist – the long-standing controversy of whether humans have D-LDH was a semantic problem. It is now generally accepted that humans have a D-LDH that is structurally and functionally an entirely different enzyme than is L-LDH. D-LDH, unlike L-LDH, is located on the inner mitochondrial membrane and catalyzes an irreversible reaction to pyruvate. The activity of this enzyme depends on transporters to deliver D-lactate to the inner surface of the mitochondrial membrane, and defects in these transporters could lead to reduced D-lactate oxidation to pyruvate.[14] D-LDH activity is widely distributed in various tissues with the highest concentrations in the liver and kidney and the lowest concentrations in brain. Since the only means of elimination of D- and L-lactate is via conversion to pyruvate followed by oxidation of pyruvate, the elimination rates of the two optical isomers are dependent upon the relative activities of D-LDH and L-LDH. Older literature reported that elimination of D-lactate was much slower than that of L-lactate. However, multiple recent studies have uniformly demonstrated that the elimination rate of D-lactate in normal subjects is about 50% of that of L-lactate."
"While L-lactate elimination is almost entirely via catabolism, D-lactate is both catabolized and excreted intact in the urine. Lactate is freely filtered by the glomerulus, and since it is more than 99.9% in the anion form (at a pH of 7), tubular reabsorption requires a carrier mediated system. During an intravenous infusion of D-lactate, Oh et al[10] quantitated the renal excretion of D- and L-lactate in normal control subjects as a function of the plasma D-lactate concentration. Tubular reabsorption of D-lactate starts to saturate at a plasma concentration of 1 mM, with near-complete saturation at a concentration of 5 mM. Thus, urinary D-lactate excretion is negligible at low concentration and increases to about 80% of the creatinine clearance at 6 mM.
While urinary excretion has been assumed to play a major role in the elimination of D-lactate at the high plasma concentrations observed in D-lactic acidosis, this clearly was not the case in patients with D-lactic acidosis for whom D-lactate clearance can be estimated.[8,15,16] As shown in Table 1, urinary D-lactate clearance when blood lactate was >6 mM was <7 mL/min, less than 10% of the 80 mL/min predicted for normal subjects. Thus, urinary excretion plays a negligible role in D-lactate elimination in patients with D-lactate acidosis."
"Since renal function was near normal in most of the subjects listed in Table 1, low urinary clearance cannot be attributed to renal failure. Rather, in these acidotic patients, a larger fraction of the tubular lactate will be in the unionized form in the acidic urine, allowing more rapid non-ionic diffusion from the tubules. At the urine pH of 5.0 observed in severe metabolic acidosis,[3] 6% of lactate will be unionized, compared to just 0.06% at pH 7.0. This hypothesis is supported by studies with salicylic acid.
- The cortical collecting duct permeability increased 6.5 fold for salicylic acid when urine pH decreased from 6.0 to 5.0,[4] and
- proximal tubule permeability increased 5.6 fold when pH decreased from 7.0 to 6.0.[5]
Since the pKa of salicylic acid is 3.0, less than that of lactic acid (3.8), the predicted increase in lactic acid permeability should be greater than that of salicylic acid. This non-ionic diffusion would not have been observed in Oh’s study[10] since lactate (not lactic acid) was infused, and the subjects would not have been acidotic."
So, don't inject yourself with D-lactate and let it coincide with acidosis because the tubules of kidneys are permeable to non-charged molecules (lactic acid). The toxin is recovered passively when it would otherwise be lost. Taking baking soda should help to regulate D-lactate level in acidosis as drugs, by promoting its elimination.
"Whole-body D-lactate clearance (catabolism plus renal excretion) has been directly assessed in four studies involving normal control subjects, summarized in Table 2. Two different techniques were used. Kuze et al[17] and Oh et al,[10] constantly infused D-lactate until a steady state was reached, at which point the rate of removal must equal the infusion rate, and clearance is determined from the steady-state concentration. Connor et al[18] constantly infused D-lactate for 20 minutes and then determined clearance using a non-compartment pharmacokinetic analysis of the plasma concentration curve. The clearance of D-lactate in these studies was surprisingly fast, ranging from 0.43 to 0.71 L/min/70 kg. The results in suggest that the clearance decreases as the plasma concentration rises, decreasing from 0.71 L/min at 0.115 to 0.43 L/min at 5.24 mM. For simple Michaelis-Menten kinetics, this would correspond to a Km of about 6 mM [when half of the capacity is reached], similar to that observed in vitro measurements of rat liver metabolism[9]."
"Extensive study of L-lactate clearance in healthy controls has yielded values ranging from 0.72 L/min/70 kg to 1.89 L/min/70 kg. Thus, D-lactate clearance is about 50% of that of L-lactate. Of interest, data from two studies[2,19] in which D-lactate was infused into cattle allowed us to estimate the normal D-lactate clearance of these animals. Our calculated clearances were 40 and 31 mL/min/70 kg, only about 5 −7% of that of humans, which may explain the propensity of cattle to develop D-lactic acidosis."
"Based on in vitro tissue assays, the kidney and liver are the main sites of D-lactate metabolism, with the kidney having about 3 times the activity per gm than does the liver.[20] Fine[21] infused D-lactate into the portal circulation of dogs and directly measured the hepatic extraction from the portal vein – hepatic vein concentration difference. They found a relatively small extraction of about 14%, which, when extrapolated to humans (hepatic blood flow of about 1.5 L/min), corresponds to a clearance of about 210 mL/min, about one-third of the total human D-lactate clearance. Presumably, the other two-thirds of the catabolism is via the kidney."
"Normally, lactate is found in very low concentration (<2 mM) in crap. The well-accepted scenario for over-production of D-lactate in the colon of SBS subjects is that massive delivery of readily fermentable carbohydrate to the colonic bacteria results in rapid organic acid production and a concomitant fall in luminal pH. The acidic pH inhibits acetate and butyrate forming bacteria and selects for lactic acid bacteria,[6] and lactic acid accumulates in the feces. Mayeur et al[28] showed that lactobacilli routinely were the predominant fecal organism in 16 SBS subjects; however, 8 of these subjects had normal (<2 mM) fecal lactate concentrations, ie, the activity of the non-lactate flora was sufficient to maintain normal fecal lactate concentrations. The other 8 subjects were lactate “accumulators”, with fecal concentrations ranging from 20 mM to 165 mM. Of importance, D-lactate comprised greater than 90% of the lactate in two subjects, each of whom had a past history compatible with D-lactic acidosis."
"The quantity of carbohydrate that must be delivered to the colon to induce a predominantly lactic acid producing colonic flora was investigated by Hove and Mortenson[29] who measured the fecal lactate concentrations of a small group of healthy subjects fed varying doses of lactulose, a totally non-absorbable disaccharide. At the maximal dosage of 160 g/day, total fecal lactate concentration rose to 43 mM, of which about one-third was D-lactate."
"The quantity of lactate produced in and absorbed from the colon of SBS patients is not known. What is known is that 16 SBS subjects (without D-lactic acidosis) ingested an average of 277 g/day of carbohydrate and excreted about 17% of this carbohydrate in some form per rectum (measured as the difference between total fecal calories minus fat + protein calories).[28] Thus, an average of 230 g/day of carbohydrate “disappeared” from the intestine via either monosaccharide absorption from the small bowel or organic acid absorption from the colon. Assuming that small bowel absorption of carbohydrate in SBS is similar to the 40% absorption measured for fat and protein, 60% of 230 g/day of carbohydrate or 138 g/day of carbohydrate was absorbed from the colon, presumably almost all in the form of organic acids. If D-lactate were the predominant fecal organic acid (as shown to be likely in Mayeur’s study), the absorption rate of D-lactate theoretically might approach 1550 mmol per day, the value used for the predictions shown in Figure 3."
"Given the mechanism of action of MCT, the absorption rate of lactate should be a function of the hydrogen ion gradient across the epithelial membrane. Such was found to be the case in in vivo studies in the sheep intestine[31] where the absorption rate of D-lactate increased by 6 fold, as the luminal pH was reduced from 6.3 to 4.3, a range of values observed in the feces of SBS subjects. Thus, the very acid luminal pH resulting from the rapid fermentation of malabsorbed sugars in SBS facilitates the absorption of D-lactate at a rate sufficient to produce the syndrome. As will be discussed, the movement of a proton with D-lactate during MCT facilitated transport is the likely cause of the acidosis of the D-lactic acidosis syndrome."
"Methylglyoxal, a highly toxic intermediate in the metabolism of a variety of compounds, may be catabolized to D-lactate.[32] This pathway is thought to be the major, non-gut, endogenous source of D-lactate. Assuming this pathway to be the sole source of blood D-lactate in healthy people, the rate this pathway normally delivers D-lactate to the circulation can be calculated from D-lactate clearance and the plasma D-lactate concentration. Normal plasma lactate concentration has been reported to range from 0.006 mM (high performance liquid chromatography) to 0.25 mM. For illustrative purposes, a clearance of 600 mL/min/70 kg and a steady-state plasma D-lactate concentration of 0.010 mM yields a D-lactate elimination rate = input rate of about 0.006 mmol/min/70 kg, or about 8.6 mmol/day."
"The output of D-lactate from the methylglyoxal pathway can increase in several pathological conditions. An association between diabetic ketoacidosis and plasma D-lactate elevations was initially observed in cats[33] and more recently in humans,[34] who had plasma D-lactate concentrations averaging 3.82 mM (15 and 8 times greater, respectively, than controls and non-ketotic diabetic subjects). The highly significant, positive correlation between the D-lactate concentration and anion gap suggested that D-lactic acidosis was contributing to the diabetic acidosis. The source of the D-lactate in ketoacidosis is thought to be via increased input of ketone bodies into the methylglyoxal pathway."
"Propylene glycol is a widely used solvent that exists as a racemic mixture of the D- and L- enantiomer. The D-fraction is metabolized via the methylglyoxal pathway to D-lactate, and markedly increased plasma D-lactate concentrations have been observed in cats fed large doses of propylene glycol (> 1 g/kg).[35] Similarly, a patient who mistakenly ingested a large quantity of propylene glycol was reported to have D-lactate concentrations as high as 110 mM/l (a seemingly impossible concentration given the anion gap of only 27 mM).[36] The solubilizing/preservative/anti-caking properties of propylene glycol has led to its incorporation into a wide a variety of foods. The average 70 kg US subject ingests about 2.4 g (31 mmol) of propylene glycol per day.[37] About 45% of this propylene glycol is excreted unchanged in urine, and about 50% of the remainder appears to be metabolized to D-lactate. Thus, about 8 mmol per day (25% of the normal ingestion) might be converted to D-lactate. Although probably coincidental, the daily normal intake of propylene glycol could roughly account for the small quantity of D-lactate, about 9 mmol, previously calculated to enter the plasma each day of healthy subjects."
"Propylene glycol is present in very high concentrations (up to 80% by volume) in some intravenous medications including lorazepam, phenobarbital, phenytoin and nitroglycerine. Prolonged infusions of these drugs have been well documented to produce lactic acidosis although the exact roles played by D- and L-lactate have not been well defined.[38]"
"The ingestion of D-lactate containing foods or infusion of D-lactate intravenous fluids provide a source of D-lactate. Lactic acid bacteria play a role in virtually all food fermentation processes, and a variable fraction of the resulting lactate is D-lactate. Yoghurt and sauerkraut have received the most study. Two bacteria, Lactobacillus bulgaricus and Streptococcus thermophilus, are commonly added to milk to bring about fermentation to yoghurt. The relative proportions of each lactate isomer varies with the bacteria employed. In one study of different yoghurts, D-lactate concentrations ranged from 29 to 122 mmol/l [2.5 to 11 g/L].[39] DeVrese and Barth[40] measured plasma D-lactate concentrations after ingestion of 74 mmol/70 kg of D-lactate (800–1600 g of yoghurt). The plasma concentration peaked at only 0.20 mM at one hour (
Figure 4). Calculation of the fractional absorption of D-lactate utilizing the PBPK modeling procedure indicated that 38.2 mmol (52% of the ingested D-lactate) reached the peripheral circulation (Figure 4), with absorption rate constants of TT = 21.6 and TA = 120 minutes, similar to the slow absorption rate assumed in Figures 3, 6 and 7.""Defective D-lactate elimination could reflect a baseline loss of D-LDH activity due to renal or hepatic tissue injury. Alternatively, there could be inhibitors of D-LDH activity that function at baseline or are operative only during an episode of D-lactic acidosis. An example of the former is oxalate, a potent in vitro inhibitor of D-lactate oxidation; eg, an oxalate concentration of 15 µM halved the rate of catabolism of 3 mM D-lactate.[45] Normal plasma oxalate concentrations are <2 uM, and there appear to be no measurements of plasma oxalate concentration in SBS subjects. However, hyperoxaluria, calcium oxalate stones, and oxalate nephropathy, complications of SBS, are indicative of elevated plasma oxalate concentration. Patients with end-stage renal disease have plasma oxalate concentrations of >50 uM,[46] and thus would be expected to have very slow D-lactate clearance if oxalate were an in vivo inhibitor of D-LDH. While patients with renal failure being treated with chronic peritoneal dialysis had baseline plasma D-lactate concentrations of about 0.07 mM (seven times normal), intraperitoneally infused D-lactate was metabolized at a normal rate, a result that does not support a role for oxalate in the pathogenesis of D-lactic acidosis."
"It also has been proposed that acidosis associated with elevated plasma D-lactate concentrations inhibit D-LDH. This concept derives from an in vitro study of Tubbs and Greville[11] showing that D-lactate oxidation has a broad pH optimum around 8.0, and that this activity falls off rapidly at pH 7.4. The pH optimum of 8.0 makes “sense” given the location of D-LDH in the mitochondrial matrix which maintains a very alkaline pH.[47] It seems unlikely that the plasma pH decrement observed in D-lactic acidosis would have an appreciable effect on D-LDH activity via an alteration of intra-mitochondrial pH. The effect of acidosis on human D-lactate catabolism has not been investigated – all measurements of lactate catabolism have utilized an IV infusion of D-lactate, which has an alkalizing effect. However, there are two D-lactate infusion studies in calves, one that used acidified D-lactate such that the plasma pH fell to 7.24[2] and a second study using D-lactate in a neutral solution where no reduction in pH occurred.[21] Our calculated D-lactate clearance for the study with acidosis was 40 mL/min/70 kg and with no acidosis, 31 mL/min/70 kg, a result that does not support the concept that acidosis inhibits D-lactate catabolism."
"In contrast to yoghurt, sauerkraut is fermented by lactobacilli naturally attached to the cabbage. Measurements made on the sauerkraut supernatant showed that D-LDH activity far exceeded that of L-LDH and that D-lactate was the predominant form of lactate (concentrations of roughly 80 mmol/l [7 g/L]).[41] As discussed with yoghurt, ingestion of sauerkraut, even at doses of 1 liter, would result in a trivial increase in blood lactate."
"Another source of exogenous D-lactate is lactate containing intravenous solutions that usually contain 28 meq/l of racemic lactate, ie, 14 meq/l of each isomer. Our modeling studies indicate that infusion of this quantity of D-lactate should result in only minor increases in plasma D-lactate, and Kuze et al[17] found that subjects infused with D-lactate at a rate of 14 mmol/hour (equivalent to 1 liter of Ringers-lactate/hour) for 3.5 hour rapidly developed a steady-state plasma lactate concentration of only about 0.3 mM. Similarly, the use of a lactate containing solution for peritoneal dialysis showed peak plasma D-lactate concentrations of only about 0.25 mM that returned to normal before the next instillation of dialysate.[42]"
"The belief that defective D-lactate catabolism plays a major role in the pathogenesis of D-lactic acidosis has led to a good deal of speculation as to factors that might reduce D-LDH activity of SBS subjects. Defective D-lactate elimination could reflect a baseline loss of D-LDH activity due to renal or hepatic tissue injury. Alternatively, there could be inhibitors of D-LDH activity that function at baseline or are operative only during an episode of D-lactic acidosis. An example of the former is oxalate, a potent in vitro inhibitor of D-lactate oxidation; eg, an oxalate concentration of 15 µM halved the rate of catabolism of 3 mM D-lactate.[45] Normal plasma oxalate concentrations are <2 uM, and there appear to be no measurements of plasma oxalate concentration in SBS subjects. However, hyperoxaluria, calcium oxalate stones, and oxalate nephropathy, complications of SBS, are indicative of elevated plasma oxalate concentration. Patients with end-stage renal disease have plasma oxalate concentrations of >50 uM,[46] and thus would be expected to have very slow D-lactate clearance if oxalate were an in vivo inhibitor of D-LDH. While patients with renal failure being treated with chronic peritoneal dialysis had baseline plasma D-lactate concentrations of about 0.07 mM (seven times normal), intraperitoneally infused D-lactate was metabolized at a normal rate, a result that does not support a role for oxalate in the pathogenesis of D-lactic acidosis.[42]"
"It also has been proposed that acidosis associated with elevated plasma D-lactate concentrations inhibit D-LDH. This concept derives from an in vitro study of Tubbs and Greville[11] showing that D-lactate oxidation has a broad pH optimum around 8.0, and that this activity falls off rapidly at pH 7.4. The pH optimum of 8.0 makes “sense” given the location of D-LDH in the mitochondrial matrix which maintains a very alkaline pH.[47] It seems unlikely that the plasma pH decrement observed in D-lactic acidosis would have an appreciable effect on D-LDH activity via an alteration of intra-mitochondrial pH. The effect of acidosis on human D-lactate catabolism has not been investigated – all measurements of lactate catabolism have utilized an IV infusion of D-lactate, which has an alkalizing effect. However, there are two D-lactate infusion studies in calves, one that used acidified D-lactate such that the plasma pH fell to 7.24[2] and a second study using D-lactate in a neutral solution where no reduction in pH occurred.[21] Our calculated D-lactate clearance for the study with acidosis was 40 mL/min/70 kg and with no acidosis, 31 mL/min/70 kg, a result that does not support the concept that acidosis inhibits D-lactate catabolism."
D-Lactic Acidosis: An Underrecognized Complication of Short Bowel Syndrome
Alteration of the colonic microbiota plays a major role in the production of D-lactate. Short bowel syndrome leads to an increased load of undigested carbohydrates (including simple sugars) in the colon. As a result, the amount of organic acid produced exceeds the amount that can be metabolized by healthy individuals. This leads to an accumulation of organic acids, including SCFA and lactate, resulting in a more acidic environment than normal. Interestingly, the lower pH favors the growth of bacteria responsible for producing D- and L-lactate as they are acid-resistant and this leads to a further decrease in the pH thus generating a vicious cycle. These bacteria include Lactobacillus fermenti and L. acidophilus amongst a few others [25,26]. As mentioned previously, the primary enzyme responsible for metabolizing D-lactate in humans is D-2-HDH, which is inhibited in the acidic environment. Caldarini et al. [27] demonstrated this in an in vitro study performed on stool samples of a child. Thus, SBS leads to initiation and propagation of D-lactic acid formation.
Other conditions that can mimic SBS in producing the complications of D-la include inflammatory disease of the small bowel, especially Crohn’s disease, antibiotics, and even probiotics that can alter the existing flora of the colon.
Patients with SBS have fat malabsorption and this can lead to calcium soap formation in the gut with free oxalate being absorbed with the risk of renal stones. Patients should stay well hydrated to keep up with the losses. Also oxalate can inhibit D-2-HDH, and hence oxalate intake should be limited. Small amounts of calcium supplementation (up to 1 g/day) may be beneficial. This will also increase the pH in the bowel, which could decrease D-lactate production as shown by Caldarini et al. [27].
D-Lactic Acidosis in Humans: Review of Update
"D-lactate is normally produced by the fermentative organisms of the gastrointestinal tract, mainly by lactobacilli and bifidobacteria. Under normal condition, lactate is not produced in acid-base imbalance because it is converted by other microbes to acetate and fatty acids. The major benefit of these organic acids in the gastrointestinal tract is to provide a fuel for oxidative metabolism and ion pumping for mucosal cells of the colon11). The colon is protected from large influxes of carbohydrate, being regulated by gastric emptying and effective small intestinal digestion and absorption."
-
The resynthesis of methionine through betaine (BHMT) is confined to the liver and kidneys
Intestinal metabolism of sulfur amino acids
"Because homocysteine methylation by betaine via betaine-homocysteine methyltransferase activity is confined to the liver and the kidney (3), choline and betaine dietary intake may have less impact on the methylation of homocysteine in the colon than folate since methionine synthase, that methylates homocysteine to methionine using 5-methyltetrahydrofolate as a methyl donor, is ubiquitously distributed (3). One of the consequences of folate deficiency is SAM deficiency since folate is involved in the remethylation of homocysteine to methionine, the precursor of SAM (
Fig. 1). However, folate supplementation can either prevent or exacerbate intestinal tumorigenesis, depending on the timing and dose of folate intervention (126). This may be explained by the function of folate in nucleotide synthesis (Fig. 1) where rapidly proliferating tissues, including tumours, have an increased requirement for nucleotides. At present, based on lack of compelling supportive evidence on the potential tumour-promoting effect and presence of some adverse effects (127, 128), a recent review concludes that folate supplementation should not be recommended as a chemopreventive measure against colorectal cancer (129)." -
On choline
"[..]it is well documented that the mouse model of chronic choline deficiency differs from rats because most mouse strains do not develop liver cirrhosis and hemorrhagic necrosis that is typical of chronic choline deficiency in rats (DeCarmago et al., 1985). It is also generally recognized that susceptibility to develop fatty liver in choline deficiency is age-dependent. The majority of studies examining choline deficiency began dietary modulation in weanling animals, which are highly susceptible to choline deficiency (Rogers et al., 1987). Susceptibility to choline deficiency declines rapidly, and young adults (10–12 weeks of age) are unlikely to develop features of fully expressed choline deficiency. Secondly, dietary fat composition also contributes to the development of fatty liver in choline deficiency. Specifically, the fat composition of choline deficient diets is often augmented to at least 20%, whereas standard laboratory chows contain about 5% fat. Additionally, variations in fatty liver development are observed when the fat is derived from animal or plant origins (Rogers et al., 1987; DeCarmargo et al., 1985)."
"[..]there are marked species differences in susceptibility to choline deficiency, with rats and mice being far more susceptible than other species including humans (Zeisel and Blusztajn, 1994). These differences are attributed to quantitative differences in the enzyme kinetics controlling choline metabolism. Rats and mice rapidly metabolize choline to betaine in the liver and it is likely that choline oxidase activity determines choline requirements and controls species sensitivity to choline deficiency (Sidransky and Farber, 1960). For example, choline oxidase activity is much lower in primates than rodents and primates are less sensitive to choline deficiency (Hoffbauer and Zaki, 1965). Humans have the lowest choline oxidase activity of all species and are generally refractory to choline deficiency, with evidence of choline deficiency observed only after prolonged fasting, significantly depressed liver function or deficient parenteral feeding (Zeisel and Blusztajn, 1994)."
Sex and menopausal status influence human dietary requirements for the nutrient choline
Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-L-methionine and glutathione (on immature mice)
"The pathogenesis and treatment of nonalcoholic steatohepatitis (NASH) are not well established. Feeding a diet deficient in both methionine and choline (MCD) is one of the most common models of NASH, which is characterized by steatosis, mitochondrial dysfunction, hepatocellular injury, oxidative stress, inflammation, and fibrosis. However, the individual contribution of the lack of methionine and choline in liver steatosis, advanced pathology and impact on mitochondrial S-adenosyl-L-methionine (SAM) and glutathione (GSH), known regulators of disease progression, has not been specifically addressed. Here, we examined the regulation of mitochondrial SAM and GSH and signs of disease in mice fed a MCD, methionine-deficient (MD), or choline-deficient (CD) diet. The MD diet reproduced most of the deleterious effects of MCD feeding, including weight loss, hepatocellular injury, oxidative stress, inflammation, and fibrosis, whereas CD feeding was mainly responsible for steatosis, characterized by triglycerides and free fatty acids accumulation."
[..]the decrease in membrane fluidity induced by the lack of methionine is accompanied by a lower PC/PE ratio, which is also considered an important modulator of membrane fluidity. Indeed, previous findings in PE methyltransferase knock-out mice fed a CD diet resulted in steatohepatitis due to low plasma membrane PC/PE ratio, which contributed to disrupted membrane integrity and decreased membrane fluidity (31). The observed outcome is intriguing as, unlike MCD diet, the MD diet contains an adequate choline level, which would be expected to drive the CDP-choline branch of the Kennedy pathway to synthesize PC de novo (11, 32), although the PC synthesis from PE methylation would be predicted to be impaired due to the limitation of SAM. To account for this unexpected finding (decreased PC/PE ratio despite choline in the MD group), we observed that methionine deficiency increased hepatic ceramide levels in agreement with previous observations in PC12 cells (35) and in mice fed the MCD diet (37). Although we did not determine whether the lack of methionine stimulated de novo ceramide synthesis from palmitoyl-CoA and serine, we did observe the activation of ASMase but not NSMase. The mechanism, however, underlying this observation is currently unknown and deserves further investigation. Moreover, based on previous observations in neuroblastoma cells exposed to C2-ceramide, the increase in ceramide levels induced by MD or MCD would be expected to inhibit the CDP-choline pathway and hence the synthesis of PC (34). The alternative synthesis of PC from PE by PE methyltransferases is anticipated to be impaired without methionine because of reduced SAM availability. Thus, the impact of methionine deficiency on mitochondrial GSH depletion is mediated by increasing ceramide levels and subsequent impaired PC synthesis (from either the CDP-choline pathway and PE methylation) resulting in lower PC/PE ratio, which determines reduced mitochondrial membrane fluidity and impaired transport of cytosolic GSH into mitochondria."
"Having observed the depletion of mitochondrial GSH in the MCD model (which is reproduced by MD diet feeding), we next addressed the effect of GSH precursors in the course of disease and replenishment of mitochondrial GSH. Our findings indicate that not all GSH prodrugs are equal. Although CysNAc, a GSH precursor, reverses the moderate depletion of hepatic GSH, it fails to restore the mitochondrial pool of GSH following MCD or MD feeding. The newly synthesized GSH from CysNAc in the cytosol is not effectively transported to mitochondria because of the block imposed by the loss of membrane fluidity associated with a decreased PC/PE ratio, consistent with previous observations in alcohol-fed rats (36). In a total enteral nutrition, the NASH model induced by overfeeding a diet enriched in polyunsaturated fat, CysNAc attenuated the progression of the liver pathology, which was associated with increased total hepatic GSH (39). However, the effect of CysNAc on the specific pool of mitochondrial GSH was not examined, nor was the impact of overfeeding on mitochondrial membrane composition and dynamics. In contrast to CysNAc, we report for the first time that GSH-EE [ethyl ester] attenuates the deleterious effects of feeding the MCD diet in terms of hepatocellular damage, fibrosis, and inflammation, and these effects are due to its ability to replenish mitochondrial GSH. Unlike CysNAc, GSH-EE is permeable to mitochondria and has been shown to boost GSH stores directly in conditions of impaired transport imposed by perturbed membrane fluidity (36)."
-
RE: Conditional problems with vitamin A: a place for sane discussions
By the way, you can find various reports of 'undetectable' vitamin D levels; some because of analysis error (it can be challenging to quantify toxins that occur in modest amounts), but others not.
Controlling the availability of the precursor molecule can be a means to make up for an overactive pathway:
Undetectable serum calcidiol: not everything that glitters is gold
"Granulomatous hypercalcaemia is particularly sensitive to vitamin D administration even though toxic 25(OH) vitamin D levels are not reached [5]. This has been attributed to avid 25(OH) vitamin D metabolism into 1,25(OH)2 vitamin D by macrophage 1α-hydroxylase. Availability of 25(OH) vitamin D becomes the main regulator of 1,25(OH)2 vitamin D synthesis. Under these circumstances, treatment of vitamin D deficiency will increase the availability of 25(OH) vitamin D and lead to high 1,25(OH)2 vitamin D levels and hypercalcaemia [8, 9]."
-
RE: Conditional problems with vitamin A: a place for sane discussions
@thyroidchor27 said in Conditional problems with vitamin A: a place for sane discussions:
@Amazoniac in the plasma or in the liver????
That claim is based on what?
-
RE: Conditional problems with vitamin A: a place for sane discussions
They pride themselves on the fact that it's possible to put psoriasis into remission through poison A deprivation, but what about Coimbra's experiment who accomplished the same with "vitamin" D3 (875 mcg/d) and minor dietary modifications?
These approaches work, but are rudimentary. They manipulate upstream processes rather favoring targeting downstream specifics, that minimize the risk of having to compromise other functions to reach the therapeutic dose (for low or for high).
Psoriasis and beyond: targeting the IL-17 pathway | Nature
Even though targeting what's downstream is more sophisticated, the best thing to do is to try to address the pathogen above it all.
-
RE: Calcium supplement
@CO3 said in Calcium supplement:
@Amazoniac "Just eat the toxic mold slave! It's good for you!"
@Amazoniac said in Calcium supplement:
@Not_James_Bond
Calcium doesn't have to be paired with industrial citrate.
-
RE: Calcium supplement
@Not_James_Bond
If people consume massive amounts of citrate from foods without problems and calcium carbonate isn't considered troubling, why would the combination lead to issues? Calcium doesn't have to be paired with industrial citrate.
Dietary citrate is metabolized primarily in the liver, any effect on the kidneys must be indirect. Induction of calcium loss seems unlikely, but if it occurs, it's compensated by its enhancing effect on absorption.
It's a good salt and exposure to it shouldn't be regulated as drugs.
-
RE: A list of members banned from the Ray Peat Forum
@Truth said in A list of members banned from the Ray Peat Forum:
@Amazoniac hi, blossom has already said that it's Charlie who has authority over her on all banning and moderation decisions if they disagree, it's him who has the final decision, so every ban that Charlie knows about and doesn't lift is a ban from Charlie
Hi!
Being a leader with privileges is not all flowers and they have to intervene not only when expedient. The disgrace is happening in front of her: is she sedated? Apathetic Melissa should be held accountable for her permissiveness for as long as she stays in command next to him by choice.
In an optimistic scenario where she would be revolting behind the scenes at the abusive practices and would have exhausted her resources trying to protect the community from reckless treatment, the least that our angel would do if her efforts were futile would be to renounce her position to not condone, claiming incapacity and misalignment of principles. Or the lion has authority over integrity too?
The window for her to show concern through actions has passed, changing her conduct only now would characterize opportunism if she senses that the ship may sink. Maybe the leader joins us when convenient, and with her access to exclusive information, she would be able to name a series of members to help us expand our list.
In any case, if you're aware of more ban instances going back to the creation of the forum, let us know.
-
RE: A dedicated Ray Peat archive website in plain format?
The volume of work is impressive.
I'm aware of both archives. The text to exemplify was from the first. I've contacted the creator of the second a while ago; it's a friendly fox, but it couldn't do much about a separate option at the time.
They're great archives, but are wasting their potential with fluff.
When automatic transcriptions are inconsistent, it's faster to transcribe manually than to fix error by error. We used to transcribe them on the Ray Peat Forum, but each person has a writing style that shows up in the result. Someone I know is transcribing and refining interviews (not from Ray) with artificial intelligence, the outcomes are consistent and decent. It's a kind of standardization that helps.
-
RE: A list of members banned from the Ray Peat Forum
@Verdad said in A list of members banned from the Ray Peat Forum:
Amazoniac were you banned?! I had no idea the banning was so extensive. My god Charlie really has gotten completely mad and out of control. This is the exact kind of behaviour cult leaders do. Explains his anti vitamin A stance.
Yes, Blossom misunderstood me for a pedophile after twisted humor with kids and banned me. If you want details, you can find them here:
- https://prolactinia.com/rpf-ban/ (sheepsweep)
Some passages may seem obvious now, but the majority of updates were before the uninhibited phase when forum chaos ensued.
I would prefer to not discuss it further because my report is comprehensive and there isn't much else to add, but I'm willing to clarify anything.
If you think that the list of banned cases so far is extensive, it hasn't even scratched the surface yet.
-
RE: A list of members banned from the Ray Peat Forum
@yerrag said in Banned from RP forum : Can you do better than this.:
Que lastima! Blossom is loyal to charlie to a fault. I nominated her to replace him in one of my last posts before I got banned. She had been an admin there for a long time, and doing a good job. But her banning @Amazoniac was something that is a mystery to me.
yerrag, there is no mystery: if something triggers the leaders of that forum, you're discarded without remorse.
-
RE: A list of members banned from the Ray Peat Forum
@Kvothe said in A list of members banned from the Ray Peat Forum:
@Amazoniac How nice to have both of my banned accounts right next to each other in the list
Dear Kvothe, if both accounts were banned and reasons were different, it doesn't seem justified to disconsider one or the other.
-
RE: A list of members banned from the Ray Peat Forum
Scattered ban complaints are ineffective, easily missed and the story repeats for more than a decade. But the situation changes when members start to organize: a compilation of cases is practical and tough to ignore. It's the first step for members to grasp the extent of the mismanagement and question the merit of each exclusion.
Could any staff member modify the original post to include the names brought up and update it on occasion as more are listed?
- Androsclerosis
- Atman
- HeyThere
- jaguar43
- JamesGatz
- Jamsey
- Ktbridge
- max93
- peter88
- questforhealth
- S.Holmes
- sunny
I consider noteworthy cases anyone who hasn't joined a community to pollute it.
-
Lactobacilli to outcompete sulfidogenic microbes
Volatile sulfur compounds produced by probiotic bacteria in the presence of cysteine or methionine
"It is well established that volatile sulfur compounds (VSCs) with very low-odour thresholds (ppb or ppt range) are important contributors to the flavour of cheese and many other fermented foods and can be derived from amino acid (cysteine and methionine) catabolism by starter culture or ripening bacteria and yeasts (Landaud et al. 2008). Methanethiol (MeSH) and oxidized MeSH derivatives, including dimethyl disulfide (DMDS) and dimethyltrisulfide (DMTS), as well as hydrogen sulfide (H2S) have been shown to have a significant impact on cheese sensory characteristics (Weimer et al. 1999; Smit et al. 2005)."
"This study compares several commercial and noncommercial probiotics as well as food lactic acid bacteria for their abilities to convert cysteine and methionine to VSCs. Understanding more regarding the abilities of probiotic bacteria to produce compounds typically involved in flavour and aroma will assist the development of new probiotic containing functional foods."
It can be unfair to incriminate an entire specie because of problems with a strain.
-
A dedicated Ray Peat archive website in plain format?
Even though we have different archives in the community popping up, they're extensions of other projects, contain personalized elements, and the presentations are funny. While I don't mind characterization and playfulness (#toxicbileapocalypse), these are not ideal for an archive to be adopted as main.
Ray's work is read by people of various backgrounds, and the more neutral the archive can be, the better. For someone with controversial ideas, every oddity in approaching the material increases resistance.
It's preferable for the archive to be separate from other collections to prevent associations as well.
Any decorative element must be discreet and relate to Ray (as the hat in his website) rather than the archiver.
I had in mind something simple along the following lines, using as reference one of the existing archives:
- Dedicated website (raypeatarchive.org?)
- Plain appearance
- Theme resembles his newsletter
- Only his name on the screen
- No distractions or strange elements
-
RE: Conditional problems with vitamin A: a place for sane discussions
@thyroidchor27 said in Conditional problems with vitamin A: a place for sane discussions:
Vitamin A increases SCD1 7x. That alone is reason to take it easy
Retinoic acids levels are kept relatively stable. What are the conditions for it to occur?
Guys, it was member 'schultz' who started the kill- term trend.
-
RE: Conditional problems with vitamin A: a place for sane discussions
On niacin for NAD
Nicotinamide is now regarded as toxic and nicotinic acid is being favored. It's supplemented intending to increase the synthesis of NAD to detoxify poisons.
They're not using pharmacological amounts of niacin that would lead to marked differences in how each form is eliminated. The moderate doses in use should be readily converted to nicotinamide. This is how forms are metabolized in mice:
The Management of Nicotinamide and Nicotinic Acid in the Mouse
DPN = NAD
desDPN = NaAD (immediate precursor to NAD)
↳ 'des' here stands for 'desamidated' NAD.Nicotinamide as yield happens with nicotinamide riboside or mononucleotide too:
"NR and NMN were administered by i.v. bolus or oral gavage at 50 mg/kg, which is equivalent to 290 mg in a 70-kg human on a body surface area basis, in the range of common nutraceuticals."
"Unlike in cell culture, where NR and NMN are readily incorporated into NAD (Ratajczak et al., 2016; Frederick et al., 2016), oral administration fails to deliver NR or NMN to tissues without breaking the nicotinamide-ribose bond."
"Irrespective of the route of delivery, the main circulating product of the administered NR or NMN was NAM, which increased by ~20⨯ within 5 min of i.v. NR or NMN; oral NR or NMN administration led to a more modest rise in circulating NAM (Figure 7C)."
I wonder how they justify their aversion to nicotinamide in moderate doses.
-
A list of members banned from the Ray Peat Forum
Thread placed in the junkyard to spare the main categories of external issues.
Could you list the names that come to mind for being banned from the Ray Peat Forum? Temporary bans dispirit, promote submission (a condition to revert them), and count too.
I'm only aware of a tiny fraction of noteworthy cases and can't keep track of what happens, but the list can be expanded with your help.
A phase of ideological delusion can't be confused with a decade of conscious, recurrent abusive practices and disrespects in managing the community. The feasts may continue, but this time they will continue with records.
If you remain a member there and don't want to be blacklisted and soon erased, you may send the information to someone else through private messages.
The staff had no choice but to ban:
- Androsclerosis
- Arrade
- Atman
- Borz?
- brightside
- burtlancast?
- cantstoppeating
- CLASH
- Crazycoco
- CreakyJoints
- deeri681
- deliciousfruit
- Drareg
- Edward
- feedandseed
- Gabriel
- gbolduev
- GreekDemiGod
- gummybear
- haidut
- HeyThere
- ilovethesea
- Impero
- iPeat
- j.
- jaa
- jaguar43
- JamesGatz
- Jamsey
- Kartoffel
- Korven
- Ktbridge
- Kvothe
- LadyRae?
- Logan
- Lucenzo01
- -Luke-
- Mauritio
- max93
- Me
- Mephisto
- mostlylurking
- Mr Joe
- narouz
- Nighteyes
- Nomane Euger
- Not_James_Bond
- pboy?
- Peater
- Peatful
- Peatress?
- peter88
- questforhealth
- raypeatclips
- Razvan
- Revenant
- risingfire
- S.Holmes
- SamYo123
- Source Code
- sunny
- Tenacity
- TheSir
- ThinPicking
- Truth
- visionofstrength
- Waynish
- Westside PUFAs
- wzuo
- yerrag
- Zachs