Incomprehensive/ble Notes On Choline

[Amazoniac]

- Differential metabolism of choline supplements in adult volunteers

"Because animal data indicate that the metabolism of free choline, GPC and PC is different [31], we set out to compare GPC, as characteristic for milk, and egg-PC, as characteristic of mixed and vegetarian food, with free choline in the forms of its chloride and bitartrate salts to elucidate potential clinically relevant differences in bioavailability, plasma kinetics, and metabolism. Phosphocholine was not analyzed because it is not available as a food supplement."

"The test subjects had to drink the adequate intake (AI) of choline according to NAM (550 mg/d) [12] in the form of:

– 740 mg choline chloride
– 1336 mg choline bitartrate
– 1358 mg GPC
– 4018 mg egg-PC."​

"Notably, all supplements tested increased choline concentrations by a similar extent. A single dose of 550 mg choline temporarily increased plasma concentrations followed by a rapid decline thereafter so that concentrations after 6 h had nearly reached baseline values for all components. This is surprising as previous data demonstrated a longer-lasting increase in plasma choline in response to egg or soya PC [32]. However, aspects of solubility, i.e., product quality, may contribute to the velocity of PC assimilation, and we only supplemented 4018 mg egg-PC equivalent to 550 mg choline, whereas others used the five-fold amount (20 g) [32]."

Spoiler

"However, the increase of plasma choline and betaine was delayed after egg-PC compared to other supplements, with a flatter slope of increase and a time to peak concentration of approximately 3 h rather than 1–2 h. This delay is consistent with the mechanism of choline assimilation from PC that requires cleavage of PC at the surface of duodenal lipid micelles to lyso-PC and free fatty acid by pancreatic phospholipase A2 IB (sPLA2IB) at alkaline small intestinal pH [33]. While choline, according to our data and those of other researchers, is readily assimilated from PC in healthy individuals it must be noted that this process is compromised in exocrine pancreas insufficiency and acidic small intestine pH, as the case in CF patients [26, 34]."

Spoiler

"All supplements increased plasma betaine concentrations to a similar extent and with similar kinetics, demonstrating that for all supplements a comparable fraction of choline is rapidly degraded to betaine, and that the similar absorption kinetic of choline resulted in a similar kinetic of betaine. Hence, there are apparently no major differences between choline-containing components with respect to their oxidation to betaine. For all substances, the increase in plasma betaine is higher than that of choline, suggesting that feeding the one-carbon pool via betaine is an important aspect of any choline supplementation. Although, for the administration of egg-PC, part of the absorbed lyso-PC is re-acylated to PC and used for the formation of chylomicrons, our data show that there is no difference between PC and the other components with respect to plasma betaine. It is unclear whether this will change after consuming larger amounts of PC or if PC is administered with larger amounts of fat rather than those contained in a butter pretzel."

"Notably, egg-PC did not induce an increase in plasma TMAO in any study participant, including those forming high amounts of TMAO upon the ingestion of choline chloride, choline bitartrate, and GPC. Moreover, the ingestion of choline bitartrate exerted the highest increase in three out of five individuals, although individual responses were different. Apparently, the formation of TMA and TMAO depends on individual microbiota, but may be influenced by many factors, like occult inflammation or intestinal transit time."

Spoiler

"In this study, we assessed healthy male adults. Women were excluded because of the impact of estrogens on PEMT activity and hence choline metabolism. Transfer of the results of this study to other patient groups such as women and particularly preterm infants should be undertaken with caution. Whereas the kinetics of choline chloride are identical in adult CF patients compared to healthy persons, age, hormones, the microbiome, pancreatic insufficiency and immature digestive enzymes may influence the uptake and metabolism of choline supplements [1; 16], suggesting further studies."​

 

[Mauritio]

In people, maternal choline intake modulated epigenetic marks in the placenta; women with higher intake of choline had higher placental promoter methylation in the corticotrophin releasing hormone (CRH) and glucocorticoid receptor (NR3C1) genes and this was associated with lower placental expression of the corticotrophin-releasing hormone [40].

A meta-analysis of 11 studies in people calculated that diets low in choline increased the overall relative risk for developing cancer [69] with the largest reported effects found for lung (30% increase; also see [70]), nasopharyngeal (58% increase; also see [70]) and breast cancer (60% increase; also see [71]). An increment in diet intake of 100 mg/day of choline and betaine (a metabolite derived from choline) helped reduce cancer incidence by 11% [69].

Choline, Other Methyl-Donors and Epigenetics

Choline dietary intake varies such that many people do not achieve adequate intakes. Diet intake of choline can modulate methylation because, via betaine homocysteine methyltransferase (BHMT), this nutrient (and its metabolite, betaine) regulate the concentrations ...

www.ncbi.nlm.nih.gov

 

[Mauritio]

"GPC administration decreased the inflammatory activation in line with the reduced oxidative and nitrosative stress markers."

"GPC, by preserving the mitochondrial complex I function respiration, reduced the biochemical signs of oxidative stress after an IR episode. "

Targeting Mitochondrial Dysfunction with L-Alpha Glycerylphosphorylcholine

We hypothesized that L-alpha-glycerylphosphorylcholine (GPC), a deacylatedphosphatidylcholine derivative, can influence the mitochondrial respiratory activity and in this way, may exert tissue protective effects.Rat liver mitochondria were examined with ...

www.ncbi.nlm.nih.gov

"Analysis of TSH revealed a significant main effect by group. Post hoc analysis revealed significantly lower TSH levels (500 mg of A-GPC 2.29 ± 0.51μIU/ml, 3.17 ± 1.6 μIU/ml for placebo, 2.97 ± 1.03 μIU/ml for 250 mg of A-GPC and 3.08 ± 0.83 μIU/ml for Caffeine) with the 500 mg A-GPC dose as compared to all other treatment (p < 0.04)."

Evaluation of the effects of two doses of alpha glycerylphosphorylcholine on physical and psychomotor performance - PubMed

Based upon this evidence, and previous evidence regarding A-GPC, it should be considered as an emerging ergogenic supplement.

pubmed.ncbi.nlm.nih.gov

 

[Brandin]

Excess niacin supplementation can aggravate a lack of choline:

"It is [] apparent that catabolism of NAD places a substantial strain on the methylating capacity of hepatocytes. If we assume that 80% of a 2 gram daily dose of time-release niacin will be methylated, this will require the methyl groups from about 2 grams of methionine (in the form of S-adenosylmethionine). Under ordinary circumstances, the lion's share of the liver's methylating capacity is used for creatine synthesis (14), since creatine turnover (in males) is about 2 grams daily (of which the diet provides a variable quantity, up to 1 gram) (15), it can be estimated that less than 2 grams of methionine are required for daily endogenous creatine production. Thus, the methylation requirements imposed by high daily doses of niacin are large compared to the liver's normal methylating activity. Fortunately, the methionine synthase reaction (in which 5-methyltetrahydrofolate donates a serine-derived methyl group to homocysteine with the assistance of vitamin B12) can 'recycle' methionine so that a limited dietary intake of methionine is often sufficient to support ordinary methylation requirements. Theoretically, when methyl group demand is high, upregulated activity of enzymes required for de-novo serine synthesis and folate pool turnover might be expected to maintain adequate methylating capacity; however, it seems likely that at least in some individuals these adaptive mechanisms would function suboptimally. Thus, the additional methyl requirements imposed by high-dose niacin therapy may have the potential to strain the capacity of the methionine synthase reaction, such that the hepatocyte pool of S-adenosylmethionine (SAM) becomes significantly depleted. As a result, other crucial methylation reactions in hepatocytes – such as synthesis of membrane phosphatidylcholine – will be underactive. I postulate that this is the chief metabolic mechanism whereby high-dose niacin therapy evokes hepatotoxicity. Furthermore, inasmuch as S-adenosylmethionine is a potent allosteric activator of the enzyme cystathioninebeta-synthase (16), required for the irreversible disposal of homocysteine, it is reasonable to expect that such therapy will tend to raise serum levels of homocysteine – a phenomenon that presumably would have a countervailing negative impact on the vascular benefits of niacin treatment."

"The fact that methyl donors (namely choline and methionine) are reported to correct niacinamide hepatotoxicity in rats (21), can be viewed as confirmatory of the role of methyl depletion in niacin toxicity. While one could postulate that some other factor associated with accelerated NAD production was responsible for niacin/niacinamide toxicity – for example, depletion of the hepatic pool of phosphoribosylpyrophosphate or of ATP (24) – such a mechanism would appear inconsistent with the ameliorative impact of lipotropes in niacinamide-treated rats."

"Although supplements of methionine or SAM presumably could be used to increase the hepatic SAM pool, this strategy would have the disadvantages of increasing daily homocysteine production and of promoting calciuria (38). SAM has the further drawback that it is very expensive. (However, in syndromes mediated by oxidative damage, SAM has the advantage of increasing hepatic glutathione levels) (34). With respect to choline, it is a poor source of labile methyl groups in humans owing to the fact that human hepatic choline oxidase activity is very low compared to that found in rodents (39) (in which choline is an effective lipotrope). Thus, while supplemental choline may aid phosphatidylcholine synthesis by the salvage pathway, it could not be expected to correct a deficit of SAM."

Shouldnt raw eggs have enough vitamin e to counteract the pufa?

 

[Amazoniac]

Shouldnt raw eggs have enough vitamin e to counteract the pufa?

The proposed milligram requirements of "vitamin" E to protect a gram of unsaturated fats are:

0.09 - Monoenoic acids​

0.60 - Dienoic acids​

0.90 - Trienoic acids​

1.20 - Tetraenoic acids​

1.50 - Pentaenoic acids​

1.80 - Hexaenoic acids​

Example: 1 g of terminoleic acid (C18:2) requires 0.6 mg of Diokine-tocoinphernal.

- Egg, whole, raw, fresh | SELF Nutrition Data

Large egg:

1.90 g C#:1 → 0.17 mg E​

0.57 g C#:2 → 0.35 mg E​

​

0.07 g C#:4 → 0.09 mg E​

​

0.02 g C#:6 → 0.03 mg E​

Might be needing about 0.7 mg of Diokine-tocoinphernal, which surpasses the content. However, these are conventional eggs and other contaminants present in it must help in the protection of lipids.

Running low on nutrients in an obsessive attempt to avoid unsaturated fat can create an inflammatory state that might make the person need way more "vitamin" E just to keep this inflammation (Mauritio, 2021) in check.

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- Finding the balance: The role of S-adenosylmethionine and phosphatidylcholine metabolism in development of nonalcoholic fatty liver disease

Spoiler

"The glycine N-methyltransferase (GNMT) knockout mouse (Gnmt−/−) reveals an additional level of complexity to the relationship between hepatic SAMe and NAFLD.[8] GNMT methylates glycine to form sarcosine (methyl-glycine). Sarcosine has no known metabolic function but is demethylated to regenerate glycine. This futile cycle enables the catabolism of excess hepatic SAMe without aberrant production of methylated products. Deletion of GNMT increased steady-state SAMe levels 40-fold and induced NAFLD in mice.[8] Gnmt−/− mice developed NAFLD by 3 months and hepatocellular carcinoma by 8 months of age."

"Martínez-Uña et al.[9] provide new insight into mechanisms by which both low and high SAMe levels promote hepatic lipid accumulation (Fig. 1B). Deletion of GNMT decreased hepatic PE and increased PC, diacylglycerol (DG), and TG. VLDL secretion was increased in Gnmt−/− mice and fatty acid synthesis and oxidation were unchanged; these findings did not explain the hepatic TG accumulation. Through a series of careful experiments, the authors showed that elevated hepatic SAMe in Gnmt−/− mice induces the conversion of PE to PC by way of PEMT.[9] Consequently, in order to maintain a normal membrane PC/PE ratio, the liver stimulates PC secretion by way of VLDL and high-density lipoproteins and increases PC degradation by way of phospholipase D or C, leading to increased DG production (Fig. 1A). Thus, PC catabolism promotes hepatic TG accumulation. When Gnmt−/− mice were fed a methionine-deficient diet, hepatic SAMe and flux of PE to PC flux were normalized, and hepatic lipids were restored to control levels. Thus, the authors show that excess SAMe levels stimulate both PC synthesis and catabolism, thereby contributing to the development of hepatic steatosis."

"Since the Km of GNMT for SAMe is relatively high compared to other methyltransferases, the primary role of GNMT is postulated to be the elimination of excess hepatic SAMe. Thus, PEMT may be an “overflow pathway” for SAMe when GNMT is absent.[11] However, increased flux of methyl groups through PEMT, unlike GNMT, enhances TG synthesis. The level of hepatic SAMe is altered by the transition from the fed to fasting state and by consumption of a high versus low protein diet.[10]"

"Wiggins and Gibbons[11] reported that PC serves as a source of TG in rat hepatocytes. Several studies have shown that lipoprotein-derived PC is a quantitatively important direct precursor of hepatic TG.[12,13] For example, 50% of LDL-PC taken up by mouse hepatocytes is converted into TG by way of hydrolysis of PC to DG and esterification of DG by acyl-CoA:diacylglycerol acyltransferase.[13] Moreover, ∼50% of hepatic PC is derived from circulating lipoproteins[12] and 30% of HDL-derived PC in mouse liver was converted to TG.[12] Hence, PC in circulating lipoproteins should be considered a significant source of TG for the etiology of NAFLD."

"PC made both by PE methylation and supplied by lipoproteins contributes to hepatic steatosis. Ling et al.[14] provided evidence that a decreased hepatic PC/PE molar ratio is associated with NAFLD progression in mice. A reduced hepatic PC/PE ratio was also observed in some patients with nonalcoholic steatohepatitis (NASH).[15] The amounts of hepatic PC and PE are regulated to maintain membrane integrity and control the movement of metabolites across membranes.[15] A reduction in the PC/PE ratio increases membrane permeability, leading to leakage of cellular contents to the extracellular space, thereby activating resident Kupffer cells and promoting cytokine-mediated hepatocyte injury. Together, these changes contribute to cellular injury and the pathogenesis of NASH.[15]"

"The Gnmt−/− mice have elevated PC/PE and develop steatohepatitis. TG accumulation and the PC/PE ratio are normalized when Gnmt−/− mice are fed a methionine-deficient diet.[9] Taken together, it is clear that both abnormally high and low levels of SAMe and PC/PE ratio can be a determinant of NAFLD (Fig. 1C). It is also clear that maintaining a balance among these metabolites is important in preventing fatty liver disease."

 

[Amazoniac]

Saving for later..

- Why is taurine cytoprotective?

"Biological membranes are naturally arranged as bilayers. However, some of the phospholipids found in the membrane are capable of disrupting the bilayer structure. Phosphatidylethanolamine belongs to a group of disrupting phospholipids known as hexagonal formers. Interestingly, phosphatidylethanolamine can be converted into a bilayer former, phosphatidylcholine. Hamaguchi et al.[56] found that taurine inhibits the enzyme phospholipid N-methyltransferase, which catalyzes the conversion of phosphatidylethanolamine to phosphatidylcholine. Besides blocking the conversion of a hexagonal former into a bilayer former, taurine also affects the distribution of phospholipids within the membrane. Phosphatidylethanolamine is preferentially located on the inner bilayer (the cytosolic side) of the cell membrane, while phosphatidylcholine is preferentially found on the outer bilayer facing the extracellular space. By inhibiting the N-methyltransferase reaction, taurine prevents the movement of phospholipids from the inner bilayer to the outer bilayer. Taurine is also capable of forming an ionic interaction with the zwitterionic headgroups of certain phospholipids[65]. Because of these myriad of actions, it would not be surprising if taurine indirectly affects lipid peroxidation."​

- Role of lipid polymorphism in G protein-membrane interactions: Nonlamellar-prone phospholipids and peripheral protein binding to membranes

Spoiler

 

[Amazoniac]

There's a similar figure on a earlier post, but the ones below show the modifications of the molecules.

- Nutrient Metabolism: Structures, Functions, and Genes (978-0-12-387784-0)

Spoiler

"The breakdown of choline occurs mainly in the liver and kidneys and depends on adequate supplies of riboflavin, niacin, and folate (Figure 8.110). Choline in the liver can be transported from cytosol into mitochondria and oxidized to betaine aldehyde (by choline dehydrogenase, EC1.1.99.1), and then to betaine (by betaine aldehyde dehydrogenase, EC1.2.1.8). Betaine provides one methyl group for the remethylation of homocysteine (by betaine homocysteine methyltransferase, EC2.1.1.5, contains zinc). The oxidation of the choline metabolite dimethylglycine by the flavoenzyme dimethylglycine dehydrogenase (EC1.5.99.2, FAD) releases formaldehyde. The next step of choline metabolism, catalyzed by FMN-containing sarcosine dehydrogenase (EC1.5.99.1), also releases formaldehyde. An alternative pathway in the kidneys uses H2O2-producing sarcosine oxidase (Reuber et al., 1997). Glycine may be used for one of its various metabolic functions or oxidized by the glycine cleavage system."

- The toxic side of one-carbon metabolism and epigenetics

 

[Lejeboca]

Choline and Its Products Acetylcholine and Phosphatidylcholine

"Choline (2‐hydroxyethyl‐trimethyl‐ammonium), a simple but unusual compound, consists of a 2‐carbon chain in which one carbon is attached to a hydroxyl group and the other to an amine nitrogen (Figure 18‐1). The particularly unusual quality of choline is that this amine nitrogen bonds with a total of four hydrogen or carbon atoms instead of with the usual three, and thus carries a partial positive charge. Though choline is not an amino acid, it shares with that family of compounds the property of being present in cells both in free form and—like the amino acids in proteins—within subunits (e.g., PC) of a macromolecule (biologic membranes). Moreover, like tyrosine, tryptophan (Cansev and Wurtman, 2006), and histidine, choline is the precursor of a neurotransmitter (ACh), and also like tyrosine and histidine, choline must be obtained from both endogenous synthesis and dietary sources."

"Plasma choline derives from three sources—dietary choline, consumed as the free base or as a constituent of phospholipid molecules; endogenous synthesis, principally in liver; and liberation from its reservoir within the membrane phosphatides of all mammalian cells."

"Dietary PC is deacylated within the gut to form lyso‐PC. About half of this product is further degraded to free choline within the gut or liver. The remainder is reacylated to regenerate PC (Houtsmuller, 1979), which is then absorbed into the lymphatic circulation (Fox et al., 1979) and eventually enters the blood stream."

"Much of the dietary choline that reaches the liver through the portal circulation is destroyed by oxidation to betaine, as described later (Figure 18‐2), ultimately providing methyl groups that can be used to regenerate S‐adenosylmethionine (SAM) from homocysteine. The rest of the choline in portal venous blood passes into the systemic circulation (Fox et al., 1979; Houtsmuller, 1979)."

"Endogenous choline is produced, principally in liver (Bremer and Greenberg, 1960) but also to a small extent within brain (Blusztajn et al., 1979; Crews et al., 1980), by the sequential addition of three methyl groups to the amine nitrogen of phosphatidylethanolamine (PE); this forms PC, which can then be broken down to liberate the choline (Figure 18‐3). The methylation reactions are catalyzed by two enzymes, phosphatidylethanolamine‐N‐methyltransferase (PEMT1; EC: 2.1.1.17), which converts PE to its monomethyl derivative, and phosphatidyl‐N‐methylethanolamine‐N‐methyltransferase (PEMT2; EC: 2.1.1.71), which adds the second and third methyl groups (A single enzyme may catalyze all three methylations in liver). Both enzymes use SAM as the methyl donor (Bremer and Greenberg, 1960; Hirata et al., 1978). Their Kms for SAM are 2–4 ⨯ 10^−6 M and 20–110 ⨯ 10^−6 M, respectively (Crews et al., 1980; Blusztajn et al., 1982; Hitzemann, 1982; Percy et al., 1982), whereas brain SAM concentrations are 10–17 mg/g wet weight [50–85 mM assuming about 50% of the brain mass is aqueous (Wurtman and Rose, 1970; Ordonez and Wurtman, 1974)]. Hence, PEMT1 is probably fully saturated with SAM whereas PEMT2 is not."

"It is estimated that, on average, about 15% of the free choline that enters the human blood stream derives from endogenous synthesis, the rest coming principally from dietary sources (Zeisel, 1981)."

"Cellular membranes contain most of the choline in the body, principally in the form of the phosphatide PC, but also as PC’s products SM (Figure 18‐6) and lyso‐PC (Figure 18‐5b), or as less‐abundant choline-containing phospholipids like the PAF (1‐O‐alkyl‐2‐acetyl‐sn‐glycero‐3‐phosphocholine). Membranes also contain the phosphatides PS, PE, and phosphatidylinositol (PI), as well as specific proteins, cholesterol, and various minor lipids. The quantities of choline present in brain as PC (2–2.5 mmoles/g) or as SM (0.25 mmoles/g) are orders of magnitude greater than those of free choline (30–60 mM). The proportion of any membrane’s phospholipids represented by PC can vary depending on the species and age of the animal, the particular brain region or cell type being studied, and the membrane’s function within the cell (e.g., nuclear membrane and plasma membrane) (Suzuki, 1981)."

"Newly synthesized phosphatide molecules contain relatively larger quantities of polyunsaturated fatty acids (PUFA) than the phosphatide molecules present at steady state (Tacconi and Wurtman, 1985). This reflects either faster turnover of PUFA‐containing phosphatides, or their rapid deacylation followed by reacylation with more saturated fatty acid species (Houtsmuller, 1979), or both."

"The choline oxidase system in mammals is composed of two enzymes; in microorganisms a single enzyme, also termed "choline oxidase" (EC 1.1.3.17) converts choline to betaine. In mammals, the choline is first oxidized to betaine aldehyde by choline dehydrogenase (EC 1.1.99.1) (Figure 18‐2), an enzyme located at (or bound to) the inner membrane of mitochondria (Streumer‐Svobodova and Drahota, 1977; Lin and Wu, 1986). This enzyme can also convert the aldehyde to betaine; however, unlike the choline oxidase of microorganisms, its affinity for betaine aldehyde is very low (only about 5% its affinity for choline), so choline dehydrogenase has only a minor effect on net betaine synthesis (Tsuge et al., 1980). This enzyme is a monomeric flavoprotein with a molecular weight of 61.000 Da (Lin andWu, 1986); its activity requires FAD (Rothschild et al., 1954) and molecular oxygen serves as the primary electron acceptor (Zhang et al., 1992). One molecule of choline oxidized through the respiratory chain yields two molecules of mitochondrial ATP (Lin and Wu, 1986). Choline dehydrogenase has been cloned from rat liver mitochondria using a cDNA formed from the enzyme’s terminal amino acid sequence (Huang and Lin, 2003). The enzyme is most active in liver and kidney (Bernheim and Bernheim, 1933; Mann and Quastel, 1937), and, as discussed earlier, only negligible choline dehydrogenase activity is observed in brain (Haubrich et al., 1979; Haubrich and Gerber, 1981). Recent estimates of choline dehydrogenase's Km for choline—140–270 mM (Zhang et al., 1992)—suggest values that are substantially lower than those estimated earlier (5–7 mM; Rendina and Singer, 1959; Tsuge et al., 1980; Haubrich and Gerber, 1981). However, this revised Km is still high compared with actual liver choline concentrations (60–230 mM; Sundler et al., 1972; Haubrich and Gerber, 1981), suggesting that treatments that increase hepatic choline levels also increase its rate of degradation. Very high portal venous choline concentrations (~2.5 mM; Zeisel et al., 1980b) produced experimentally in studies on isolated perfused livers can fully saturate the enzyme."

"Betaine aldehyde dehydrogenase (EC 1.2.1.8) further oxidizes betaine aldehyde to betaine (Figure 18‐2). This enzyme, found both in cytoplasm and mitochondria (Wilken et al., 1970; Pietruszko and Chern, 2001), uses NAD as a cofactor (Wilken et al., 1970). Its Km for betaine aldehyde (118 mM in rat liver mitochondria, Chern and Pietruszko, 1995; 123 mM in rat liver cytoplasm, Vaz et al., 2000; 182 mM in human liver cytoplasm, Vaz et al., 2000) is probably substantially higher than actual in vivo concentrations of the aldehyde; hence, the betaine aldehyde formed when hepatic choline levels rise is rapidly metabolized."

"Several studies have shown that plasma‐free choline concentrations decrease significantly by about 25–40% after prolonged exercise, e.g., running a marathon (Conlay et al., 1986, 1992; Buchman et al., 1999, 2000a), and remain depressed for at least 48 h after the race (Buchman et al., 1999)."

"Serum‐free choline concentrations decrease by 20–45% during (Ulus et al., 1998; Ilcol et al., 2002d) and after surgery, in humans (Ulus et al., 1998; Ilcol et al., 2002d, 2004, 2006) or dogs (Ilcol et al., 2003b). This phenomenon is a response to surgical stress and is inversely correlated with the stress-induced elevations in serum cortisol, adrenocorticotropic hormone (ACTH), prolactin, and b‐endorphin (Ilcol et al., 2002a). The magnitude and duration of surgery‐induced declines in serum choline depend on the severity and the type of surgery (Ulus et al., 1998; Ilcol et al., 2002d, 2003b, 2005b). Thus, free choline concentrations return to presurgical values within 24 or 48 h after a cesarean section (Ilcol et al., 2002e), or a transurethral prostatectomy (Ulus et al., 1998), but require 72 h to do so after abdominal surgery (Ilcol et al., 2003b) or 96 h after coronary artery bypass surgery (Ilcol et al., 2004, 2006) or removal of a brain tumor (Ilcol et al., 2004). The decline in serum‐free choline concentration associated with surgery can be mimicked in dogs by the administration of methylprednisolone (Ilcol et al., 2003b)."

"Mammalian brains contain choline as the free base; as such water‐soluble phosphorylated metabolites as phosphocholine and GPC (Nitsch et al., 1992), and as constituents of membrane phospholipids including PC, SM, and lyso‐PC. Free choline levels in the brains of humans and rats reportedly vary between 36–44 mM (Ross et al., 1997) and 30–60 mM (Stavinoha and Weintraub, 1974; Klein et al., 1993), whereas PC and SM levels are orders of magnitude higher (~2000–2500 mM and 250 mM, respectively; Marshall et al., 1996). These high levels reflect the ubiquity of phospholipids, and the numerous essential roles they mediate when they form membranes. Membrane phospholipids also serve as reservoirs for choline and for such "second messenger" molecules as DAG, AA, inositol trisphosphate (IP3), and phosphatidic acid."

"Free choline molecules in the brain derive from four known sources such as uptake from the plasma; liberation from the PC in brain membranes; high‐affinity uptake from the synaptic cleft after ACh released from a cholinergic terminal has been hydrolyzed; and, probably to a minor extent, the breakdown of newly synthesized PC formed from the methylation of PE."

"The release of choline from PC can also be enhanced, and its reincorporation into PC is diminished by sustained neuronal depolarization (Farber et al., 1996). This process has been termed "autocannibalism" when some of the choline is diverted for the synthesis of ACh (Blusztajn et al., 1986; Ulus et al., 1989). Autocannibalism may, by decreasing the quantities of phosphatide molecules, and thus of neuronal membranes, underlie the particular vulnerability of cholinergic neurons in certain diseases (Blusztajn et al., 1986; Ulus et al., 1989). It is not known whether the accelerated breakdown of PC associated with sustained neuronal depolarization results from changes in ion flux or requires the release of local neurotransmitters and activation of particular receptors. The depletion of membrane PC and other phosphatides— including those not containing choline—caused by frequent or sustained depolarizations can be diminished or blocked entirely, and the release of ACh is enhanced by providing the brain with supplemental choline (Ulus et al., 1989)."

"ACh released into synapses is rapidly hydrolyzed to free choline and acetate. This process terminates the neurotransmitter's physiologic actions, i.e., its ability to combine with and activate its pre‐ or postsynaptic muscarinic or nicotinic receptors. (The inactivation of ACh differs from that of other aminergic transmitters, e.g., dopamine and serotonin, in which it involves a chemical change in the neurotransmitter molecule, and not simply physical removal of that molecule from the synaptic cleft by reuptake into its nerve terminal of origin.)"

"Most of the free choline liberated by the intrasynaptic hydrolysis of ACh is taken back up into its nerve terminal of origin by the high‐affinity choline transporter (CHT) described later, and either reacetylated to form ACh or phosphorylated for ultimate conversion to membrane PC (Ulus et al., 1989)."

"ChAT (acetyl‐CoA: choline‐O‐acetyltransferase, EC 2.3.1.6) mediates a single reaction, the transfer of an acetyl group from acetyl‐coenzyme A (acetyl‐coA) to choline, which thereby generates the neurotransmitter ACh in cholinergic neurons."

"ChAT probably exists in at least two forms within cholinergic nerve terminals—a soluble form (80–90% of the total enzyme activity) and a membrane‐associated form (10–20%; Benishin and Carroll, 1981; Salem et al., 1994; Pahud et al., 1998). These two forms exhibit different physicochemical and biochemical properties (Benishin and Carroll, 1983; Eder‐Colli et al., 1986; Pahud et al., 2003). The soluble form is hydrophilic, and the membrane‐bound form is amphiphilic (Benishin and Carroll, 1983; Eder Colli et al., 1986; Pahud et al., 2003). Soluble ChAT has higher affinities for both of its substrates, choline and acetyl‐CoA, when assayed at low ionic strength (Km for choline 350 mM; for acetyl‐CoA 2.5 mM) than that when assayed at higher ionic strengths (Km for choline 6700 mM; for acetyl‐CoA 77 mM; Rossier, 1977). The activity of ChAT in crude synaptosomal preparations (presumably representing a mixture of the soluble and membrane‐bound forms) also varies with ionic strength; the affinity of synaptosomal ChAT for choline appears to be greater than that of soluble ChAT (Km = 22 mM at low ionic strength and 540 mM at high ionic strength; Rossier, 1977). In any case, ChAT is invariably unsaturated with choline at the choline concentrations that could exist within nerve terminals (Tucek, 1990), indicating that ChAT is in kinetic excess (Hersh, 1982; Tucek, 1990), and that its substrate‐saturation, not its levels, is rate limiting in ACh synthesis. Both choline and acetyl‐CoA (Rossier, 1977; Hersh, 1982; Tucek, 1990) levels can affect the rate at which ACh is produced."

"There is also evidence that phosphorylation and dephosphorylation of ChAT can alter its catalytic activity, subcellular distribution, and interactions with other cellular proteins (see review of Dobransky and Rylett, 2005). ChAT is a substrate for multiple PKs; 69 kDa ChAT is phosphorylated by PK‐C, PK‐CK2, and a Ca2+/calmodulin‐dependent PK‐II (CaM‐kinase) but not by PK‐A, whereas 82 kDa ChAT is phosphorylated by PK‐C and CaM‐kinase (Dobransky et al., 2000, 2001)." "Phosphorylation of ChAT by PK‐C alone can double the enzyme’s activity, whereas coordinated phosphorylation of ChAT at threonine 456 (by CaM‐kinase II) and serine 440 (by PK‐C) can treble ChAT activity (Dobransky et al., 2003). Whether the phosphorylation and dephosphorylation of ChAT also alter the enzyme’s affinities for choline or acetyl‐CoA in intact cells is clear."

"CK (ATP:choline phosphotransferase; EC 2.7.1.32) catalyzes the first phosphorylation reaction in the Kennedy cycle of PC synthesis (Figure 18‐4); ATP is the phosphate donor and the presence of Mg2+ is required (Wittenberg and Kornberg, 1953). CK can also catalyze the phosphorylation of ethanolamine, as well as N‐monomethylethanolamine and N,N‐dimethylethanolamine (Ishidate et al., 1985; Porter and Kent, 1990; Uchida and Yamashita, 1990); however, a separate ethanolamine kinase enzyme exists, demonstrated by cloning cDNA from human liver (Lykidis et al., 2001). CK is mainly cytosolic but is also associated with particulate (membrane‐bound) fractions of rat striatum (Reinhardt and Wecker, 1983). The enzyme has been purified to homogeneity from various rat tissues (Ishidate et al., 1985; Porter and Kent, 1990), including brain (Uchida and Yamashita, 1990). HC3 (Ansell and Spanner, 1974) and ADP (Burt and Brody, 1975) inhibit CK activity in vitro, whereas high concentrations of the polyamines spermine and spermidine (Uchida and Yamashita, 1990) enhance its activity."

"In some circumstances, CK activity may be rate limiting in PC synthesis; for example, a 3.5 fold increase in CK activity in livers of rats deficient in essential fatty acids was accompanied by a parallel increase in PC synthesis (Infante and Kinsella, 1978). Similar relationships have been described in livers of estrogen‐treated roosters (Vigo and Vance, 1981) or quiescent murine 3T3 cells in culture (Warden and Friedkin, 1985). However, it is probably not the activity of CK per se, but rather its degree of substrate saturation that affects the rate of PC synthesis. The Km of CK for choline in rat brain is 14–134 mM (Uchida and Yamashita, 1990; Cao and Kanfer, 1995); this value is 32–310 mM in rabbit brain (Haubrich, 1973). An even higher Km value (2.6 mM) was described by Spanner and Ansell (1979) who assayed the enzyme at a more physiological pH (7.5) than that customarily used (pH = 9.0); this allowed phosphocholine, CK’s reaction product, to be assayed without first being hydrolyzed. Hence, CK is unsaturated with choline at normal brain choline concentrations (30–60 mM), and the production of phosphocholine through CK, like that of ACh by ChAT, is controlled principally by brain choline levels (Millington and Wurtman, 1982; Cohen et al., 1995)."

"Choline in sufficiently high concentrations can directly activate both muscarinic (mAChRs) and the nicotinic (nAChRs) acetylcholine receptors. The five muscarinic receptors (M1–M5) mediate slow metabolic responses to ACh, and the nicotinic receptors, which are ligand‐gated ion channels, implement fast, ACh‐mediated synaptic transmission in the CNS, ganglia, and neuromuscular synapses. The M1, M3, and M5 muscarinic receptors activate phospholipase C, thereby generating the second messengers IP3 and DAG (Caulfield and Birdsall, 1998); the M2 and M4 muscarinic receptors inhibit adenylate cyclase activity, thus reducing intracellular cAMP levels, or can enhance the flux of potassium and other ions through nonselective ion channels. The nicotinic receptors, pentameric structures made up of combinations of 17 known individual subunits, increase the flux of sodium into postsynaptic cells, thus increasing the likelihood of the cells' depolarization. Free choline concentrations in synaptic fluid following neuronal depolarization apparently have not been measured, and may or may not attain levels sufficient to activate cholinergic receptors under physiological circumstances. Much higher concentrations, produced experimentally, are readily shown to activate the receptors in vitro."

"All cells use choline to produce the PC and SM in their membranes. Cholinergic neurons also use choline for an additional purpose, synthesis of their neurotransmitter, ACh. Both the PC and the ACh are ultimately broken down to regenerate free choline, thus both of these compounds can also be considered "reservoirs" for free choline. The synthesis of PC (Figure 18‐4) is initiated by the phosphorylation of choline, catalyzed by an enzyme, CK, which forms phosphocholine by transferring a monophosphate group from ATP to the hydroxyl oxygen of the choline. As described later, this phosphocholine then combines with cytidine‐5'‐triphosphate (CTP) to form cytidine‐5'‐diphosphocholine (CDP‐choline), which, in turn, combines with DAG to yield PC. The synthesis of ACh, catalyzed by the enzyme ChAT, involves a single reaction, the transfer of an acetyl group from acetyl‐CoA, also to the hydroxyl oxygen of the choline. The ACh is then stored, largely within synaptic vesicles, for future release."

"Both CK and ChAT have low affinities for their choline substrate: Their Kms in brain, which describe the choline concentrations at which the enzymes operate at only half‐maximal velocity, may be as high as 2.6 mM (Spanner and Ansell, 1979) and 540 mM (Rossier, 1977), respectively, whereas brain choline levels, as noted earlier, are only about 30–60 mM, and thus well below the concentrations that would probably be needed to enable either enzyme to operate at maximal velocity. Hence, both of the enzymes are highly responsive to treatments that raise or lower brain choline levels."

"Even though brain choline concentrations shared with those of tryptophan the ability to control the rates at which the precursor is of used for neurotransmitter synthesis, the two precursors differed in an important respect: Although tryptophan and choline are both used by certain neurons for two purposes: tryptophan for conversion to serotonin and incorporation into proteins, and choline for conversion to ACh and incorporation into phospholipids, in the case of tryptophan these two processes are segregated into different parts of the neuron—the nerve terminal and perikaryon, respectively—whereas for choline both can take place within the nerve terminal, inasmuch as that structure contains both ChAT and CK. Hence, the acetylation and phosphorylation of choline sometimes compete for available substrate (Farber et al., 1996; Ulus et al., 2006): When cholinergic neurons are forced to fire frequently and to sustain the release of ACh, choline's incorporation into PC decreases (Farber et al., 1996) and the breakdown of membrane PC increases ("autocannibalism"), liberating additional choline for ACh synthesis (Maire and Wurtman, 1985; Blusztajn et al., 1986; Ulus et al., 1989). When the utilization of choline to form PC is increased (by providing supplemental uridine and an omega‐3 fatty acid; see later), ACh synthesis is not diminished, probably because so little choline is used for phosphatide formation compared with the amount used for ACh synthesis (Ulus et al., 2006)."

"ACh is synthesized in cholinergic neurons—principally their terminals—by the ChAT‐mediated acetylation of free choline. Since, as described earlier, ChAT's affinity for choline is low compared with brain choline levels, local choline concentrations normally control the rate of ACh synthesis (Blusztajn and Wurtman, 1983), and treatments which increase brain choline (e.g., administering choline; Cohen and Wurtman, 1975) or PC (Magil et al., 1981), or consuming choline‐rich foods (Cohen and Wurtman, 1976) rapidly cause parallel changes in brain ACh levels; in the amounts of ACh released when neurons fire (Maire and Wurtman, 1985; Jackson et al., 1995); and in postsynaptic ACh‐dependent functions like the control of rat striatal (Ulus and Wurtman, 1976) and adrenomedullary (Ulus et al., 1977a, b, c) tyrosine hydroxylase activities. The affinity of ChAT for its other substrate, acetyl‐CoA—formed from glucose in mitochondria—is substantially greater (Km = 77 mM; Rossier, 1977) than that for choline (Km = 540 mM), however actual acetyl‐CoA concentrations in the vicinity of ChAT may still be insufficient to saturate the enzyme, and thus might also affect the rate of ACh synthesis. In support of this possibility, administration of glucose has been found to stimulate ACh synthesis (Dolezal and Tucek, 1982), and to attenutate the depletion of brain ACh induced by giving a muscarinic antagonist (Ricny et al., 1992). In microdialysis studies, glucose enhanced the rise in ACh output produced by scopolamine (Ragozzino et al., 1994; Ragozzino and Gold, 1995). Systemic administration of glucose also increased hippocampal ACh release (Ragozzino et al., 1996, 1998; Kopf et al., 2001)."

"If choline levels in nerve terminals are reduced pharmacologically by administering a drug, HC3 that blocks the reuptake of free choline from the synapse, the synthesis and release of ACh also decline in parallel (Maire and Wurtman, 1985). Although such experiments confirm the importance of choline availability in controlling ACh synthesis, they do not necessarily allow it to be concluded that high‐affinity choline uptake is the rate‐limiting factor controlling intracellular choline levels or ACh biosynthesis. This synthesis is affected by any process that modifies the neuron’s concentration of free choline, and these levels vary considerably as a function of plasma choline concentrations in addition, possibly, to changes in reuptake efficiency. Moreover, the choline that enters the neuron via high‐affinity uptake apparently is not selectively used for acetylation as opposed to phosphorylation (Kessler and Marchbanks, 1979; Jope and Jenden, 1981). As discussed earlier, it is possible, but not yet clearly demonstrated, that the density or activity of high‐affinity choline uptake sites in presynaptic membranes is affected by phosphorylation, neuronal firing, or the rate at which ACh is being released (Simon and Kuhar, 1975; Ferguson et al., 2003; Gates et al., 2004)."

- Choline and acetylcholine: what a difference an acetate makes!

- Applied Choline-Omics: Lessons from Human Metabolic Studies for the Integration of Genomics Research into Nutrition Practice

- Abnormal liver phosphatidylcholine synthesis revealed in patients with acute respiratory distress syndrome
- Choline intakes exceeding recommendations during human lactation improve breast milk choline content by increasing PEMT pathway metabolites
- P4: PEMT, PCs, PUFAs, and prematurity

- De novo phosphatidylcholine synthesis in intestinal lipid metabolism and disease
- Butyrate Protects Mice Against Methionine–Choline-Deficient Diet-Induced Non-alcoholic Steatohepatitis by Improving Gut Barrier Function, Attenuating Inflammation and Reducing Endotoxin Levels
- Betaine and Choline Improve Lipid Homeostasis in Obesity by Participation in Mitochondrial Oxidative Demethylation

- Effects of Dietary Folate, Vitamin B12 and Methionine/Choline Deficiency on Immune Function

- The Form of Choline in the Maternal Diet Affects Immune Development in Suckled Rat Offspring
- Replacement of choline chloride by a vegetal source of choline in diets for broilers

"Choline is usually added to animal diets in the choline chloride form. However, this source has some disadvantages such as high hygroscopicity, the acceleration of oxidative loss of vitamins in the diet, and the formation of trimethylamine in the gastrointestinal tract of the birds(5). Trimethylamine is a short-chain aliphatic amine that is formed from dietary choline in a reaction catalyzed by enzymes within gut bacteria(6). This metabolite is found in high concentrations in fish, and is responsible for the characteristic odor of seafood(7). However, choline is also present in plants in the phosphatidylcholine form, free choline and sphingomyelin. Currently there are natural products, produced from selected plants, with high content of choline in esterified form and with high bioavailability, which may be an important alternative to the use of synthetic choline chloride. Many researches have shown that these products can replace choline chloride in diets for poultry(8-11)."

 

[FitnessMike]

so how many egg yolks do we recommend "therapeutically" to get rid of excess fat in the liver?

Recently started lower fat and higher carbs and excluded 3 yolks I had too, my pulse is so much lower probably due to high carbs + not enough choline fattened my liver further.

 

[Apple]

so how many egg yolks do we recommend "therapeutically" to get rid of excess fat in the liver?

bump

 

[pubh12]

- Choline deficiency

"Betaine is formed from choline via the intermediate betaine aldehyde. Choline dehydrogenase (EC 1.1.99.1) catalyzes the conversion of choline to betaine aldehyde and uses molecular oxygen as the electron acceptor; this activity also is capable of converting betaine aldehyde to betaine in the presence of NAD.[74] Choline dehydrogenase in mammalian liver and kidney is mitochondrial, located on the matrix side of the inner membrane.[73,75,76] There is another enzyme, betaine aldehyde dehydrogenase (EC 1.2.1.8), which also catalyzes conversion of betaine aldehyde to betaine. This enzyme requires NAD+, and is found in both mitochondria (this mitochondrial enzyme may be identical to choline dehydrogenase) and cytosol.[76] Choline dehydrogenase activity is present in rat liver > kidney > brain > lung and is not detected in muscle.[77] Activities in rat liver and kidney are 100 fold higher than in other organs.[77] Human liver and kidney have activity (kidney 7-fold more than liver) but less than that measured in the rat.[77] In the kidney, choline dehydrogenase activity is located in the inner medulla and proximal tubules.[47] Mitochondria extracted with n-pentane lose choline dehydrogenase activity, which can be restored by addition of ubiquinone[78] or coenzyme Q2.[74] It has been suggested that pyrroloquinoline quinone (PQQ) is the endogenous cofactor.[79,80]"​

Does this mean taking PQQ could lower choline levels by increasing choline dehydrogenase activity ? I’m trying figure out ways to lower it but I’m having trouble interpreting some of this.

 

[AinmAnseo]

I've been having 4 on most days based on that Chris Masterjohn podcast. But now that I look at it, most sources are saying eggs yolks are down closer to 115-140mg of choline, so I'm thinking that may not actually get into the 900-1200mg range he suggests.

Dan,
Have you ever seen reliable data on how many grams of PUFA are in egg yolks?