How genetic variation can alter choline metabolism from a known choline load.
Cornell University, Division of Nutritional Sciences.
Marie Caudill et al.
Common FMO3 polymorph E158G is mentioned.
Unclear how it affects choline metabolism (from the abstract).
This is a new paper by a lab that has some history in Choline research. It gave women certain doses of choline and followed the fate of the choline. They checked how certain genetic variations affected choline metabolism. Most of the genes seem to be to do with choline metabolism, but they also mention the common FMO3 variant E158K.
E158K (rs2266782).
It's estimated perhaps 40% of whites carry the E158K polymorph. The 'textbook' advice currently is that it is 'harmless', except perhaps in tandem with other FMO3 variants. However, some anecdotal stories (such as people having both copies of E158K) puts this in the 'still to be fully documented' category. Certainly it seems 40% of whites do not smell of FMO3 smells, so it would seem that one copy of E158K alone does not mean smelling. And yet it seems it might be a slight weakness in certain situations.
E158K in this paper.
The abstract does not say how E158K affected choline metabolism. A guess would be it made it less efficient at choline metabolism in some way.
My suspicion on FMO3 faults and Choline metabolism.
My current suspicion is that FMO3 faults may make a person prone to being prone to 'TMA-friendly microbes' in the gut, and that the (TMAU) person will BE DEFICIENT IN CHOLINE EVEN BEFORE TRYING THE LOW CHOLINE DIET.
example :
normal person - eats choline - choline absorbed into plasma.
my theory for TMAU person - eats lots of choline - choline is altered to TMA by gut microbes - low levels get in plasma - person is choline deficient despite eating choline.
The only way to prove/disprove a TMAU persons choline status would be a Choline Plasma test.
Overall opinion on this paper :
It's hard to say how relevant it is to TMAU/FMO3 malodor. It could be something 'low-level' important, or not.
From the Paper
3.5. FMO3 (dbSNP: rs2266782; c.472 G > A; p.E158K)
FMO3 is a (largely) hepatic enzyme that converts trimethylamine, a breakdown product of choline produced by anaerobic intestinal microbiota, to trimethylamine N-oxide (TMAO) [36]. The rs2266782 SNP is a common polymorphism that encodes a glutamate to lysine amino acid change (E158K) in flavin monooxygenase isoform 3 (FMO3) [37]. This variant is associated with a relative loss-of-function and, when in cis with other common variants, can cause mild trimethylaminuria (due to a relative excess of trimethylamine), which has largely unknown metabolic consequences [22]. FMO3 is activated by insulin, and knockout in insulin resistant mice prevents hyperglycemia, hyperlipidemia, and atherosclerosis [38]. FMO3 is suppressed by testosterone and up regulated by bile acids, which also stimulate hepatic cholesterol absorption [39].
Differences in TMAO metabolism are known to alter cholesterol transport and influence risk for cardiovascular disease [40,41]. TMAO supplementation in mice has been shown to increase macrophage cholesterol accumulation, which subsequently increases risk for atherosclerosis [41]. More recently, Brown and colleagues identified FMO3 itself (rather than TMAO) as a direct regulator of cholesterol balance, lipid metabolism, and inflammation in mice. FMO3 knockdowns had decreased hepatic cholesterol production, decreased intestinal absorption, and increased hepatic inflammation along with activation of liver X receptor (LXR)-stimulated macrophage reverse cholesterol transport [42]. While a previous study from our group suggested that the variant might be associated with increased use of choline as a methyl donor in men (based on increased DMG pool size) [43], results from the present study, indicate that women with the variant actually use choline less as methyl donor. Variant women tended to have a lower turnover of betaine → methionine over the study period. In addition, variant women exhibited a greater turnover of choline-derived methionine → PEMT-PC over the study period, which is consistent with previous findings from our lab that have identified lower methionine excretion among variant individuals (i.e., a greater use of methionine may reduce excretion) [43]. While it is not clear how these findings relate to data in mice, our results strengthen previous evidence of a relationship between FMO3 and phospholipid metabolism and demonstrate that this SNP exerts an effect on the metabolic use of dietary choline.
Full Paper : Genetic Variation in Choline-Metabolizing Enzymes Alters Choline Metabolism in Young Women ...
3.5. FMO3 (dbSNP: rs2266782; c.472 G > A; p.E158K)
FMO3 is a (largely) hepatic enzyme that converts trimethylamine, a breakdown product of choline produced by anaerobic intestinal microbiota, to trimethylamine N-oxide (TMAO) [36]. The rs2266782 SNP is a common polymorphism that encodes a glutamate to lysine amino acid change (E158K) in flavin monooxygenase isoform 3 (FMO3) [37]. This variant is associated with a relative loss-of-function and, when in cis with other common variants, can cause mild trimethylaminuria (due to a relative excess of trimethylamine), which has largely unknown metabolic consequences [22]. FMO3 is activated by insulin, and knockout in insulin resistant mice prevents hyperglycemia, hyperlipidemia, and atherosclerosis [38]. FMO3 is suppressed by testosterone and up regulated by bile acids, which also stimulate hepatic cholesterol absorption [39].
Differences in TMAO metabolism are known to alter cholesterol transport and influence risk for cardiovascular disease [40,41]. TMAO supplementation in mice has been shown to increase macrophage cholesterol accumulation, which subsequently increases risk for atherosclerosis [41]. More recently, Brown and colleagues identified FMO3 itself (rather than TMAO) as a direct regulator of cholesterol balance, lipid metabolism, and inflammation in mice. FMO3 knockdowns had decreased hepatic cholesterol production, decreased intestinal absorption, and increased hepatic inflammation along with activation of liver X receptor (LXR)-stimulated macrophage reverse cholesterol transport [42]. While a previous study from our group suggested that the variant might be associated with increased use of choline as a methyl donor in men (based on increased DMG pool size) [43], results from the present study, indicate that women with the variant actually use choline less as methyl donor. Variant women tended to have a lower turnover of betaine → methionine over the study period. In addition, variant women exhibited a greater turnover of choline-derived methionine → PEMT-PC over the study period, which is consistent with previous findings from our lab that have identified lower methionine excretion among variant individuals (i.e., a greater use of methionine may reduce excretion) [43]. While it is not clear how these findings relate to data in mice, our results strengthen previous evidence of a relationship between FMO3 and phospholipid metabolism and demonstrate that this SNP exerts an effect on the metabolic use of dietary choline.
Full Paper : Genetic Variation in Choline-Metabolizing Enzymes Alters Choline Metabolism in Young Women ...
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