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The Importance of the Fatty Acid Transporter L-Carnitine in (NAFLD)
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<blockquote data-quote="madman" data-source="post: 183519" data-attributes="member: 13851"><p><strong>Trimethylamine-N-Oxide: <span style="color: rgb(184, 49, 47)">Heart of the microbiotacardiovascular disease nexus? </span></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>ABSTRACT </strong></p><p></p><p><span style="color: rgb(184, 49, 47)"><em>We critically review the potential involvement of trimethylamine-N-oxide (TMAO) as a link between diet, gut microbiota, and cardiovascular disease (CVD).</em> <em>Generated primarily from dietary choline and carnitine by gut bacteria and hepatic flavin monooxygenase (FMO) activity, TMAO could promote cardiometabolic disease when chronically elevated.<u> However, control of circulating TMAO is poorly understood, and diet, age, body mass, sex hormones, renal clearance, FMO3 expression, and genetic background may explain as little as 25% of TMAO variance</u>.</em></span> The basis of elevations with obesity, diabetes, atherosclerosis, or coronary heart disease (CHD) is similarly ill-defined, although gut microbiota profiles/remodeling appear critical. <span style="color: rgb(184, 49, 47)">Elevated TMAO could promote CVD via inflammation, oxidative stress, scavenger receptor (SR) up-regulation, reverse cholesterol transport (RCT) inhibition, and cardiovascular dysfunction. <u>However, concentrations influencing inflammation, SRs and RCT (≥100 µM) are only achieved in advanced heart failure (HF) or chronic kidney disease (CKD), and greatly exceed pathogenicity of <1-5 µM levels implied in some TMAO-CVD associations</u>. </span><span style="color: rgb(44, 130, 201)">T<em>here is also evidence CVD risk is insensitive to TMAO variance beyond these levels in omnivores and vegetarians, and that <u>major TMAO sources are cardioprotective</u>. </em></span><em><span style="color: rgb(44, 130, 201)">Assessing available evidence suggests modest elevations in TMAO (≤10 µM) are a non-pathogenic consequence of diverse risk factors (aging, obesity, dyslipidemia, insulin-resistance/diabetes, renal dysfunction), indirectly reflecting CVD risk without participating mechanistically.</span></em> Nonetheless, TMAO may surpass a pathogenic threshold as a consequence of CVD/CKD, secondarily promoting disease progression. TMAO might thus reflect early CVD risk while providing a prognostic biomarker or secondary target in established disease, although mechanistic contributions to CVD await confirmation.</p><p></p><p></p><p><strong>Carnitine.</strong></p><p></p><p>L-Carnitine is produced from lysine in eukaryotes and is catabolized by prokaryotic organisms [108], the latter begin able to yield TMA and malic semialdehyde via cleavage of the backbone carbon-nitrogen bond of carnitine [109]. Carnitine is an essential component of fatty acid metabolism, transporting activated long-chain fatty acyl groups into the mitochondrial matrix [110]. Similar to choline, carnitine uptake from the human small intestine is not well defined and deserves further study. <em><span style="color: rgb(184, 49, 47)">Mucosal carnitine uptake appears saturated with 2 g orally administered l-carnitine [111]. Saturation is also reported with 3 x 1 g doses of carnitine, <u>significantly elevating plasma TMAO [112], although baseline concentrations of ~35 µM in this study are over an order of magnitude higher than widely reported [59]</u>.</span></em> Consumption of ~225 g of sirloin steak (~180 mg of carnitine) transiently increases plasma TMAO concentration [20]. Prolonged daily supplementation of L-carnitine (1 g/day over more than 1 year) has been shown to increase median plasma TMAO by ~12-fold in a cohort of 9 patients with mitochondrial disorders [113]. The gut microbiota may also be able to produce γbutryobetaine from l-carnitine metabolism [108], a metabolite that bacteria can subsequently convert to TMA [95].<em><span style="color: rgb(184, 49, 47)"> Collective evidence indicates that high and chronic dietary loads of carnitine are required to elevate TMAO towards pathological concentrations (>10 µM) in the long-term. Again, this may reflect substrate-driven remodeling of the gut microbiota, favoring TMAO generation (see below). </span></em><span style="color: rgb(44, 130, 201)"><em>Importantly, while carnitine intake increases TMAO concentrations, i<u>t reduces the risk of CVD and metabolic disorders [114], protecting against diabetes [115] and metabolic syndrome [116]. Meta-analysis indicates carnitine reduces all-cause mortality, ventricular arrhythmias, and angina symptoms in infarct patients [117]</u>. </em></span>As for choline and seafood, the proposed pathogenic role of TMAO awaits reconciliation with these observations.</p><p></p><p></p><p><strong>CONCLUSIONS AND FUTURE DIRECTIONS </strong></p><p></p><p>Cardiovascular disease remains the leading cause of morbidity and mortality globally, placing an enormous burden on health systems, economies, and individuals directly and indirectly affected. <em><span style="color: rgb(184, 49, 47)">A proposed role for the microbiota-dependent amine TMAO as a new and modifiable determinant of CVD has thus generated much excitement. <u>However, much remains to be clarified regarding the control of TMAO concentrations and their potential involvement in disease</u>.</span></em> <em><span style="color: rgb(184, 49, 47)">Variations in human TMAO concentrations remain largely unexplained, and whether pathologically relevant elevations arise independently of other disorders is unclear. </span></em><span style="color: rgb(44, 130, 201)"><em><u>Although increased concentrations of TMAO can promote inflammation, atherosclerosis, vascular and cardiac dysfunction, and remodeling, levels inducing these effects may only be achieved in HF or CKD, or potentially CHD with comorbid conditions (or AMI)</u>. In these select settings, TMAO could play a secondary reinforcing role (Figures 2 and 4), though even this mechanistic contribution awaits confirmation.<u> A mechanistic role for TMAO in the development of CVD also requires reconciliation with the protective effects of its dietary precursors (particularly seafood and carnitine) and the low CVD risk associated with red meat intake</u>. </em></span>Future studies should more directly test the mechanistic relevance of TMAO in CVD, clarify the effects of chronic low-grade changes in TMAO, and test whether speculative positive feedbacks (as outlined in Figure 2) might lead to progressive elevations in TMAO and dysfunction in CVD. This model is untested, though informed by the knowledge that putative effects of TMAO (e.g. inflammation, renal dysfunction, and hypoperfusion) can further enhance TMAO accumulation and observations that TMAO and renal dysfunction may up-regulate FMO3 [40], for example. Importantly, even a secondary reinforcing role supports both the utility of TMAO as a biomarker of CVD risk and as a therapeutic target in high-risk subjects with multiple comorbidities or extant CVD. <span style="color: rgb(184, 49, 47)"><em><u>How to specifically reduce TMAO without potentially detrimental effects nonetheless poses a challenge. Enhanced understanding of the specific roles of bacteria in governing TMAO concentrations and how they respond to dietary modulation, together with factors influencing FMO3 activity and other determinants of TMAO concentration is necessary before potential benefits of TMAO manipulation might be realized in select disease settings</u>. </em></span></p></blockquote><p></p>
[QUOTE="madman, post: 183519, member: 13851"] [B]Trimethylamine-N-Oxide: [COLOR=rgb(184, 49, 47)]Heart of the microbiotacardiovascular disease nexus? [/COLOR] ABSTRACT [/B] [COLOR=rgb(184, 49, 47)][I]We critically review the potential involvement of trimethylamine-N-oxide (TMAO) as a link between diet, gut microbiota, and cardiovascular disease (CVD).[/I] [I]Generated primarily from dietary choline and carnitine by gut bacteria and hepatic flavin monooxygenase (FMO) activity, TMAO could promote cardiometabolic disease when chronically elevated.[U] However, control of circulating TMAO is poorly understood, and diet, age, body mass, sex hormones, renal clearance, FMO3 expression, and genetic background may explain as little as 25% of TMAO variance[/U].[/I][/COLOR] The basis of elevations with obesity, diabetes, atherosclerosis, or coronary heart disease (CHD) is similarly ill-defined, although gut microbiota profiles/remodeling appear critical. [COLOR=rgb(184, 49, 47)]Elevated TMAO could promote CVD via inflammation, oxidative stress, scavenger receptor (SR) up-regulation, reverse cholesterol transport (RCT) inhibition, and cardiovascular dysfunction. [U]However, concentrations influencing inflammation, SRs and RCT (≥100 µM) are only achieved in advanced heart failure (HF) or chronic kidney disease (CKD), and greatly exceed pathogenicity of <1-5 µM levels implied in some TMAO-CVD associations[/U]. [/COLOR][COLOR=rgb(44, 130, 201)]T[I]here is also evidence CVD risk is insensitive to TMAO variance beyond these levels in omnivores and vegetarians, and that [U]major TMAO sources are cardioprotective[/U]. [/I][/COLOR][I][COLOR=rgb(44, 130, 201)]Assessing available evidence suggests modest elevations in TMAO (≤10 µM) are a non-pathogenic consequence of diverse risk factors (aging, obesity, dyslipidemia, insulin-resistance/diabetes, renal dysfunction), indirectly reflecting CVD risk without participating mechanistically.[/COLOR][/I] Nonetheless, TMAO may surpass a pathogenic threshold as a consequence of CVD/CKD, secondarily promoting disease progression. TMAO might thus reflect early CVD risk while providing a prognostic biomarker or secondary target in established disease, although mechanistic contributions to CVD await confirmation. [B]Carnitine.[/B] L-Carnitine is produced from lysine in eukaryotes and is catabolized by prokaryotic organisms [108], the latter begin able to yield TMA and malic semialdehyde via cleavage of the backbone carbon-nitrogen bond of carnitine [109]. Carnitine is an essential component of fatty acid metabolism, transporting activated long-chain fatty acyl groups into the mitochondrial matrix [110]. Similar to choline, carnitine uptake from the human small intestine is not well defined and deserves further study. [I][COLOR=rgb(184, 49, 47)]Mucosal carnitine uptake appears saturated with 2 g orally administered l-carnitine [111]. Saturation is also reported with 3 x 1 g doses of carnitine, [U]significantly elevating plasma TMAO [112], although baseline concentrations of ~35 µM in this study are over an order of magnitude higher than widely reported [59][/U].[/COLOR][/I] Consumption of ~225 g of sirloin steak (~180 mg of carnitine) transiently increases plasma TMAO concentration [20]. Prolonged daily supplementation of L-carnitine (1 g/day over more than 1 year) has been shown to increase median plasma TMAO by ~12-fold in a cohort of 9 patients with mitochondrial disorders [113]. The gut microbiota may also be able to produce γbutryobetaine from l-carnitine metabolism [108], a metabolite that bacteria can subsequently convert to TMA [95].[I][COLOR=rgb(184, 49, 47)] Collective evidence indicates that high and chronic dietary loads of carnitine are required to elevate TMAO towards pathological concentrations (>10 µM) in the long-term. Again, this may reflect substrate-driven remodeling of the gut microbiota, favoring TMAO generation (see below). [/COLOR][/I][COLOR=rgb(44, 130, 201)][I]Importantly, while carnitine intake increases TMAO concentrations, i[U]t reduces the risk of CVD and metabolic disorders [114], protecting against diabetes [115] and metabolic syndrome [116]. Meta-analysis indicates carnitine reduces all-cause mortality, ventricular arrhythmias, and angina symptoms in infarct patients [117][/U]. [/I][/COLOR]As for choline and seafood, the proposed pathogenic role of TMAO awaits reconciliation with these observations. [B]CONCLUSIONS AND FUTURE DIRECTIONS [/B] Cardiovascular disease remains the leading cause of morbidity and mortality globally, placing an enormous burden on health systems, economies, and individuals directly and indirectly affected. [I][COLOR=rgb(184, 49, 47)]A proposed role for the microbiota-dependent amine TMAO as a new and modifiable determinant of CVD has thus generated much excitement. [U]However, much remains to be clarified regarding the control of TMAO concentrations and their potential involvement in disease[/U].[/COLOR][/I] [I][COLOR=rgb(184, 49, 47)]Variations in human TMAO concentrations remain largely unexplained, and whether pathologically relevant elevations arise independently of other disorders is unclear. [/COLOR][/I][COLOR=rgb(44, 130, 201)][I][U]Although increased concentrations of TMAO can promote inflammation, atherosclerosis, vascular and cardiac dysfunction, and remodeling, levels inducing these effects may only be achieved in HF or CKD, or potentially CHD with comorbid conditions (or AMI)[/U]. In these select settings, TMAO could play a secondary reinforcing role (Figures 2 and 4), though even this mechanistic contribution awaits confirmation.[U] A mechanistic role for TMAO in the development of CVD also requires reconciliation with the protective effects of its dietary precursors (particularly seafood and carnitine) and the low CVD risk associated with red meat intake[/U]. [/I][/COLOR]Future studies should more directly test the mechanistic relevance of TMAO in CVD, clarify the effects of chronic low-grade changes in TMAO, and test whether speculative positive feedbacks (as outlined in Figure 2) might lead to progressive elevations in TMAO and dysfunction in CVD. This model is untested, though informed by the knowledge that putative effects of TMAO (e.g. inflammation, renal dysfunction, and hypoperfusion) can further enhance TMAO accumulation and observations that TMAO and renal dysfunction may up-regulate FMO3 [40], for example. Importantly, even a secondary reinforcing role supports both the utility of TMAO as a biomarker of CVD risk and as a therapeutic target in high-risk subjects with multiple comorbidities or extant CVD. [COLOR=rgb(184, 49, 47)][I][U]How to specifically reduce TMAO without potentially detrimental effects nonetheless poses a challenge. Enhanced understanding of the specific roles of bacteria in governing TMAO concentrations and how they respond to dietary modulation, together with factors influencing FMO3 activity and other determinants of TMAO concentration is necessary before potential benefits of TMAO manipulation might be realized in select disease settings[/U]. [/I][/COLOR] [/QUOTE]
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The Importance of the Fatty Acid Transporter L-Carnitine in (NAFLD)
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