Upregulation of flavin-containing monooxygenase 3 mimics calorie restriction to retard liver aging by inducing autophagy

Guo, Donghao; Shen, Yun; Li, Wei; Li, Qinjie; Miao, Ya; Zhong, Yuan

doi:10.18632/aging.102666

Cited by 19 publications

(19 citation statements)

References 42 publications

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“…Thus, rapid conversion to TMAO will occur in a substrate-dependent manner in healthy individuals (TMA about 20-25 μM) (51) . There is evidence that hepatic FMO3 expression or activity is sensitive to sex steroids (28,138,139) , dietary factors (140) and energy intake (141,142) , NO signalling (143) and the transcriptional regulator CCAAT/ enhancer-binding protein β (144) . Hepatic FMO3 expression also increases postnatally in humans, with an apparent plateau after early adulthood (145,146) .…”

Section: Hepatic Flavin-containing Mono-oxygenasementioning

confidence: 99%

“…Conversely, in female mice hepatic FMO3 transcript may decline following this phase of maturational up-regulation (147) . While there is some debate regarding hepatic FMO expression in male rodents, an ageing-dependent increase in FMO3 protein is reported in male mice (44,141,142) . Sex is a particularly strong determinant of FMO3 expression patterns, a linkage not strictly consistent with involvement of TMAO in CVD risk: hepatic FMO3 is substantially higher in female v. male mice and human subjects (28) , paralleled by dimorphism in TMAO concentrations in mice (8,28,40) and to a lesser extent humans (148) , yet females enjoy protection against CVD over much of the lifespan.…”

Section: Hepatic Flavin-containing Mono-oxygenasementioning

confidence: 99%

“…Pregnancy further up-regulates FMO3 (149) , and trimethylaminuria (a disorder in which TMA conversion to TMAO is impaired, leading to odour in sweat, urine and breath from rising TMA) is also exacerbated in women during menstruation (149) . Circadian patterns of FMO3 expression may also differ markedly between sexes, a dimorphism reduced by cardioprotective energy restriction which up-regulates FMO3 in males, 'feminising' the transcriptional profile (141,142) . However, there remains some debate regarding hepatic expression of FMO3 in male mice: there is evidence that FMO3 mRNA is below detection limits (147) or detectable at 0•1-10 % of the levels in females (141,142) ; and that FMO3 protein is not detectable in males (9,28) , or lowly expressed and augmented with adenoviral delivery, energy restriction or ageing (44,141,142) .…”

Section: Hepatic Flavin-containing Mono-oxygenasementioning

confidence: 99%

“…These observations raise questions regarding the utility of male murine models in assessing the role of FMO3 and TMAO in human disease. Expression of FMO3 is modified by chronic disease and CVD risk factors, including renal dysfunction and disease (150) , inflammation (151) , insulin resistance and diabetes (2,14,54,55) , ageing (44,141,142) , pollutants and hepatic toxins (152) . Elevations in TMAO itself may up-regulate FMO3 expression, with evidence of up to 5-fold induction in male mice supplemented with TMAO (40) .…”

Section: Hepatic Flavin-containing Mono-oxygenasementioning

confidence: 99%

“…Metabolic effects of FMO3 manipulation in LDL receptor knockout mice are TMA/TMAO independent (28,159) . Furthermore, while FMO3-dependent elevations in TMAO are suggested to promote tissue ageing (8,40,43) , and FMO3 expression may rise with age (44) , recent evidence indicates that increased FMO3 expression is protective, exerting anti-ageing effects that mimic those of energy restriction (142) . Thus, not only does FMO3 exert beneficial effects, but linkages between FMO3 and disease do not necessarily reflect a role for TMAO.…”

Section: Hepatic Flavin-containing Mono-oxygenasementioning

confidence: 99%

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TrimethylamineN-oxide: heart of the microbiota–CVD nexus?

et al. 2020

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We critically review potential involvement of trimethylamine-N-oxide (TMAO) as a link between diet, the gut microbiota and cardiovascular disease (CVD). Generated primarily from dietary choline and carnitine by gut bacteria and hepatic flavin monooxygenase (FMO) activity, TMAO could promote cardiometabolic disease when chronically elevated. 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. The basis of elevations with obesity, diabetes, atherosclerosis or coronary heart disease (CHD) is similarly ill-defined, although gut microbiota profiles/remodelling appear critical. Elevated TMAO could promote CVD via inflammation, oxidative stress, scavenger receptor (SR) up-regulation, reverse cholesterol transport (RCT) inhibition, and cardiovascular dysfunction. 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. There is also evidence CVD risk is insensitive to TMAO variance beyond these levels in omnivores and vegetarians, and that major TMAO sources are cardioprotective. Assessing available evidence suggests modest elevations in TMAO (≤10 µM) are a non-pathogenic consequence of diverse risk factors (aging, obesity, dyslipidaemia, insulin-resistance/diabetes, renal dysfunction), indirectly reflecting CVD risk without participating mechanistically. 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.

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Section: Hepatic Flavin-containing Mono-oxygenasementioning

confidence: 99%

Section: Hepatic Flavin-containing Mono-oxygenasementioning

confidence: 99%

Section: Hepatic Flavin-containing Mono-oxygenasementioning

confidence: 99%

Section: Hepatic Flavin-containing Mono-oxygenasementioning

confidence: 99%

Section: Hepatic Flavin-containing Mono-oxygenasementioning

confidence: 99%

See 3 more Smart Citations

TrimethylamineN-oxide: heart of the microbiota–CVD nexus?

et al. 2020

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Flavin‐containing monooxygenase (FMO): Beyond xenobiotics

Bhat,

Carranza,

Tuckowski

et al. 2024

BioEssays

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Flavin‐containing monooxygenases (FMOs), traditionally known for detoxifying xenobiotics, are now recognized for their involvement in endogenous metabolism. We recently discovered that an isoform of FMO, fmo‐2 in Caenorhabditis elegans, alters endogenous metabolism to impact longevity and stress tolerance. Increased expression of fmo‐2 in C. elegans modifies the flux through the key pathway known as One Carbon Metabolism (OCM). This modified flux results in a decrease in the ratio of S‐adenosyl‐methionine (SAM) to S‐adenosyl‐homocysteine (SAH), consequently diminishing methylation capacity. Here we discuss how FMO‐2‐mediated formate production during tryptophan metabolism may serve as a trigger for changing the flux in OCM. We suggest formate bridges tryptophan and OCM, altering metabolic flux away from methylation during fmo‐2 overexpression. Additionally, we highlight how these metabolic results intersect with the mTOR and AMPK pathways, in addition to mitochondrial metabolism. In conclusion, the goal of this essay is to bring attention to the central role of FMO enzymes but lack of understanding of their mechanisms. We justify a call for a deeper understanding of FMO enzyme's role in metabolic rewiring through tryptophan/formate or other yet unidentified substrates. Additionally, we emphasize the identification of novel drugs and microbes to induce FMO activity and extend lifespan.

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TFEB ameliorates DEHP‐induced neurotoxicity by activating GAL3/TRIM16 axis dependent lysophagy and alleviating lysosomal dysfunction

Xing,

Xu,

et al. 2024

Environmental Toxicology

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Di‐(2‐ethylhexyl) phthalate (DEHP) is a commonly used plasticizer with known neurotoxic effects. However, the specific mechanism underlying this neurotoxicity remains unclear. This study aimed to investigate the role of lysosomal function and lysophagy in DEHP‐induced neurotoxicity, with a particular focus on the regulatory role of Transcription factor EB (TFEB). To achieve this, we utilized in vitro models of DEHP‐exposed SH‐SY5Y cells and HT22 cells. Our findings revealed that DEHP exposure led to lysosomal damage and dysfunction. Moreover, we observed impaired autophagic degradation, characterized by elevated levels of LC3II and p62. DEHP treatment downregulated the expression of TFEB, GAL3, and TRIM16, while upregulating the expression of PARP. This led to the inhibition of GAL3/TRIM16 axis dependent lysophagy and ultimately excessive apoptosis in neuronal cells. Importantly, TFEB overexpression alleviated lysosomal dysfunction, activated lysophagy, and mitigated DEHP‐induced apoptosis. Overall, our results suggest that DEHP induces not only lysosomal dysfunction, but also inhibits lysophagy through the suppression of GAL3/TRIM16 axis. Consequently, impaired clearance of damaged lysosomes occurs, culminating in neuronal apoptosis. Taken together, our findings highlight the critical role of TFEB in regulating lysophagy and lysosomal function. Furthermore, TFEB may serve as a potential therapeutic target for mitigating DEHP‐induced neuronal toxicity.

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Upregulation of flavin-containing monooxygenase 3 mimics calorie restriction to retard liver aging by inducing autophagy

Cited by 19 publications

References 42 publications

TrimethylamineN-oxide: heart of the microbiota–CVD nexus?

TrimethylamineN-oxide: heart of the microbiota–CVD nexus?

Flavin‐containing monooxygenase (FMO): Beyond xenobiotics

TFEB ameliorates DEHP‐induced neurotoxicity by activating GAL3/TRIM16 axis dependent lysophagy and alleviating lysosomal dysfunction

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