Trimethylamine N-oxide levels are associated with NASH in obese subjects with type 2 diabetes

León-Mimila, Paola; Villamil‐Ramírez, Hugo; Li, Xinmin S.; Shih, Diana M.; Hui, Simon T.; Ocampo-Medina, Elvira; López-Contreras, Blanca E.; Morán-Ramos, Sofía; Olivares-Arevalo, Marisol; Grandini-Rosales, Paula; Macías-Kauffer, Luis; González-González, Israel; Hernández-Pando, Rogelio; Gómez-Pérez, Francisco J.; Campos-Pérez, Francisco; Aguilar-Salinas, Carlos A.; Larrieta‐Carrasco, Elena; Villarreal‐Molina, Teresa; Wang, Zeneng; Lusis, Aldons J.; Hazen, Stanley L.; Huertas‐Vazquez, Adriana; Canizales‐Quinteros, Samuel

doi:10.1016/j.diabet.2020.07.010

Cited by 66 publications

(51 citation statements)

References 60 publications

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“…The Nox4 allele from the CAST strain contained a number of SNPs divergent from B6, and this difference is consistent with strain effects identified in liver Nox4 transcript and TMAO. More interestingly, Nox4 was revealed to be one of the genes that showed the highest correlation with liver TG among the genes identified in the magenta module, which is consistent with previous studies that demonstrated the association between Nox4 and fatty liver in the mouse and humans (67,84,85,99). Both NOX4 and TMAO induce protein kinase R (PKR)/PKR-like endoplasmic reticulum kinase (PERK) activation (99,100), leading to propagation of endoplasmic reticulum (ER) stress, which may contribute to the pathogenesis of fatty liver and MetSyn.…”

Section: Discussionsupporting

confidence: 90%

“…NOX4 is a hydrogen peroxide NADPH oxidase isoform and major producers of reactive oxidative species by transferring electrons from NADPH to molecular oxygen. NOX4 is found in various cardiovascular cells and tissues, which is involved in conditions related to MetSyn such as atherosclerosis (81, 82), hypertension (83), fatty liver (84,85), insulin resistance (86), obesity (87), and kidney injury (88). Similar to NOX4, FMOs catalyze the NADPH-dependent oxidative metabolism of a variety of foreign chemicals, including dietary compounds, drugs, and environmental pollutants (89).…”

Section: Discussionmentioning

confidence: 99%

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Hepatic transcriptional profile reveals the role of diet and genetic backgrounds on metabolic traits in female progenitor strains of the Collaborative Cross

Kim

Huda

O’Connor

et al. 2021

Physiological Genomics

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Mice have provided critical mechanistic understandings of clinical traits underlying Metabolic Syndrome (MetSyn) and susceptibility to MetSyn in mice is known to vary among inbred strains. We investigated the diet- and strain-dependent effects on metabolic traits in the eight Collaborative Cross (CC) founder strains (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Liver transcriptomics analysis showed that both atherogenic diet and host genetics have profound effects on the liver transcriptome, which may be related to differences in metabolic traits observed between strains. We found strain differences in circulating trimethylamine N-Oxide (TMAO) concentration and liver triglyceride content, both of which are traits associated with metabolic diseases. Using a network approach, we identified a module of transcripts associated with TMAO and liver triglyceride content which was enriched in functional pathways. Interrogation of the module related to metabolic traits identified NADPH oxidase 4 (Nox4), a gene for a key enzyme in the production of reactive oxygen species, which showed a strong association with plasma TMAO and liver triglyceride. Interestingly, Nox4 was identified as the highest expressed in the C57BL/6J and NZO/HILtJ strains and the lowest expressed in the CAST/EiJ strain. Based on these results, we suggest that there may be genetic variation in the contribution of Nox4 to the regulation of plasma TMAO and liver triglyceride content. In summary, we show that liver transcriptomic analysis identified diet- or strain-specific pathways for metabolic traits in the Collaborative Cross (CC) founder strains.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Hepatic transcriptional profile reveals the role of diet and genetic backgrounds on metabolic traits in female progenitor strains of the Collaborative Cross

Kim

Huda

O’Connor

et al. 2021

Physiological Genomics

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“… 26 , 27 A high TMAO concentration was linked to several psoriasis comorbidities, i.e. obesity, 28 hypertension, 29 metabolic syndrome, 30 nonalcoholic fatty liver disease 31 and insulin resistance. 32 Before our study was conducted, TMAO levels had not been assessed in psoriasis, although its concentration correlates significantly with skin and joint involvement in patients with psoriatic arthritis.…”

Section: Discussionmentioning

confidence: 99%

Clinical Implications of Intestinal Barrier Damage in Psoriasis

Sikora¹,

Stec²,

Chrabąszcz³

et al. 2021

JIR

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Background An increasing amount of evidence suggests an association between increased intestinal permeability and the pathogenesis of chronic inflammatory diseases. However, the clinical significance of gut barrier dysfunction in psoriasis remains to be established. Objective To evaluate whether there are differences in disease activity, the severity of gastrointestinal symptoms and the blood concentration of bacterial metabolites in psoriatic patients with a normal and altered intestinal barrier. Patients and Methods Gut barrier integrity was assessed with the serum concentrations of claudin-3, a modulator of intestinal tight junctions and an intestinal fatty acid-binding protein, a marker of enterocyte damage. Gastrointestinal symptoms were evaluated with a validated questionnaire. The concentration of trimethylamine N-oxide (TMAO), a gut microbiota-associated metabolite, was measured with high-performance liquid chromatography. Results One hundred and fourteen patients with psoriasis were finally enrolled in the study – 68 with an altered gut barrier and 46 with a properly functioning intestinal barrier. Patients with an altered gut barrier showed a significantly higher score in the Gastrointestinal Symptom Rating Scale (3.20 vs 1.46, p<0.001). Moreover, patients with psoriasis and a disrupted intestinal barrier demonstrated a higher disease activity (PASI: 19.7 vs 10.3, p<0.001) and systemic inflammatory parameters (neutrophil-to-lymphocyte ratio: 2.86 vs 1.71, p<0.001; C-reactive protein 3.76 vs 1.92; p<0.05). The marker of bacterial translocation was significantly higher in psoriatic patients with damaged gut integrity (TMAO: 375.7±51.9 vs 119.4±27.5 ng/mL; p<0.05). Conclusion The altered gut barrier in psoriasis is associated with gastrointestinal symptoms, systemic inflammatory profile and the increased blood concentration of gut microbiota-derived metabolite – TMAO. Intestinal barrier modulation represents a new promising therapeutic approach.

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“…Its precursor trimethyllysine predicts near‐ and long‐term CV events in patients with chest pain and acute coronary syndrome 168 . Conversely, although few studies have described changes in circulating levels of TMAO in NAFLD, it seems that TMAO associates with the severity of disease 169 particularly in obese T2D patients with NASH 170 …”

Section: Nafld and Risk Of Cardiovascular Diseasesmentioning

confidence: 99%

Nonalcoholic fatty liver disease or metabolic dysfunction‐associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches

Dongiovanni

Paolini

Corsini

et al. 2021

Eur J Clin Investigation

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Background A consensus of experts has proposed to replace the term nonalcoholic fatty liver disease (NAFLD), whose global prevalence is 25%, with metabolic dysfunction‐associated fatty liver disease (MAFLD), to describe more appropriately the liver disease related to metabolic derangements. MAFLD is closely intertwined with type 2 diabetes, obesity, dyslipidaemia, all linked to a rise in the risk of cardiovascular disease (CVDs). Since controversy still stands on whether or not NAFLD/MAFLD raises the odds of CVD, the present review aims to evaluate the impact of NAFLD/MAFLD aetiologies on CV health and the potential correction by dietary and drug approaches. Results Epidemiological studies indicate that NAFLD raises risk of fatal or non‐fatal CVD events. NAFLD patients have a higher prevalence of arterial plaques and stiffness, coronary calcification, and endothelial dysfunction. Although genetic and environmental factors strongly contribute to NAFLD pathogenesis, a Mendelian randomization analysis indicated that the PNPLA3 genetic variant leading to NAFLD may not be causally associated with CVD risk. Among other genetic variants related to NAFLD, TM6SF2 appears to be protective, whereas MBOAT7 may favour venous thromboembolism. Conclusions NAFLD is correlated to a higher CVD risk which may be ameliorated by dietary interventions. This is not surprising, since new criteria defining MAFLD include other metabolic risk abnormalities fuelling development of serious adverse extrahepatic outcomes, for example CVD. The present lack of a targeted pharmacological approach makes the identification of patients with liver disease at higher CVD risk (eg diabetes, hypertension, obesity or high levels of C‐reactive protein) of major clinical interest.

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Trimethylamine N-oxide levels are associated with NASH in obese subjects with type 2 diabetes

Cited by 66 publications

References 60 publications

Hepatic transcriptional profile reveals the role of diet and genetic backgrounds on metabolic traits in female progenitor strains of the Collaborative Cross

Hepatic transcriptional profile reveals the role of diet and genetic backgrounds on metabolic traits in female progenitor strains of the Collaborative Cross

Clinical Implications of Intestinal Barrier Damage in Psoriasis

Nonalcoholic fatty liver disease or metabolic dysfunction‐associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches

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