Current insights into the interplay between gut microbiota-derived metabolites and metabolic-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent and challenging disease associated with a significant health and economic burden. MAFLD has been subjected to and widely investigated in many studies; however, the underlying pathogenesis and its progression have yet to understand fully. Furthermore, precise biomarkers for diagnosing and specific drugs for treatment are yet to be discovered. Increasing evidence has proven gut microbiota as the neglected endocrine organ that regulates homeostasis and immune response. Targeting gut microbiota is an essential strategy for metabolic diseases, including MAFLD. Gut microbiota in the gut-liver axis is connected through tight bidirectional links through the biliary tract, portal vein, and systemic circulation, producing gut microbiota metabolites. This review focuses on the specific correlation between gut microbiota metabolites and MAFLD. Gut microbiota metabolites are biologically active in the host and, through subsequent changes and biological activities, provide implications for MAFLD. Based on the review studies, gut-liver axis related-metabolites including short-chain fatty acids, bile acids (BAs), lipopolysaccharide, choline and its metabolites, indole and its derivates, branched-chain amino acids, and methionine cycle derivates was associated with MAFLD and could be promising MAFLD diagnosis biomarkers, as well as the targets for MAFLD new drug discovery.

Determination of Major Endogenous FAHFAs in Healthy Human Circulation: The Correlations with Several Circulating Cardiovascular-Related Biomarkers and Anti-Inflammatory Effects on RAW 264.7 Cells.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are newly discovered long-chain fatty acids. However, the major endogenous FAHFAs in healthy human circulation, their correlation with cardiovascular (CV) biomarkers, and their anti-inflammatory effects have not been investigated and remain unclear. In the present study, a total of 57 healthy subjects were recruited. Liquid chromatography-mass spectrometry (LC-MS) was developed for the simultaneous determination of seven FAHFAs, four long-chain fatty acids, and four non-traditional circulating CV-related biomarkers. We found two major types of FAHFAs in healthy human circulation, palmitoleic acid ester of 9-hydroxystearic acid (9-POHSA), and oleic acid ester of 9-hydroxystearic acid (9-OAHSA). Both 9-POHSA and 9-OAHSA had a strong positive correlation with each other and were negatively correlated with fasting blood glucose, S-adenosyl-l-homocysteine (SAH), and trimethylamine N-oxide (TMAO), but not with l-homocysteine. 9-POHSA was also positively correlated with l-carnitine. Moreover, we confirmed that both 9-POHSA and 9-OAHSA exhibited an anti-inflammatory effect by suppressing LPS stimulated cytokines, including IL-1ß and IL-6 in RAW 264.7 cells. In addition, palmitoleic acid also had a positive correlation with 9-POHSA and 9-OAHSA. As far as we know, this is the first report showing the major endogenous FAHFAs in healthy subjects and their CV protection potential which might be correlated with SAH and TMAO reduction, l-Carnitine elevation, and their anti-inflammatory effects.

Serum indoxyl sulfate as a potential biomarker of aortic arterial stiffness in coronary artery disease.

BACKGROUND AND AIMS: Indoxyl sulfate (IS), a dietary tryptophan metabolite, acts as a cardiotoxin and uremic toxin. High IS levels are associated with chronic kidney disease and cardiovascular diseases. This study investigated the association between serum IS levels and aortic arterial stiffness (AAS) in coronary artery disease (CAD) patients. METHODS AND RESULTS: The carotid-femoral pulse wave velocity (cfPWV) was measured by the SphygmoCor system and patients with values of >10 m/s were classified in the AAS group. The baseline characteristics were recorded and measured (including biochemical and clinical data). Serum IS levels were determined using liquid chromatography-mass spectrometry. AAS occurred in 50 (34.7%) of 144 patients with CAD. They were older, had higher IS levels and percentages of diabetes, systolic blood pressure, blood urea nitrogen, and creatinine but lower estimated glomerular filtration rates. The IS level and older age significantly correlated with AAS [odds ratio (OR) = 3.834, p = 0.031; OR = 1.095, p = 0.002, respectively]. Furthermore, the serum IS level (ß = 0.167, adjusted R2 change: 0.026, p = 0.027) had a significant positive correlation with cfPWV. CONCLUSIONS: Taken together, higher serum IS levels are potential independent biomarkers for AAS in patients with CAD. Therefore, early checking of serum IS levels may help prevent CAD progression and have clinical implications in the near future.

Anti-Proliferative Effect of Statins Is Mediated by DNMT1 Inhibition and p21 Expression in OSCC Cells.

Statins, also known as HMG-CoA reductase inhibitors, are a class of cholesterol-lowering drugs and their anti-cancer effects have been studied in different types of malignant diseases. In the present study, we investigated the anti-proliferative effects of statins, including cerivastatin and simvastatin, on oral squamous cell carcinoma (OSCC) cells. Our data showed that statins inhibited the proliferation of three OSCC cell lines in a dose-dependent manner and this growth inhibition was confirmed through G0/G1 cell cycle arrest. Accordingly, we found the upregulation of p21 and downregulation of cyclin-dependent kinases, including CDK2, CDK4, and CDK6, in the statin-treated cells. Importantly, we clearly showed that statins were able to inhibit the expression of DNA methyltransferase 1 (DNMT1) and further promote the expression of p21. Taken together, our data demonstrated that the anti-proliferative effect of statins is mediated by suppressing DNMT1 expression, thus promoting p21 expression and leading to G0/G1 cell cycle arrest in OSCC cells.

A comparison of L-carnitine and several cardiovascular-related biomarkers between healthy vegetarians and omnivores.

OBJECTIVE: A plant-based diet has been associated with a reduced risk of cardiovascular (CV) diseases. This study aimed to determine the levels and correlations of CV-related biomarkers and the beneficial role of dietary habits. METHODS: A total of 63 healthy vegetarians (n = 32) and omnivores (n = 31) were recruited. The baseline characteristics were recorded and measured (including lipid profiles, blood glucose, etc.). Liquid chromatography-mass spectrometry method was developed for the simultaneous determination of seven circulating CV-related biomarkers. RESULTS: L-carnitine (L-Car), L-methionine, and ascorbic acid (AA) were significantly higher in vegetarians than in omnivores. In the vegetarians, L-Car had a negative correlation with triacylglycerols (P = 0.042) and blood glucose (P = 0.048) and a positive correlation with high-density lipoprotein cholesterol (P = 0.049). L-Car was also positively correlated with L-lysine (P = 0.009), L-methionine (P = 0.006), and AA (P = 0.035). The vegetarians' AA also had a negative correlation with L-homocysteine (P = 0.028). In the omnivores, L-Car was negatively correlated with total cholesterol (P = 0.008), low-density lipoprotein cholesterol (P = 0.004), and high-density lipoprotein cholesterol (P = 0.038). Omnivores' body mass index was positively correlated with L-homocysteine (P = 0.033), and age was positively correlated with trimethylamine N-oxide (P < 0.001) and blood glucose (P = 0.007), but not in vegetarians. CONCLUSIONS: Our results suggest that vegetarians have an elevated level of L-Car, which might be associated with endogenous biosynthesis and diet composition. Circulating L-Car might play an important role in CV protection, especially in vegetarians.