Qiao Zhang,Xiaomin Guo,Cao Xie,Zhonglian Cao,Xin Wang,Li Liu,Ping Yang
Trimethylamine-N-oxide (TMAO) has emerged as a promising new therapeutic target for the treatment of central nervous system diseases , atherosclerosis and other diseases. However, its origin in the brain is unclear. Gynostemma pentaphyllum (Thunb.) Makino can reduce the increase of TMAO level caused by a high fat diet. But its effective chemical composition and specific mechanism have not been reported. The study confirmed that TMA was more easily to penetrate blood brain barrier than TMAO, the MAO enzyme was partly involved in the transformation of the TMA in brain, which further supplemented the choline-TMA-TMAO pathway. Based on the above metabolic pathway, using multi-omics approaches, such as microbiodiversity, metagenomics and lipidomics, it was demonstrated that the reduction of plasma TMAO levels by gypenosides did not act on FMO3 and MAO in the pathway, but remodeled the microbiota and affected the trimethylamine lyase needed in the conversion of choline to TMA in intestinal flora . At the same time, gypenosides interfered with enzymes associated with TCA and lipid metabolism, thus affecting TMAO and lipid metabolism. Considering the bidirectional transformation of phosphatidycholine and choline, lipid metabolism and TMAO metabolism could affected each other to some extent. In conclusion, our study revealed the intrinsic correlation between long-term application of gypenosides to lipid reduction and nervous system protection, and explained why gypenosides were used to treat brain diseases, even though they had a poor ability to enter the brain. Besides, it provided a theoretical basis for clinical application of gypenosides and the development of new drugs.
Evidence shows that trimethylamine (TMA)/trimethylamine-N-oxide (TMAO) is closely related to non-alcoholic fatty liver disease (NAFLD). The conversion of TMA to TMAO is mainly catalyzed by flavin-containing monooxygenases 3 (FMO3) and FMO1. In this study, we explored the role of TMA in the process of NAFLD. The human NAFLD liver puncture data set GSE89632 and rat TMAO gene chip GSE135856 was downloaded for gene differential expression analysis. Besides, oleic acid (OA) combined with palmitate were used to establish high-fat cell model. TMA, TMAO and FMO1-siRNA were used to stimulate L02 cells. Contents of free fatty acid (FFA), triglyceride (TG), TMAO, FMO1 and unfolded protein response (UPR) related proteins GRP78, XBP1 , Derlin-1 were detected. Our results showed that FMO1 and PEG10 were important in the progression of NAFLD. Immunohistochemistry showed that FMO1 in NAFLD liver was increased. In addition, the contents of FFA, TG, FMO1 expression, and TMAO were significantly increased after OA + palmitate and TMA stimulation. However, after silencing FMO1 with siRNA, the expressions of these molecules were decreased. Besides, the protein levels of GRP78, XBP1, Derlin-1 were increased after TMAO treatment (all P < 0.05). In Conclusion, high fat and TMA could induce the expression of FMO1 and its metabolite TMAO. When FMO1 is silenced, the effects of high fat and TMA on TMAO are blocked. And the role of TMAO in NAFLD may be through the activation of UPR.
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