Exploring the potential mechanism of Rhodomyrtus tomentosa (Ait.) Hassk fruit phenolic rich extract on ameliorating nonalcoholic fatty liver disease by integration of transcriptomics and metabolomics profiling

Nonalcoholic fatty liver disease (NAFLD), as the commonest form of chronic liver disease, is accompanied by liver oxidative stress and inflammatory responses. Rhodomyrtus tomentosa (Ait.) Hassk fruit phenolic rich extract (RTE) possesses multiple pharmacological effects in management of chronic diseases. In this study, the liver-protective effect of RTE on mice with high-fat-diet (HFD)-induced NAFLD was investigated for the first time, and the underlying molecular mechanism was explored via integration of transcriptomics and metabolomics. The results showed that RTE mitigated liver damage, which was evidenced by declined inflammatory cell infiltration in liver, decreased liver function markers, oxidative stress indexes, lipid profile levels and inflammatory cytokines levels. The differential metabolites by metabonomics illustrated supplementation of RTE affected metabolomics pathways including tryptophan metabolism, alanine, aspartate and glutamate metabolism, D-glutamine and D-glutamate metabolism, cysteine and methionine metabolism, arginine and proline metabolism, which are all involved in oxidative stress and inflammation. Furthermore, the five differential expression genes (DEGs) through liver transcriptomics were screened and recognized, namely Tnfrsf21, Ifit1, Inhbb, Mapk15 and Gadd45g, which revealed that HFD induced Cytokine-cytokine receptor interaction pathway, NF-kappa B signaling pathway NOD-like receptor pathway, TNF signaling pathway. Integrated analysis of transcriptomics and metabolomics confirmed the supplementation of RTE had significantly regulatory effects on the metabolic pathways involved in inflammatory responses. Additionally, RT-PCR and western blot authenticated RTE intervention regulated the mRNA levels of liver genes involved in inflammation response and inhibited the liver endotoxin-TLR4-NF-kappa B pathway triggered by HFD, thus alleviating NAFLD. Our findings strongly support the possibility that RTE can be regarded as a potential therapeutic method for obesity-associated NAFLD.

Automated summary

The study demonstrated that Rhodomyrtus tomentosa fruit phenolic rich extract (RTE) has a liver-protective effect on mice with high-fat-diet-induced nonalcoholic fatty liver disease (NAFLD), alleviating liver damage by reducing inflammatory cell infiltration, oxidative stress indexes, lipid profile levels, and inflammatory cytokines levels. Metabolomics analysis showed that RTE affected various metabolic pathways associated with oxidative stress and inflammation. Transcriptomics analysis identified five differential expression genes involved in pathways related to cytokine-cytokine receptor interaction, NF-kappa B signaling, and TNF signaling, confirming the regulatory effects of RTE on inflammatory response-related metabolic pathways.