Dataset Information

Gut-liver axis modulation of Panax notoginseng saponins in nonalcoholic fatty liver disease.

ABSTRACT:

Background and aims

Nonalcoholic fatty liver disease (NAFLD) is an obesity-related comorbidity, and it is characterized as a spectrum of liver abnormalities, including inflammation, steatosis, and fibrosis. The gut-liver axis is implicated in the pathogenesis and development of NAFLD. A promising drug agent targeting the gut-liver axis is expected to reverse NAFLD.

Methods

We utilized high-fat diet (HFD)-induced obese mice and obesity-prone Lep^ob mice to examine the gut-liver regulation of the natural medicine Panax Notoginseng Saponins (PNS) on NAFLD.

Results

PNS exhibited potent anti-lipogenesis and anti-fibrotic effects in NAFLD mice, that was associated with the TLR4-induced inflammatory signalling pathway in liver. More strikingly, PNS treatment caused a deceleration of gut-to-liver translocation of microbiota-derived short chain fatty acids (SCFAs) products. PNS-induced TLR4 inhibition and restoration of Claudin-1 and ZO-1 proteins in the gut-liver axis contributed to the reverse of leaky gut, which in turn abolished by the addition of lipopolysaccharide (LPS), an agonist of TLR4. Specifically, hepatic steatosis in HFD-treated mice was attenuated by PNS through regulating AMPKα, but restored by the replenishment of LPS. Meanwhile, the anti-fibrotic effect of PNS was abolished by LPS stimulation via the overproduction of collagen I/IV and α-SMA.

Conclusion

PNS exerted hepatoprotection against NAFLD in both ob/ob and HFD-induced obese mice, primarily by mediating the gut-liver axis in a TLR4-dependent manner. Panax notoginseng saponins (PNS) ameliorated hepatic steatosis and fibrosis, and gut-liver axis-mediated pathogenesis of NAFLD is proposed to occur in a TLR4-dependent manner.

SUBMITTER: Xu Y

PROVIDER: S-EPMC8144126 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Panax notoginseng saponins (PNS) may have an inhibitory effect against coronary artery disease (CAD); however, the mechanism is unclear. Recent research has begun to evaluate the role of epigenetics in CAD. Our team found that hypomethylation of miR-194 could be an important mechanism of CAD. Purpose: The aim of this study was to investigate the effect of PNS against CAD and evaluate whether the mechanism is related to methylation of mi-R194. Methods: We conducted a randomized controlled trial with a double-blind placebo design on 84 patients with CAD. Treatment was continued for 4 weeks, and the clinical effect of PNS on CAD was observed. Methylation of miR-194, its promoter, and the key nodes of the MAPK pathway were measured by pyrosequencing and qRT-PCR. We then conducted a pharmacological analysis of the active components of PNS. The effects of PNS on oxidized human umbilical vein endothelial cells and the methylation of miR-194, its promoter, and the key nodes of the MAPK pathway were measured in vitro through methylation-specific PCR (MSPCR), qRT-PCR, Western blot analysis, and annexin V/propidium iodide apoptosis assay. Results: PNS improved symptoms of CAD. High-density lipoprotein and white blood cell count demonstrated significant changes after treatment in the PNS group. No significant difference was observed between miR-194 and mRNA MAPK, FAS, RAS, and FOS in the PNS group after treatment. However, some notable trends were observed in these genes. The targets of PNS were predicted by the pharmacological components. Some targets were found to be differentially expressed genes in CAD sequencing. Six genes, including MAPK1, RAS, and FASL, were common targets of PNS in CAD sequencing. Correlations were observed between genes in the interaction network and clinical parameters. In vitro experiments confirmed that PNS could change the methylation of miR-194, its promoter, and MAPK, FAS, RAS, and FOS. Intervention with PNS is likely to improve apoptosis. Conclusion: We reported the regulation of miR-194 promoter, miR-194, and MAPK methylation by PNS through cell experiments and a randomized controlled trial. PNS can be used for intervention in CAD by targeting the miR-194 promoter-miR-194-MAPK signaling pathway. Clinical Trial Registration: https://www.clinicaltrials.gov/, NCT03083119.