Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Abstract

Background Alcohol-induced intestinal dysbiosis disrupts and inflammatory responses are essential in the development of alcoholic fatty liver disease (AFLD). Here, we investigated the effects of Fmo5 on changes in enteric microbiome composition in a model of AFLD and dissected the pathogenic role of Fmo5 in AFLD-induced liver pathology. Methods The expression profile data of GSE8006 and GSE40334 datasets were downloaded from the GEO database. The WGCNA approach allowed us to investigate the AFLD-correlated module. DEGs were used to perform KEGG pathway enrichment analyses. Four PPI networks were constructed using the STRING database and visualized using Cytoscape software. The Cytohubba plug-in was used to identify the hub genes. Western blot and immunohistochemistry assays were used to detect protein expression. ELISA assay was used to detect the levels of serum inflammatory cytokines. Lipid droplets in the cytoplasm were observed using Oil Red O staining. Apoptosis was detected using a TUNEL assay and flow cytometry analysis. ROS levels were detected using flow cytometry analysis. Nuclear translocation of NF-κB p65 was observed using immunofluorescence staining. Co-immunoprecipitation was used to detect the co-expression of PPARα and Fmo5 in L02 cells. 16S rDNA sequencing defined the bacterial communities in mice with AFLD. Results Fmo5 is a key DEG and is closely associated with the gut microbiota and PPAR signaling pathway. Gut microbiome function in AFLD was significantly related to the PPAR signaling pathway. AFLD induced shifts in various bacterial phyla in the cecum, including a reduction in Bacteroidetes and increased Firmicutes. Fmo5 and PPARα co-expression in cell and animal models with AFLD, which decreased significantly. Silencing of Fmo5 and PPARα aggravated the functions of AFLD inducing apoptosis and inflammatory response, promoting liver injury, and activating the NF-κB signaling pathway in vivo and in vitro. The NF-κB inhibitor abolished the functions of silencing of Fmo5 and PPARα promoting AFLD-induced apoptosis, inflammatory response, and liver injury. Conclusion Our data indicated that the co-expression of Fmo5 and PPARα was involved in AFLD-related gut microbiota composition and alleviated AFLD-induced liver injury, apoptosis, and inflammatory response by inhibiting the nuclear translocation of NF-κB p65 to inhibit the NF-κB signaling pathway.

PGK1 contributes to tumorigenesis and sorafenib resistance of renal clear cell carcinoma via activating CXCR4/ERK signaling pathway and accelerating glycolysis

“…Hub genes are genes that play crucial roles in biological processes. We constructed the coexpression network of overlapped DEGs to screen KIRC-related hub genes according to previous reports [ 49 , 50 ], and the results showed that both PGK1 and CXCR4 are KIRC-related hub genes and highly expressed in KIRC tissues, and there is a strong interaction between PGK1 and CXCR4. The KIRC clinical samples with high mRNA level of PGK1 often own high mRNA expression of CXCR4 correspondingly.…”

Peroxisome Proliferator–Activated Receptor-α: A Pivotal Regulator of the Gastrointestinal Tract

“…This endows them with a wide range of roles, including immune functions all over the body and regulations of a specific organ ( Mandard et al, 2004 ). The well-recognized roles in alleviating heart dysfunction and hypertension in the cardiovascular system have been well-characterized ( Goikoetxea et al, 2004 ; Usuda and Kanda, 2014 ), and their abilities to regulate fatty acid transportation and oxidation in the liver have been well-illustrated, further unveiling its association with various kinds of liver injuries ( Botta et al, 2018 ; Kong et al, 2021 ). These could lead to some systematic diseases including diabetes and result in pathological dysfunctions in multiple organs ( R. Moschen et al, 2012 ).…”

Five metastasis-related mRNAs signature predicting the survival of patients with liver hepatocellular carcinoma

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