Irpex lacteus metabolites ameliorate hyperlipidemic mice via CYP7A1/HMGCR/FXR/AMPK signalling pathways and gut microbiota

This study investigated the underlying mechanism and efficacy of metabolites of Irpex lacteus (MIL) in improving the symptoms of hyperlipidemia in mice by examining the gut microbiome and metabolic pathways. The analysis revealed the presence of four components: 3-(4-hydroxyphenyl)-5,7-dimethoxy-6-(3-methylbut-2-en-1-yl)4-4H-chromen-4-one, N-acetylformamide, methyl 2-((3S,4R)-4-(4,4-dimethyl-2-vinylcyclopent-1-en-1-yl)- 2-oxotetrahydrofuran-3-yl)acetate, and (1R,4S,Z)-5-(2-acetoxy-1-(5-oxotetrahydrofuran-3-yl)ethylidene)-2,2-dimethyl-4-vinylcyclopentyl acetate were detected by HPLC in MIL, and their lipid-lowering activity was validated in vitro. A hyperlipidemic C57BL/6J male mouse model was established. Serum and liver tissues were collected for biochemical, protein, and mRNA analysis, and the gut microbiota was examined. Treatment with MIL or simvastatin significantly reduced the liver index and concentrations of total cholesterol, triglycerides, low-density lipoprotein cholesterol, aspartate transaminase, alanine aminotransferase, alkaline phosphatase, lipopolysaccharide, interleukin-6, and total bile acid. These treatments increased high-density lipoprotein concentrations. Western blotting and RT-qPCR showed that MIL downregulated 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase and upregulated cholesterol 7-alpha-monooxygenase (CYP7A1), farnesoid X receptor (FXR), adenosine 5′-monophosphate-activated protein kinase (AMPK), silent information regulator 1 (SIRT1), and peroxisome proliferator-activated receptor γ (PPARγ) protein and gene expression in the liver. A pathological examination and Oil Red O staining showed that nucleolal shift, cell rupture, cell inflammation, and fat particle accumulation were reduced by MIL treatment. The gut microbiota test results showed that MIL significantly reduced the proportion of Bacteroides and increased the proportion of Actinobacteria, Staphylococcus, Corynebacterium, Rummeliibacillus, and Psychrobacter. These findings suggested that MIL alleviated hyperlipidemia by regulating CYP7A1/HMGCR/FXR signaling pathway and AMPK signaling pathway, and by modulating the composition of the gut microbiota.