Resveratrol ameliorates nutritional steatohepatitis through the mmu‑miR‑599/PXR pathway

The aim of the present study was to elucidate the effect of resveratrol on non‑alcoholic steatohepatitis (NASH), and the molecular basis in mice and Hepa1‑6 cells, in order to verify its therapeutic effect. C57BL/6J mice were fed a methionine‑choline‑deficient (MCD) diet to induce steatohepatitis and were treated with resveratrol. Mouse sera were collected for biochemical analysis and enzyme‑linked immunosorbent assay, and livers were obtained for histological observation, and mmu‑microRNA (miR)‑599 and inflammation‑related gene expression analysis. Hepa1‑6 cells were treated with palmitic acid to establish a NASH cell model, and were then treated with resveratrol, or transfected with mmu‑miR‑599 mimic, mmu‑miR‑599 inhibitor or recombinant pregnane X receptor (PXR) plasmid. Subsequently, the cells were collected for mmu‑miR‑599 and inflammation‑related gene expression analysis. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to assess mmu‑miR‑599 expression levels, and the mRNA and protein expression levels of PXR and inflammation‑related genes. The binding site of mmu‑miR‑599 in the PXR mRNA was verified by the luciferase activity assay. Mice fed an MCD diet for 4 weeks exhibited steatosis, focal necrosis and inflammatory infiltration in the liver. Resveratrol significantly reduced serum aminotransferase and malondialdehyde levels, and ameliorated hepatic injury. These effects were associated with reduced mmu‑miR‑599 expression, enhanced PXR expression, and downregulated levels of nuclear factor‑κB, tumour necrosis factor‑α, interleukin (IL)‑1β, IL‑6, NOD‑like receptor family pyrin domain‑containing protein 3 and signal transducer and activator of transcription 3. Administration of the mmu‑miR‑599 mimic inhibited PXR expression in Hepa1‑6 cells, whereas the mmu‑miR‑599 inhibitor exerted the opposite effect. A binding site for mmu‑miR‑599 was identified in the PXR mRNA sequence. Furthermore, overexpression of PXR inhibited the expression of inflammatory factors in Hepa1‑6 cells. The present study provided evidence for the protective role of resveratrol in ameliorating steatohepatitis through regulating the mmu‑miR‑599/PXR pathway and the consequent suppression of related inflammatory factors. Resveratrol may serve as a potential candidate for steatohepatitis management.