Lycopene alleviates lipopolysaccharide-induced testicular injury in rats by activating the PPAR signaling pathway to integrate lipid metabolism and the inflammatory response.

Abstract

Male fertility can be hampered by systemic and testicular infections and inflammation, which can lead to impaired spermatogenesis that often cannot be reversed by antibiotic treatment. There has been some suggestion that lycopene (LYC) may be useful in the preservation of fertility, although its mechanisms are complex. This current study examined the therapeutic efficacy of LYC on testicular damage and its underlying mechanisms. Lipopolysaccharide (LPS; 5 mg/kg) was injected intraperitoneally to induce inflammation of the testes in mature male rats. The rats in the experimental group were administered 5 mg/kg LYC intragastrically for 4 weeks. The testes were harvested from the euthanized rats for lipidomics, RNA sequencing, and related experimental tests. Laboratory data suggested that LPS-induced systemic inflammation induced cytokine excess and oxidative stress in the testes. Administration of oral LYC inhibited the excess cytokine production and oxidative stress, mitigating damage to the testes. Lipidomic studies identified significant changes to 258 lipids and 5 metabolism pathways. Coupled with RNA sequencing analysis, 1,116 genes were found to be significantly regulated and many lipid metabolism-related signaling pathways were identified. The expression of retinoid X receptor alpha (RXR) in the peroxisome proliferator-activated receptor (PPAR) signaling pathway was significantly upregulated after LYC treatment, which activated the RXR/PPAR easy dimer. The expression of downstream genes such as fatty acid binding protein 3 (FABP3) and carnitine palmitoyltransferase 1A (CPT1A) was increased. These genes are involved in the control of fatty acid metabolism, fatty acid degradation, fatty acid chain elongation, and lipid metabolism, which partially explains the changes in the content and composition of lipids. LYC regulates the lipid metabolism of testes and lipid metabolism-related signaling pathways, such as the PPAR signaling pathway. Furthermore, LYC ameliorated the LPS-induced dysregulation of lipid metabolism in the testes, as well as the LPS-induced inflammatory response. This study offers a new perspective for the investigation of the mechanisms in inflammatory testicular damage and potential therapeutic targets.