Affiliation:
1. Tianjin Medical University General Hospital, Tianjin Medical University
Abstract
Abstract
Aim of the study: The regulation molecular mechanism of the occurrence and development of AIH by PPARα and JNK signaling pathway.
Methods: Mice were fed for 16 weeks either on a normal chow diet (ND) consisting of 4.5% fat or a HFD. Mice were intravenously administered Con A (20 mg/kg) to induce the AIH. GW6471 (20 mg/kg) or WY14643 (6 mg/kg) was injected intraperitoneally for 3days. The mice and liver and spleen tissues were weighted. The histopathological analysis was performed by HE staining. The Inflammatory factors IL-1β, IL-6 and TNF-α was detected using ELISA assay. The mRNA and protein levels were detected using RT-qPCR and Western blotting.
Results: HFD could significantly exacerbate the ConA-induced AIH, including liver steatosis, fat accumulation and liver inflammation of mice. Compared with other groups, necroptosis formation and apoptosis-related proteins, which were expressed at abnormally high levels in the liver tissues of HFD + ConA group, were significantly up-regulated by HFD treatment. Therefore, HFD could promote the programmed necrosis and apoptosis in AIH mice. At the same time, HFD could inhibit the expression of PPARα and activate the JNK signaling pathway in AIH mice. Furthermore, PPARα inhibitor GW6471 could further aggravate the necrosis and apoptosis of AIH mice and PPARα agonist WY14643 could alleviate the deterioration of HFD in AIH mice. Importantly, PPARα agonist WY14643 could further alleviate the necrosis and apoptosis of AIH mice through inhibiting the JNK signaling pathway.
Conclusion: Our findings demonstrated that PPARα had the efficacy on inhibiting HFD-induced AIH progression by inhibiting the necrosis and apoptosis of hepatocyte and the lipid metabolism abnormity of liver. Further molecular mechanism study found that WY14643 could upregulate the PPARα and inhibit the function of activating JNK signaling pathway.
Publisher
Research Square Platform LLC