Immunometabolic impact of pancreastatin inhibitor PSTi8 in MCD induced mouse model of oxidative stress and steatohepatitis.

AIM: Pancreastatin, a dysglycemic hormone that encourages inflammation and steatosis in a variety of metabolic disorder animal models. The purpose of this study is to determine the effect of the pancreastatin inhibitor PSTi8 on immunometabolic changes in the liver of MCD-induced NASH mice. MAIN METHODS: Methionine and choline-deficient (MCD) diet was used for the development of NASH. Liver enzymes like SGOT, SGPT, and ALP and lipid profiles were also performed in the serum. Further, immunophenotyping study was performed in the liver through flowcytometer. Subsequently, Hematoxylin and Eosin, Picro Sirius Red and Masson's Trichrome staining were done to check the liver morphology and collagen staining, respectively. Inflammatory cytokines were measured through ELISA and gene expression through RT-PCR. The expression of α-SMA was examined using immunohistochemistry and immunofluorescence staining. KEY FINDINGS: PSTi8 inhibited the expression of lipogenic genes in the liver and attenuated bad cholesterol, SGOT, SGPT, and ALP in the serum. PSTi8 improved the liver morphology and attenuated collagen deposition. Subsequently, PSTi8 attenuated inflammatory M1-macrophages, CD8+T, CD4+T cells and increased anti-inflammatory M2 macrophages, T-reg and eosinophil populations in the liver. It also attenuated the expression of pro-inflammatory genes like Mcp1, Tnfα, and Il6. Apart from this, PSTi8 attenuated the oxidative stress marker, like ROS, and MDA and fibrosis marker α-SMA in the liver. It also decreased the apoptosis and ROS and MDA level in the liver. SIGNIFICANCE: Overall, these compressive studies revealed that PSTi8 exhibited beneficial effect on the liver of MCD-induced NASH mice by attenuating inflammation and oxidative stress.