Milk-derived hexapeptide PGPIPN prevents and attenuates acute alcoholic liver injury in mice by reducing endoplasmic reticulum stress

Abstract

Bioactive peptides are an emerging area of biomedical research in the study of numerous human diseases, including acute alcoholic liver injury (AALI). To study the role and mechanism of the milk-derived hexapeptide Pro-Gly-Pro-Ile-Pro-Asn (PGPIPN) in preventing and reducing AALI, the present study established a mouse model of AALI. PGPIPN was used as a therapeutic drug, and glutathione (GSH) was used as a positive control. The body and liver weights of mice were measured, and the liver indexes were calculated to observe mice health. The pathological morphology of liver tissues stained with hematoxylin and eosin were examined to analyze hepatic injury, and hepatocyte apoptosis was measured with a TUNEL assay. The concentrations or activities of alanine aminotransferase (ALT), aspartate aminotransferase, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, triglyceride, total cholesterol, malondialdehyde, superoxide dismutase and GSH peroxidase (GSH-PX) were detected in serum and/or liver homogenates. The 78 kDa glucose.regulated protein (GRP78), protein kinase R.like (PKR) endoplasmic reticulum kinase (PERK), phosphorylated (p)-PERK, eukaryotic initiation factor 2α (eIF-2α), p-eIF-2α, inositol-requiring enzyme 1α (IRE-1α), spliced X-box binding protein 1 (XBP-1s), C/EBP homologous protein (CHOP), caspase-3 and cleaved caspase-3 proteins associated with endoplasmic reticulum stress in hepatocytes were assessed by western blotting, and RNA levels of XBP-1s, CHOP and caspase-3 genes were assessed by reverse transcription.quantitative PCR. The results suggested that PGPIPN attenuated alcoholic hepatocyte damage in animal models and reduced hepatocyte oxidative stress in a dose-dependent manner. Moreover, PGPIPN reduced endoplasmic reticulum stress by regulating the expression levels of p-PERK, p-eIF-2α, XBP-1s, CHOP, caspase-3 and cleaved caspase-3. Collectively, the present results indicated that PGPIPN, as a potential therapeutic drug for AALI, exerted a protective effect on the liver and could reduce liver damage.