Milk-derived pentapeptide PGPIP ameliorates alcoholic fatty liver disease in the mouse model of chronic-plus-binge ethanol feeding via inhibiting the upregulation of Cytochrome P4502E1 and promoting FoxO3a-MnSOD axis

Both lipid metabolism disorders and oxidative stress are the pathogenesis of alcoholic liver disease.Reactive oxygen species and lipid peroxides produced by ethanol metabolism can damage the organelles of hepatocytes including mitochondria.This study investigated the protective properties and mechanisms of milk-derived pentapeptide PGPIP against hepatic steatosis in experimental alcoholic liver disease.Glutathione and S-Acetyl-glutathione were used as bioactive peptide controls of PGPIP.Oral administration of PGPIP signi cantly attenuated liver injury and steatosis in wild-type rather than FoxO3a gene knockout female C57BL/6 mouse alcoholic liver disease model established by chronic plus binge ethanol feeding.The protective function of PGPIP against ethanol-induced hepatocytes mitochondrial damage was con rmed by transmission electron microscopy observation.By western blotting analysis, PGPIP inhibited ethanol-induced upregulation of CYP2E1 but promoted the expression of MnSOD in livers.PGPIP differently regulated lipid metabolism related genes (phosphorylated ACC and PGC1alpha) and oxidative stress related genes (FoxO3a and MnSOD) in primary mouse hepatocytes, human MIHA, and HepG2 cells.Realtime PCR, nuclear extraction, immuno uenscene staining, and FoxO3a knockout primary mouse hepatocytes culture experiments demonstrated that PGPIP alleviated ethanol-induced oxidative stress in hepatocytes through the upregulation of FoxO3a-MnSOD axis.