Effects of Combined Tunicamycin and a High-Fat Diet Rich in Saturated Fatty Acids on the Development of Steatohepatitis

Abstract

Non-alcoholic fatty liver disease (NAFLD) is influenced by various factors including diet, genetic predisposition, adipocytokines, oxidative stress and endoplasmic reticulum (ER) stress. In this study, we examined how pre-feeding mice a high-fat diet rich in saturated fatty acids (SFAs) affected various indicators of liver disease after administering tunicamycin (TM), an ER stress inducer. We used 4-wk-old male C57BL/6J mice, dividing them into four groups: a normal diet (C), a high-fat diet (F), a normal diet with TM (CT), and a high-fat diet with TM (FT). After 8 wk of feeding, we administered TM intraperitoneally to the CT and FT groups, followed by an anatomical examination 24 h later. TM administration led to increased triglyceride (TG) and cholesterol accumulation in the liver, while significantly lowering TG, cholesterol, and ApoB levels in the plasma. Although liver TG levels were higher in the CT group compared to the FT group, large lipid droplets were present in all individuals only in the FT group. Classic non-alcoholic steatohepatitis markers, such as neutrophil infiltration and hepatocyte ballooning, were not observed. Additionally, plasma alanine aminotransferase activity and expression levels of ER stress-related proteins were significantly higher in the FT group than in the CT or F groups. These findings indicate that combining a high-fat diet rich in SFAs with TM exacerbates ER stress-induced fatty liver disease. This model may be a valuable tool for preclinical trials aimed at addressing ER stress in early-stage NAFLD.