The role of endoplasmic reticulum stress in the formation of fatty liver in high-fat diet fed mice

Objective To explore the influence of endoplasmic reticulum stress on fatty liver in mice feeding with high-fat diet. Methods The 8-week-old male C57BL/6J mice were randomly divided into two groups: high-fat diet group (with 60% calories by high saturated fatty acid) and control group (with chow diet), both groups had been fed for 16 weeks. H&E-staining and Sudan Ⅳ-staining reflected lipid deposition in liver. The levels of 78-kDa glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), phosphorylated α subunit of eukaryotic initiation factor 2 (p-eIF1α ), C/EBP homologous protein (CHOP), steroid regulated element binding proteins 1 (SREBP-1), and fatty acid synthetase (FAS) protein were determined by Western blot to reflect the endoplasmic reticulum stress and lipid synthesis. Results In liver of high fat diet (HFD) group, H&E staining showed that the cytoplasm of hepatocytes were filled with vacuoles, Sudan Ⅳ staining also displayed that many different sizes of red lipid drops exist in hepatocytes. Compared to the liver of control group, high-fat diet induced endoplasmic reticulum stress and elevated lipid synthesis, as evidenced by increases in the level of peroxisome prolif-erator-activated receptor alpha (PPARα) mRNA expression, and the protein levels of GRP78, PERK, phosphorylated eIF2α, CHOP were also significantly increased. In primary normal hepatocytes incubated with exogenous oleic acid intervention for 24-72 hours, the expression of GRP78, PERK, phosphorylated eIF2α, CHOP protein levels, and the expression of SREBP-1 and FAS protein were significantly increased in dose-dependent manner. Conclusions Feeding with high-fat diet led to accumulation of lipid deposition in liver and fatty liver, the underlying mechanisms might be related to induction of endoplasmic reticulum stress. Key words: Endoplasmic reticulum stress; High-fat diet; Fatty liver; De novo lipid synthesis