Background:A high consumption of fructose leads to hepatic steatosis.About 20-30％ of triglycerides are synthesized via de novo lipogenesis.Some studies showed that endoplasmic reticulum stress (ERS) is involved in this process,while others showed that a lipotoxic environment directly influences ER homeostasis.Here,our aim was to investigate the causal relationship between ERS and fatty acid synthesis and the effect of X-box binding protein-1 (XBP-1),one marker of ERS,on hepatic lipid accumulation stimulated by high fructose.Methods:HepG2 cells were incubated with different concentrations of fructose.Upstream regulators of de novo lipogenesis (i.e.,carbohydrate response element-binding protein [ChREBP] and sterol regulatory element-binding protein 1 c [SREBP-lc]) were measured by polymerase chain reaction and key lipogenic enzymes (acetyl-CoA carboxylase [ACC],fatty acid synthase [FAS],and stearoyl-CoA desaturase-1 [SCD-1]) by West blotting.The same lipogenesis-associated factors were then evaluated after exposure of HepG2 cells to high fructose followed by the ERS inhibitor tauroursodeoxycholic acid (TUDCA) or the ERS inducer thapsigargin.Finally,the same lipogenesis-associated factors were evaluated in HepG2 cells after XBP-1 upregulation or downregulation through cell transfection.Results:Exposure to high fructose increased triglyceride levels in a dose-and time-dependent manner and significantly increased mRNA levels of SREBP-1c and ChREBP and protein levels ofFAS,ACC,and SCD-1,concomitant with XBP-1 conversion to an active spliced form.Lipogenesis-associated factors induced by high fructose were inhibited by TUDCA and induced by thapsigargin.Triglyceride level in XBP-l-deficient group decreased significantly compared with high-fructose group (4.41 ± 0.54 μmol/g vs.6.52 ± 0.38 μmol/g,P ＜ 0.001),as mRNA expressions of SREBP-1c (2.92 ± 0.46 vs.5.08 ± 0.41,P ＜ 0.01) and protein levels of FAS (0.53 ± 0.06 vs.0.85 ± 0.05,P =0.01),SCD-1 (0.65 ± 0.06 vs.0.90 ± 0.04,P =0.04),and ACC (0.38 ± 0.03 vs.0.95 ± 0.06,P ＜ 0.01) decreased.Conversely,levels of triglyceride (4.22 ± 0.54 μmol/g vs.2.41 ± 0.35 μmol/g,P ＜ 0.001),mRNA expression of SREBP-1c (2.70 ± 0.33 vs.1.00 ± 0.00,P ＜ 0.0 1),and protein expression of SCD-1 (0.93 ± 0.06 vs.0.26 ± 0.05,P ＜ 0.01),ACC (0.98 ± 0.09 vs.0.43 ± 0.03,P ＜ 0.01),and FAS (0.90 ± 0.33 vs.0.71 ±4 0.02,P =0.04) in XBP-ls-upregulated group increased compared with the untransfected group.Conclusions:ERS is associated with de novo lipogenesis,and XBP-1 partially mediates high-fructose-induced lipid accumulation in HepG2 cells through augmentation of de novo lipogenesis.