Role of X-Box Binding Protein-1 in Fructose-Induced De Novo Lipogenesis in HepG2 Cells  

作　　者：Xian Yu Lu-Ping Ren Chao Wang Ya-Jun Zhu Han-Ying Xing Jing Zhao Guang-Yao Song 

机构地区：[1]Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050051, China [2]Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei 050051, China [3]Hebei Key Laboratory of Metabolic Disease, Hebei General Hospital, Shijiazhuang, Hebei 050051, China [4]Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei 050051, China

出　　处：《Chinese Medical Journal》2018年第19期2310-2319,共10页中华医学杂志（英文版）

摘　　要：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 Western 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 ± 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 Western 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 ±

关 键 词：Endoplasmic Reticulum Stress Fatty Liver LIPOGENESIS X-Box Binding Protein-I 

分 类 号：Q556.9[生物学—生物化学] O316[理学—一般力学与力学基础]