Endoplasmic reticulum stress is involved in hepatic SREBP-1c activation and lipid accumulation in fructose-fed mice.
A link between fructose drinking and nonalcoholic fatty liver disease (NAFLD) has been demonstrated in human and rodent animals. The aim of the present study was to investigate whether endoplasmic reticulum (ER) stress is mediated in the development of fructose-induced NAFLD. Female CD-1 mice were fed with 30% fructose solution for eight weeks. Hepatic lipid accumulation was assessed. Hepatic nuclear sterol regulatory element-binding protein (SREBP)-1c was measured. Results showed that hepatic SREBP-1c was activated in mice fed with fructose solution. Fatty acid synthase (fas) and acetyl-CoA carboxylase (acc), two target genes of SREBP-1c, were up-regulated. Fructose-evoked hepatic SREBP-1c activation seemed to be associated with insulin-induced gene (Insig)-1 depletion. An ER stress and unfolded protein response (UPR), as determined by an increased glucose-regulated protein (GRP78) expression and an increased eIF2α and PERK phosphorylation, were observed in liver of mice fed with fructose solution. Phenylbutyric acid (PBA), an ER chemical chaperone, not only significantly attenuated ER stress, but also alleviated fructose-induced hepatic Insig-1 depletion. PBA inhibited fructose-evoked hepatic SREBP-1c activation and the expression of SREBP-1c target genes, and protected against hepatic lipid accumulation. In conclusion, ER stress contributes, at least in part, to hepatic SREBP-1c activation and lipid accumulation in fructose-evoked NAFLD.
Department of Toxicology, Anhui Medical University, Hefei 230032, China.
Cheng
C
Zhang
Xi
X
Chen
Ren-Min
RM
Zhu
Ying
Y
Zhang
Tao
T
Yu
Hua
H
Wang
Hui
H
Zhao
Mei
M
Zhao
Yan-Li
YL
Ji
Yuan-Hua
YH
Chen
Xiu-Hong
XH
Meng
Wei
W
Wei
De-Xiang
DX
Xu
D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004040:Dietary Carbohydrates / Q000009:adverse effects*; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005632:Fructose / Q000008:administration & dosage*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D009687:Nuclear Proteins / Q000096:biosynthesis; D010654:Phenylbutyrates / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis*; D013312:Stress, Physiological / Q000187:drug effects; D014157:Transcription Factors / Q000096:biosynthesis; D019892:eIF-2 Kinase / Q000378:metabolism
D000103:Acetyl-CoA Carboxylase; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004040:Dietary Carbohydrates; D000091342:Endoplasmic Reticulum Chaperone BiP; D064429:Fatty Acid Synthases; D005632:Fructose; D006360:Heat-Shock Proteins; D009687:Nuclear Proteins; D010654:Phenylbutyrates; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D019892:eIF-2 Kinase; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C506001:Mlxipl protein, mouse; C497388:Srebf1 protein, mouse