title: The chemical chaperon 4-phenylbutyric acid ameliorates hepatic steatosis through inhibition of de novo lipogenesis in high-fructose-fed rats.
abstract: Non-alcoholic fatty liver disease caused by dietary factors such as a high fructose intake is a growing global concern. The aim of this study was to investigate the intervention effects of an endoplasmic reticulum stress (ERS) inhibitor 4-phenylbutyric acid (PBA) on liver steatosis induced by high-fructose feeding in rats and the possible underlying mechanisms. Wistar rats were divided into the control, high-fructose group (HFru) and PBA intervention (HFru-PBA) groups. PBA intervention was initiated following 4 weeks of high-fructose feeding. After 8 weeks of feeding, the ERS markers p-PERK, p-eIF2α, p-IRE-1, spliced XBP-1, ATF-6 were measured by western blotting. Liver triglyceride contents and morphological changes were examined. The protein expression of lipogenic key enzymes (ACC, FAS and SCD-1) and upstream transcriptional factors (SREBP-1c and ChREBP) were measured. The ERS-related cell events, oxidative stress and apoptosis, were evaluated by standard methods. Results demonstrated that PBA intervention significantly resolved hepatic ERS and improved liver steatosis induced by high-fructose feeding in rats. The protein expression of ACC, FAS, SCD-1 and SREBP-1c was upregulated in high-fructose-fed rats, whereas it decreased following PBA intervention. Oxidative stress and apoptosis were observed in livers of high-fructose-fed rats, but were alleviated by PBA intervention. ERS is involved in the development of fatty liver induced by a high fructose intake. ERS inhibition by PBA can therefore ameliorate liver steatosis through inhibition of hepatic lipogenesis.
authors.affiliation: Department of Endocrinology, General Hospital of Hebei, Shijiazhuang, Hebei 050051, P.R. China.
authors.forename: Lu-Ping
authors.initials: LP
authors.lastname: Ren
authors.forename: Guang-Yao
authors.initials: GY
authors.lastname: Song
authors.forename: Zhi-Juan
authors.initials: ZJ
authors.lastname: Hu
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhang
authors.forename: Lanbo
authors.initials: L
authors.lastname: Peng
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Chen
authors.forename: Limin
authors.initials: L
authors.lastname: Wei
authors.forename: Fan
authors.initials: F
authors.lastname: Li
authors.forename: Wen
authors.initials: W
authors.lastname: Sun
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005234:Fatty Liver / Q000188:drug therapy*; D005632:Fructose / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D050155:Lipogenesis / Q000187:drug effects; D008297:Male; D010654:Phenylbutyrates / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010654:Phenylbutyrates; D005632:Fructose; C075773:4-phenylbutyric acid