The chemical chaperon 4-phenylbutyric acid ameliorates hepatic steatosis through inhibition of de?novo lipogenesis in high-fructose-fed rats

摘要

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.