Endoplasmic reticulum stress is involved in hepatic SREBP-1c activation and lipid accumulation in fructose-fed mice
Highlights
► Fructose induces hepatic lipid accumulation and activates hepatic SREBP-1c. ► Fructose induces hepatic ER stress and decreases hepatic Insig-1 protein. ► PBA reduces fructose-induced hepatic ER stress and Insig1 depletion. ► PBA inhibits hepatic SREBP-1c activation and alleviates hepatic lipid accumulation. ► ER stress is involved in hepatic lipid accumulation in fructose-fed mice.
Introduction
Nonalcoholic fatty liver disease (NAFLD) is gaining increasing recognition as a component of the epidemic of obesity in China (Fan and Farrell, 2009). Excessive accumulation of triglyceride (TG) in hepatocytes is the hallmark of NAFLD (Fabbrini et al., 2010). The spectrum of NAFLD ranges from simple fatty liver to a potentially progressive form, nonalcoholic steatohepatitis (NASH), which may lead to liver fibrosis and cirrhosis (Farrell and Larter, 2006). Although obesity, high fat diets and insulin resistance are recognized as risk factors for NAFLD (Anderson and Borlak, 2008, Fabbrini et al., 2010, Postic and Girard, 2008), other significant factors leading to NAFLD remain to be identified.
The consumption of soft drinks, which contain high concentrations of fructose, has markedly increased in the last three decades. Several studies have demonstrated that a diet rich in fructose might be an important risk factor in the development of NAFLD (Abdelmalek et al., 2010, Ouyang et al., 2008). A link between an increased consumption of fructose and the development of NAFLD has been demonstrated in the model of rodent animals (Nagai et al., 2009). According to several recent studies, an obvious hepatic lipid accumulation was observed in mice fed fructose solution (Bergheim et al., 2008, Spruss et al., 2009). Interestingly, pretreatment with antibiotics protected against hepatic lipid accumulation in mice fed with fructose solution (Bergheim et al., 2008). In addition, a significant increase in the level of endotoxin was observed in portal blood of mice fed with fructose solution, indicating that gut-derived endotoxin might play an important role in the development of fructose-induced NAFLD. Nevertheless, the molecular mechanisms of fructose-evoked NAFLD remain poorly understood.
An increasing evidence demonstrated that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) might be involved in the development of NAFLD (Oyadomari et al., 2008, Rutkowski et al., 2008, Werstuck et al., 2001). According to a recent report, over-expression of glucose-regulated protein (GRP78), a molecular chaperone for protein folding in the ER, inhibited hepatic sterol regulatory element-binding protein (SREBP)-1c activation in obese mice (Kammoun et al., 2009). In addition, reversal of ER stress with chemical chaperones protected mice from obesity-induced NAFLD (Ozcan et al., 2006). The aim of the present study was to investigate whether ER stress is involved in hepatic SREBP-1c activation and lipid accumulation in fructose-fed mice.
Section snippets
Reagents
Fructose and phenylbutyric acid (PBA) were from Sigma Chemical Co. (St. Louis, MO). SREBP-1, carbohydrate response element binding protein (ChREBP), X-box binding protein 1 (XBP-1), Liver X receptor alpha (LXRα), Lamin A/C, SCD-1, Insulin-induced gene 1 (INSIG-1), INSIG-2 and SCAP antibodies were from Santa Cruz Biotechnologies (Santa Cruz, CA). Glucose-regulated protein 78 (GRP78), phosphor-eIF2α and phosphor-PERK antibodies were from Cell Signaling Technology (Beverley, MA). β-actin antibody
Hepatic TG content and lipid accumulation
As shown in Table 2, average food intake was significantly decreased in fructose-fed mice. No significant difference on total caloric intake per day was observed between mice fed with fructose solution and those fed with water. The absolute and relative liver weights were significantly increased in mice fed with fructose solution. The level of serum and hepatic cholesterol was significantly increased in mice fed fructose solution (Table 2). As shown in Fig. 1A, an obvious hepatic lipid
Discussion
In the present study, we found that the level of hepatic TG was significantly increased in mice fed with fructose solution. An obvious hepatic lipid accumulation, as determined by Oil Red O staining, was observed in fructose-fed mice. These results are in agreement with several earlier studies, in which the increased level of hepatic TG and the excessive hepatic lipid accumulation was shown in mice fed with fructose solution (Bergheim et al., 2008, Spruss et al., 2009). An increasing evidence
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgements
This project was supported by National Natural Science Foundation of China (30371667, 30572223, 30973544, 81001480) and Natural Science Foundation of Anhui province (090413142) and the University Excellence Young Talent Fund of Educational Commission of Anhui Province (2011SQRL058).
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These authors contributed equally to this work.