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

Ren,Lu-Ping; Song,Guang-Yao; Hu,Zhi-Juan; Zhang,Mingming; Peng,Lanbo; Chen,Shu-Chun; Wei,Limin; Li,Fan; Sun,Wen

doi:10.3892/ijmm.2013.1493

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

Authors:
- Lu-Ping Ren
- Guang-Yao Song
- Zhi-Juan Hu
- Mingming Zhang
- Lanbo Peng
- Shu-Chun Chen
- Limin Wei
- Fan Li
- Wen Sun
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Affiliations: Department of Endocrinology, General Hospital of Hebei, Shijiazhuang, Hebei 050051, P.R. China, Department of Nephrology, General Hospital of Hebei, Shijiazhuang, Hebei 050051, P.R. China, Department of Clinical Laboratory, General Hospital of Hebei, Shijiazhuang, Hebei 050051, P.R. China
Published online on: September 12, 2013 https://doi.org/10.3892/ijmm.2013.1493
Pages: 1029-1036

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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.

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1	Malavolti M, Battistini NC, Miglioli L, et al: Influence of lifestyle habits, nutritional status and insulin resistance in NAFLD. Front Biosci (Elite Ed). 4:1015–1023. 2012. View Article : Google Scholar : PubMed/NCBI
2	Cankurtaran M, Tayfur O, Yavuz BB, Geyik S, Akhan O and Arslan S: Insulin resistance and metabolic syndrome in patients with NAFLD but without diabetes: effect of a 6 month regime intervention. Acta Gastroenterol Belg. 70:253–259. 2007.PubMed/NCBI
3	Moore JB: Non-alcoholic fatty liver disease: the hepatic consequence of obesity and the metabolic syndrome. Proc Nutr Soc. 69:211–220. 2010. View Article : Google Scholar : PubMed/NCBI
4	Moore JB: Symposium 1: Overnutrition: consequences and solutions Non-alcoholic fatty liver disease: the hepatic consequence of obesity and the metabolic syndrome. Proc Nutr Soc. 1–10. 2010.
5	Ouyang X, Cirillo P, Sautin Y, et al: Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 48:993–999. 2008. View Article : Google Scholar : PubMed/NCBI
6	Nomura K and Yamanouchi T: The role of fructose-enriched diets in mechanisms of nonalcoholic fatty liver disease. J Nutr Biochem. 23:203–208. 2012. View Article : Google Scholar : PubMed/NCBI
7	Yilmaz Y: Review article: fructose in non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 35:1135–1144. 2012. View Article : Google Scholar : PubMed/NCBI
8	Kanuri G, Spruss A, Wagnerberger S, Bischoff SC and Bergheim I: Role of tumor necrosis factor α (TNFα) in the onset of fructose-induced nonalcoholic fatty liver disease in mice. J Nutr Biochem. 22:527–534. 2011.
9	Hsieh PS: Inflammatory change of fatty liver induced by intraportal low-dose lipopolysaccharide infusion deteriorates pancreatic insulin secretion in fructose-induced insulin-resistant rats. Liver Int. 28:1167–1175. 2008. View Article : Google Scholar
10	Aragno M, Tomasinelli CE, Vercellinatto I, et al: SREBP-1c in nonalcoholic fatty liver disease induced by Western-type high-fat diet plus fructose in rats. Free Radic Biol Med. 47:1067–1074. 2009. View Article : Google Scholar : PubMed/NCBI
11	Oyadomari S, Harding HP, Zhang Y, Oyadomari M and Ron D: Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab. 7:520–532. 2008. View Article : Google Scholar : PubMed/NCBI
12	Kammoun HL, Chabanon H, Hainault I, et al: GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest. 119:1201–1215. 2009. View Article : Google Scholar : PubMed/NCBI
13	Lee AH, Scapa EF, Cohen DE and Glimcher LH: Regulation of hepatic lipogenesis by the transcription factor XBP1. Science. 320:1492–1496. 2008. View Article : Google Scholar : PubMed/NCBI
14	Ozcan U, Cao Q, Yilmaz E, et al: Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 306:457–461. 2004. View Article : Google Scholar : PubMed/NCBI
15	Ozcan U, Yilmaz E, Ozcan L, et al: Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 313:1137–1140. 2006. View Article : Google Scholar : PubMed/NCBI
16	Yang JS, Kim JT, Jeon J, et al: Changes in hepatic gene expression upon oral administration of taurine-conjugated ursodeoxycholic acid in ob/ob mice. PLoS One. 5:e138582010. View Article : Google Scholar : PubMed/NCBI
17	Ren LP, Chan SM, Zeng XY, et al: Differing endoplasmic reticulum stress response to excess lipogenesis versus lipid oversupply in relation to hepatic steatosis and insulin resistance. PLoS One. 7:e308162012. View Article : Google Scholar
18	Sewter C, Berger D, Considine RV, et al: Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-alpha. Diabetes. 51:1035–1041. 2002. View Article : Google Scholar : PubMed/NCBI
19	Ye JM, Doyle PJ, Iglesias MA, Watson DG, Cooney GJ and Kraegen EW: Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation. Diabetes. 50:411–417. 2001. View Article : Google Scholar
20	Boncompagni E, Gini E, Ferrigno A, et al: Decreased apoptosis in fatty livers submitted to subnormothermic machine-perfusion respect to cold storage. Eur J Histochem. 55:e402011. View Article : Google Scholar : PubMed/NCBI
21	Yu C, Chen Y, Cline GW, et al: Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem. 277:50230–50236. 2002. View Article : Google Scholar
22	Samuel VT: Fructose induced lipogenesis: from sugar to fat to insulin resistance. Trends Endocrinol Metab. 22:60–65. 2011. View Article : Google Scholar : PubMed/NCBI
23	Iizuka K, Bruick RK, Liang G, Horton JD and Uyeda K: Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci USA. 101:7281–7286. 2004. View Article : Google Scholar : PubMed/NCBI
24	Mosbah IB, Zaouali MA, Martel C, et al: IGL-1 solution reduces endoplasmic reticulum stress and apoptosis in rat liver transplantation. Cell Death Dis. 3:e2792012. View Article : Google Scholar : PubMed/NCBI
25	Malhotra JD and Kaufman RJ: Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal. 9:2277–2293. 2007. View Article : Google Scholar : PubMed/NCBI
26	Shimizu Y and Hendershot LM: Oxidative folding: cellular strategies for dealing with the resultant equimolar production of reactive oxygen species. Antioxid Redox Signal. 11:2317–2331. 2009. View Article : Google Scholar : PubMed/NCBI
27	Cullinan SB and Diehl JA: Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol. 38:317–332. 2006. View Article : Google Scholar : PubMed/NCBI
28	Song B, Scheuner D, Ron D, Pennathur S and Kaufman RJ: Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J Clin Invest. 118:3378–3389. 2008. View Article : Google Scholar : PubMed/NCBI
29	Gentile CL, Frye MA and Pagliassotti MJ: Fatty acids and the endoplasmic reticulum in nonalcoholic fatty liver disease. Biofactors. 37:8–16. 2011. View Article : Google Scholar : PubMed/NCBI
30	Back SH, Scheuner D, Han J, et al: Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells. Cell Metab. 10:13–26. 2009. View Article : Google Scholar
31	Liu Y, Adachi M, Zhao S, et al: Preventing oxidative stress: a new role for XBP1. Cell Death Differ. 16:847–857. 2009. View Article : Google Scholar : PubMed/NCBI
32	Cao J, Dai DL, Yao L, et al: Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway. Mol Cell Biochem. 364:115–129. 2012. View Article : Google Scholar : PubMed/NCBI
33	Alkhouri N, Carter-Kent C and Feldstein AE: Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Expert Rev Gastroenterol Hepatol. 5:201–212. 2011. View Article : Google Scholar : PubMed/NCBI
34	Jin WP, Quan XQ, Meng FP, Cui XD and Piao HJ: Relationship among hepatocyte apoptosis, P450 2E1 and oxidative stress in alcoholic liver disease of rats. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 19:419–421. 2007.(In Chinese).
35	Haynes CM, Titus EA and Cooper AA: Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol Cell. 15:767–776. 2004. View Article : Google Scholar : PubMed/NCBI