Diosgenin prevents high-fat diet-induced rat non-alcoholic fatty liver disease through the AMPK and LXR signaling pathways

Cheng,Silu; Liang,Shufang; Liu,Qun; Deng,Zhengting; Zhang,Yuanhui; Du,Juan; Zhang,Ya'ni; Li,Shu; Cheng,Binbin; Ling,Changquan

doi:10.3892/ijmm.2017.3291

Diosgenin prevents high-fat diet-induced rat non-alcoholic fatty liver disease through the AMPK and LXR signaling pathways

Authors:
- Silu Cheng
- Shufang Liang
- Qun Liu
- Zhengting Deng
- Yuanhui Zhang
- Juan Du
- Ya'ni Zhang
- Shu Li
- Binbin Cheng
- Changquan Ling
View Affiliations

Affiliations: Department of Traditional Chinese Medicine, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China, Department of Gastroenterology, Baoshan Branch, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201900, P.R. China
Published online on: November 28, 2017 https://doi.org/10.3892/ijmm.2017.3291
Pages: 1089-1095

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a major public health concern worldwide. The aim of the present study was to observe the effect of diosgenin on NAFLD and investigate the underlying mechanisms. Diosgenin treatment increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in HepG2 cells. Diosgenin significantly inhibited high glucose (HG)-induced triglyceride (TG) accumulation and sterol regulatory element‑binding protein-1c (SREBP-1c) mRNA increase in HepG2 cells, which were partially abolished by the AMPK inhibitor compound C. Diosgenin also significantly inhibited the increase of liver X receptor (LXR) α mRNA induced by HG or T0901317. However, T0901317‑induced upregulation of LXRα and SREBP-1c mRNA was not blocked by compound C. Following a high-fat diet for 16 weeks, the body and liver weights of the experimental rats were significantly increased, but this effect was significantly suppressed by diosgenin. Diosgenin and fenofibrate ameliorated lipid deposition in the liver and reduced the increase of hepatic TG content. Diosgenin significantly decreased the alanine aminotransferase (ALT) level, whereas fenofibrate significantly increased the ALT and aspartate aminotransferase levels. Diosgenin also increased AMPK and ACC phosphorylation and suppressed LXRα in the liver. In conclusion, the results of the present study suggested that diosgenin is a potential agent for preventing the development of NAFLD through the AMPK and LXR signaling pathways.

View Figures

View References

1	Caballería L, Auladell MA, Torán P, Miranda D, Aznar J, Pera G, Gil D, Muñoz L, Planas J, Canut S, et al: Prevalence and factors associated with the presence of non alcoholic fatty liver disease in an apparently healthy adult population in primary care units. BMC Gastroenterol. 7:412007. View Article : Google Scholar : PubMed/NCBI
2	Hu X, Huang Y, Bao Z, Wang Y, Shi D, Liu F, Gao Z and Yu X: Prevalence and factors associated with nonalcoholic fatty liver disease in Shanghai work-units. BMC Gastroenterol. 12:1232012. View Article : Google Scholar : PubMed/NCBI
3	Welsh JA, Karpen S and Vos MB: Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988–1994 to 2007–2010. J Pediatr. 162:496–500. 2013. View Article : Google Scholar
4	Margini C and Dufour JF: The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment. Liver Int. 36:317–324. 2016. View Article : Google Scholar
5	Kahn BB, Alquier T, Carling D and Hardie DG: AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 1:15–25. 2005. View Article : Google Scholar : PubMed/NCBI
6	Hardie DG: AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 8:774–785. 2007. View Article : Google Scholar : PubMed/NCBI
7	Santamarina AB, Oliveira JL, Silva FP, Carnier J, Mennitti LV, Santana AA, de Souza GH, Ribeiro EB, Oller do Nascimento CM, Lira FS, et al: Green tea extract rich in epigallocatechin-3-gallate prevents fatty liver by AMPK activation via LKB1 in mice fed a high-fat diet. PLoS One. 10:e01412272015. View Article : Google Scholar : PubMed/NCBI
8	Li H, Min Q, Ouyang C, Lee J, He C, Zou MH and Xie Z: AMPK activation prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 signaling and endoplasmic reticulum stress response. Biochim Biophys Acta. 1842:1844–1854. 2014. View Article : Google Scholar : PubMed/NCBI
9	Yang Y, Li W, Liu Y, Sun Y, Li Y, Yao Q, Li J, Zhang Q, Gao Y, Gao L, et al: Alpha-lipoic acid improves high-fat diet-induced hepatic steatosis by modulating the transcription factors SREBP-1, FoxO1 and Nrf2 via the SIRT1/LKB1/AMPK pathway. J Nutr Biochem. 25:1207–1217. 2014. View Article : Google Scholar : PubMed/NCBI
10	Yuan H, Weng C, Yang Y, Huang L and Xing X: Resistin, an adipokine, may affect the improvement of insulin sensitivity in the metabolic syndrome patient treated with metformin. Med Hypotheses. 81:969–971. 2013. View Article : Google Scholar : PubMed/NCBI
11	de Mello VD, Kolehmainen M, Pulkkinen L, Schwab U, Mager U, Laaksonen DE, Niskanen L, Gylling H, Atalay M, Rauramaa R, et al: Downregulation of genes involved in NFkappaB activation in peripheral blood mononuclear cells after weight loss is associated with the improvement of insulin sensitivity in individuals with the metabolic syndrome: The GENOBIN study. Diabetologia. 51:2060–2067. 2008. View Article : Google Scholar : PubMed/NCBI
12	Xu X, Huang P, Yang B, Wang X and Xia J: Roles of CXCL5 on migration and invasion of liver cancer cells. J Transl Med. 12:1932014. View Article : Google Scholar : PubMed/NCBI
13	Chen Y, Xu X, Zhang Y, Liu K, Huang F, Liu B and Kou J: Diosgenin regulates adipokine expression in perivascular adipose tissue and ameliorates endothelial dysfunction via regulation of AMPK. J Steroid Biochem Mol Biol. 155:155–165. 2016. View Article : Google Scholar
14	Zang M, Zuccollo A, Hou X, Nagata D, Walsh K, Herscovitz H, Brecher P, Ruderman NB and Cohen RA: AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. J Biol Chem. 279:47898–47905. 2004. View Article : Google Scholar : PubMed/NCBI
15	Uemura T, Goto T, Kang MS, Mizoguchi N, Hirai S, Lee JY, Nakano Y, Shono J, Hoshino S, Taketani K, et al: Diosgenin, the main aglycon of fenugreek, inhibits LXRα activity in HepG2 cells and decreases plasma and hepatic triglycerides in obese diabetic mice. J Nutr. 141:17–23. 2011. View Article : Google Scholar
16	Ghosh S, Sikdar S, Mukherjee A and Khuda-Bukhsh AR: Evaluation of chemopreventive potentials of ethanolic extract of Ruta graveolens against A375 skin melanoma cells in vitro and induced skin cancer in mice in vivo. J Integr Med. 13:34–44. 2015. View Article : Google Scholar : PubMed/NCBI
17	Wu J, Zhang H, Zheng H and Jiang Y: Hepatic inflammation scores correlate with common carotid intima-media thickness in rats with NAFLD induced by a high-fat diet. BMC Vet Res. 10:1622014. View Article : Google Scholar : PubMed/NCBI
18	Akaslan SB, Degertekin CK, Yilmaz G, Cakir N, Arslan M and Toruner FB: Effects of sitagliptin on nonalcoholic fatty liver disease in diet-induced obese rats. Metab Syndr Relat Disord. 11:243–250. 2013. View Article : Google Scholar : PubMed/NCBI
19	Park KG, Min AK, Koh EH, Kim HS, Kim MO, Park HS, Kim YD, Yoon TS, Jang BK, Hwang JS, et al: Alpha-lipoic acid decreases hepatic lipogenesis through adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. Hepatology. 48:1477–1486. 2008. View Article : Google Scholar : PubMed/NCBI
20	Edwards PA, Kast HR and Anisfeld AM: BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis. J Lipid Res. 43:2–12. 2002.PubMed/NCBI
21	Gao M and Liu D: The liver X receptor agonist T0901317 protects mice from high fat diet-induced obesity and insulin resistance. AAPS J. 15:258–266. 2013. View Article : Google Scholar :
22	Chisholm JW, Hong J, Mills SA and Lawn RM: The LXR ligand T0901317 induces severe lipogenesis in the db/db diabetic mouse. J Lipid Res. 44:2039–2048. 2003. View Article : Google Scholar : PubMed/NCBI
23	Jegatheesan P, Beutheu S, Freese K, Waligora-Dupriet AJ, Nubret E, Butel MJ, Bergheim I and De Bandt JP: Preventive effects of citrulline on Western diet-induced non-alcoholic fatty liver disease in rats. Br J Nutr. 116:191–203. 2016. View Article : Google Scholar : PubMed/NCBI
24	Tsujimoto S, Kishina M, Koda M, Yamamoto Y, Tanaka K, Harada Y, Yoshida A and Hisatome I: Nimesulide, a cyclo-oxygenase-2 selective inhibitor, suppresses obesity-related non-alcoholic fatty liver disease and hepatic insulin resistance through the regulation of peroxisome proliferator-activated receptor γ. Int J Mol Med. 38:721–728. 2016. View Article : Google Scholar : PubMed/NCBI
25	Dyck JR, Kudo N, Barr AJ, Davies SP, Hardie DG and Lopaschuk GD: Phosphorylation control of cardiac acetyl-CoA carboxylase by cAMP-dependent protein kinase and 5′-AMP activated protein kinase. Eur J Biochem. 262:184–190. 1999. View Article : Google Scholar : PubMed/NCBI
26	Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, et al: AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 13:376–388. 2011. View Article : Google Scholar : PubMed/NCBI
27	Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, et al: Role of LXRs in control of lipogenesis. Genes Dev. 14:2831–2838. 2000. View Article : Google Scholar : PubMed/NCBI
28	Lee J, Hong SW, Park SE, Rhee EJ, Park CY, Oh KW, Park SW and Lee WY: AMP-activated protein kinase suppresses the expression of LXR/SREBP-1 signaling-induced ANGPTL8 in HepG2 cells. Mol Cell Endocrinol. 414:148–155. 2015. View Article : Google Scholar : PubMed/NCBI
29	Cabrera D, Ruiz A, Cabello-Verrugio C, Brandan E, Estrada L, Pizarro M, Solis N, Torres J, Barrera F and Arrese M: Diet-induced nonalcoholic fatty liver disease is associated with sarcopenia and decreased serum insulin-like growth factor-1. Dig Dis Sci. 61:3190–3198. 2016. View Article : Google Scholar : PubMed/NCBI
30	Wang C, Tao Q, Wang X, Wang X and Zhang X: Impact of high-fat diet on liver genes expression profiles in mice model of nonalcoholic fatty liver disease. Environ Toxicol Pharmacol. 45:52–62. 2016. View Article : Google Scholar : PubMed/NCBI
31	Xu ZJ, Fan JG, Ding XD, Qiao L and Wang GL: Characterization of high-fat, diet-induced, non-alcoholic steatohepatitis with fibrosis in rats. Dig Dis Sci. 55:931–940. 2010. View Article : Google Scholar :
32	Jiang SL, Hu XD and Liu P: Immunomodulation and liver protection of Yinchenhao decoction against concan-avalin A-induced chronic liver injury in mice. J Integr Med. 13:262–268. 2015. View Article : Google Scholar : PubMed/NCBI
33	Moghadam AR, Tutunchi S, Namvaran-Abbas-Abad A, Yazdi M, Bonyadi F, Mohajeri D, Mazani M, Marzban H, Łos MJ and Ghavami S: Pre-administration of turmeric prevents methotrexate-induced liver toxicity and oxidative stress. BMC Complement Altern Med. 15:2462015. View Article : Google Scholar : PubMed/NCBI