Apigenin, a modulator of PPARγ, attenuates HFD-induced NAFLD by regulating hepatocyte lipid metabolism and oxidative stress via Nrf2 activation

Biochemical Pharmacology

Volumn 136, Issue , 2017, Pages 136-149

  Feng, Xiujing ^a   Yu, Wen ^a   Li, Xinda ^a   Zhou, Feifei ^a   Zhang, Wenlong ^a   Shen, Qi ^a   Li, Jianxin ^a   Zhang, Can ^a,b   Shen, Pingping ^a  

^a NANJING UNIVERSITY   (China)

^b CHINA PHARMACEUTICAL UNIVERSITY   (China)

Author keywords

Apigenin; NAFLD; Nrf2; PPAR

Indexed keywords

APIGENIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; TRANSCRIPTION FACTOR NRF2; NFE2L2 PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; ENZYME ACTIVATION; GENE OVEREXPRESSION; IN VIVO STUDY; LIPID DIET; LIPID METABOLISM; LIPID STORAGE; LIVER CELL; MALE; METABOLIC INHIBITION; MOUSE; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN EXPRESSION; TRANSCRIPTION INITIATION; ADVERSE EFFECTS; ANIMAL; C57BL MOUSE; DRUG EFFECTS; METABOLISM; NON-ALCOHOLIC FATTY LIVER DISEASE; PHYSIOLOGY; TUMOR CELL LINE;

ANIMALS; APIGENIN; CELL LINE, TUMOR; DIET, HIGH-FAT; HEPATOCYTES; LIPID METABOLISM; MALE; MICE; MICE, INBRED C57BL; NF-E2-RELATED FACTOR 2; NON-ALCOHOLIC FATTY LIVER DISEASE; OXIDATIVE STRESS; PPAR GAMMA;

EID: 85018823277     PISSN: 00062952     EISSN: 18732968     Source Type: Journal    
DOI: 10.1016/j.bcp.2017.04.014     Document Type: Article

References (57)

1. Almeda-Valdes, P., Cuevas-Ramos, D., Aguilar-Salinas, C.A., Metabolic syndrome and non-alcoholic fatty liver disease. Ann. Hepatol. 8:Suppl. 1 (2009), S18–S24.
2. Karlas, T., Wiegand, J., Berg, T., Gastrointestinal complications of obesity: non-alcoholic fatty liver disease (NAFLD) and its sequelae. Best Pract. Res. Clin. Endocrinol. Metab. 27:2 (2013), 195–208.
3. Nonalcoholic fatty liver disease. Nat. Rev. Dis. Primers, 1, 2015, 15081.
4. Smith, B.W., Adams, L.A., Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment. Nat. Rev. Endocrinol. 7:8 (2011), 456–465.
5. Rinella, M.E., Nonalcoholic fatty liver disease: a systematic review. JAMA 313:22 (2015), 2263–2273.
6. Van De Wier, B., Koek, G.H., Bast, A., Haenen, G.R., The potential of flavonoids in the treatment of non-alcoholic fatty liver disease. Crit. Rev. Food Sci. Nutr., 2015.
7. Zhang, S., Zheng, L., Dong, D., Xu, L., Yin, L., Qi, Y., Han, X., Lin, Y., Liu, K., Peng, J., Effects of flavonoids from Rosa laevigata Michx fruit against high-fat diet-induced non-alcoholic fatty liver disease in rats. Food Chem. 141:3 (2013), 2108–2116.
8. Arango, D., Morohashi, K., Yilmaz, A., Kuramochi, K., Parihar, A., Brahimaj, B., Grotewold, E., Doseff, A.I., Molecular basis for the action of a dietary flavonoid revealed by the comprehensive identification of apigenin human targets. Proc. Natl. Acad. Sci. U.S.A. 110:24 (2013), E2153–E2162.
9. Assini, J.M., Mulvihill, E.E., Huff, M.W., Citrus flavonoids and lipid metabolism. Curr. Opin. Lipidol. 24:1 (2013), 34–40.
10. Yang, Y.M., Seo, S.Y., Kim, T.H., Kim, S.G., Decrease of microRNA-122 causes hepatic insulin resistance by inducing protein tyrosine phosphatase 1B, which is reversed by licorice flavonoid. Hepatology 56:6 (2012), 2209–2220.
11. Zhai, X., Lin, M., Zhang, F., Hu, Y., Xu, X., Li, Y., Liu, K., Ma, X., Tian, X., Yao, J., Dietary flavonoid genistein induces Nrf2 and phase II detoxification gene expression via ERKs and PKC pathways and protects against oxidative stress in Caco-2 cells. Mol. Nutr. Food Res. 57:2 (2013), 249–259.
12. Buwa, C.C., Mahajan, U.B., Patil, C.R., Goyal, S.N., Apigenin attenuates beta-receptor-stimulated myocardial injury via safeguarding cardiac functions and escalation of antioxidant defence system. Cardiovasc. Toxicol. 16:3 (2016), 286–297.
13. Tong, X., Pelling, J.C., Targeting the PI3K/Akt/mTOR axis by apigenin for cancer prevention. Anticancer Agents Med. Chem. 13:7 (2013), 971–978.
14. Panda, S., Kar, A., Apigenin (4′,5,7-trihydroxyflavone) regulates hyperglycaemia, thyroid dysfunction and lipid peroxidation in alloxan-induced diabetic mice. J. Pharm. Pharmacol. 59:11 (2007), 1543–1548.
15. Feng, X., Weng, D., Zhou, F., Owen, Y.D., Qin, H., Zhao, J., WenYu, Huang, Y., Chen, J., Fu, H., Yang, N., Chen, D., Li, J., Tan, R., Shen, P., Activation of PPARgamma by a natural flavonoid modulator, apigenin ameliorates obesity-related inflammation via regulation of macrophage polarization. EBioMedicine, 2016.
16. Bataille, A.M., Manautou, J.E., Nrf2: a potential target for new therapeutics in liver disease. Clin. Pharmacol. Ther. 92:3 (2012), 340–348.
17. Zhang, Y.K., Yeager, R.L., Tanaka, Y., Klaassen, C.D., Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet. Toxicol. Appl. Pharmacol. 245:3 (2010), 326–334.
18. Tanaka, Y., Aleksunes, L.M., Yeager, R.L., Gyamfi, M.A., Esterly, N., Guo, G.L., Klaassen, C.D., NF-E2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet. J. Pharmacol. Exp. Ther. 325:2 (2008), 655–664.
19. Itoh, K., Mimura, J., Yamamoto, M., Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Antioxid. Redox Signal. 13:11 (2010), 1665–1678.
20. Lamle, J., Marhenke, S., Borlak, J., von Wasielewski, R., Eriksson, C.J., Geffers, R., Manns, M.P., Yamamoto, M., Vogel, A., Nuclear factor-erythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury. Gastroenterology 134:4 (2008), 1159–1168.
21. Paredes-Gonzalez, X., Fuentes, F., Su, Z.Y., Kong, A.N., Apigenin reactivates Nrf2 anti-oxidative stress signaling in mouse skin epidermal JB6 P + cells through epigenetics modifications. AAPS J. 16:4 (2014), 727–735.
22. Paredes-Gonzalez, X., Fuentes, F., Jeffery, S., Saw, C.L., Shu, L., Su, Z.Y., Kong, A.N., Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharm. Drug Dispos. 36:7 (2015), 440–451.
23. Machado, M.V., Michelotti, G.A., Xie, G., Almeida Pereira, T., Boursier, J., Bohnic, B., Guy, C.D., Diehl, A.M., Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PLoS ONE, 10(5), 2015, e0127991.
24. Tailleux, A., Wouters, K., Staels, B., Roles of PPARs in NAFLD: potential therapeutic targets. Biochim. Biophys. Acta 1821:5 (2012), 809–818.
25. Moran-Salvador, E., Lopez-Parra, M., Garcia-Alonso, V., Titos, E., Martinez-Clemente, M., Gonzalez-Periz, A., Lopez-Vicario, C., Barak, Y., Arroyo, V., Claria, J., Role for PPARgamma in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts. FASEB J. 25:8 (2011), 2538–2550.
26. Yamazaki, T., Shiraishi, S., Kishimoto, K., Miura, S., Ezaki, O., An increase in liver PPARgamma2 is an initial event to induce fatty liver in response to a diet high in butter: PPARgamma2 knockdown improves fatty liver induced by high-saturated fat. J. Nutr. Biochem. 22:6 (2011), 543–553.
27. Garcia-Ruiz, I., Rodriguez-Juan, C., Diaz-Sanjuan, T., Martinez, M.A., Munoz-Yague, T., Solis-Herruzo, J.A., Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice. Hepatology 46:2 (2007), 414–423.
28. Peyrou, M., Ramadori, P., Bourgoin, L., Foti, M., PPARs in liver diseases and cancer: epigenetic regulation by microRNAs. PPAR Res., 2012, 2012, 757803.
29. Gupte, A.A., Liu, J.Z., Ren, Y., Minze, L.J., Wiles, J.R., Collins, A.R., Lyon, C.J., Pratico, D., Finegold, M.J., Wong, S.T., Webb, P., Baxter, J.D., Moore, D.D., Hsueh, W.A., Rosiglitazone attenuates age- and diet-associated nonalcoholic steatohepatitis in male low-density lipoprotein receptor knockout mice. Hepatology 52:6 (2010), 2001–2011.
30. Salam, N.K., Huang, T.H., Kota, B.P., Kim, M.S., Li, Y., Hibbs, D.E., Novel PPAR-gamma agonists identified from a natural product library: a virtual screening, induced-fit docking and biological assay study. Chem. Biol. Drug Des. 71:1 (2008), 57–70.
31. Mueller, M., Lukas, B., Novak, J., Simoncini, T., Genazzani, A.R., Jungbauer, A., Oregano: a source for peroxisome proliferator-activated receptor gamma antagonists. J. Agric. Food Chem. 56:24 (2008), 11621–11630.
32. Feldstein, A.E., Werneburg, N.W., Canbay, A., Guicciardi, M.E., Bronk, S.F., Rydzewski, R., Burgart, L.J., Gores, G.J., Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 40:1 (2004), 185–194.
33. Shi, D., Zhan, X., Yu, X., Jia, M., Zhang, Y., Yao, J., Hu, X., Bao, Z., Inhibiting CB1 receptors improves lipogenesis in an in vitro non-alcoholic fatty liver disease model. Lipids Health Dis., 13, 2014, 173.
34. Shalem, O., Sanjana, N.E., Hartenian, E., Shi, X., Scott, D.A., Mikkelsen, T.S., Heckl, D., Ebert, B.L., Root, D.E., Doench, J.G., Zhang, F., Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343:6166 (2014), 84–87.
35. Livak, K.J., Schmittgen, T.D., Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25:4 (2001), 402–408.
36. Feng, X., Weng, D., Zhou, F., Owen, Y.D., Qin, H., Zhao, J., WenYu, Huang, Y., Chen, J., Fu, H., Yang, N., Chen, D., Li, J., Tan, R., Shen, P., Activation of PPARgamma by a natural flavonoid modulator, apigenin ameliorates obesity-related inflammation via regulation of macrophage polarization. EBioMedicine 9 (2016), 61–76.
37. Kirpich, I.A., Gobejishvili, L.N., Bon Homme, M., Waigel, S., Cave, M., Arteel, G., Barve, S.S., McClain, C.J., Deaciuc, I.V., Integrated hepatic transcriptome and proteome analysis of mice with high-fat diet-induced nonalcoholic fatty liver disease. J. Nutr. Biochem. 22:1 (2011), 38–45.
38. Mokdad, A.H., Ford, E.S., Bowman, B.A., Dietz, W.H., Vinicor, F., Bales, V.S., Marks, J.S., Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 289:1 (2003), 76–79.
39. Abdelmegeed, M.A., Yoo, S.H., Henderson, L.E., Gonzalez, F.J., Woodcroft, K.J., Song, B.J., PPARalpha expression protects male mice from high fat-induced nonalcoholic fatty liver. J. Nutr. 141:4 (2011), 603–610.
40. Day, C.P., James, O.F., Steatohepatitis: a tale of two “hits”?. Gastroenterology 114:4 (1998), 842–845.
41. Colombo, G., Clerici, M., Garavaglia, M.E., Giustarini, D., Rossi, R., Milzani, A., Dalle-Donne, I., A step-by-step protocol for assaying protein carbonylation in biological samples. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2015.
42. Kitteringham, N.R., Abdullah, A., Walsh, J., Randle, L., Jenkins, R.E., Sison, R., Goldring, C.E., Powell, H., Sanderson, C., Williams, S., Higgins, L., Yamamoto, M., Hayes, J., Park, B.K., Proteomic analysis of Nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary Nrf2-dependent pathways in the liver. J. Proteomics 73:8 (2010), 1612–1631.
43. Yan, C., Sun, W., Wang, X., Long, J., Liu, X., Feng, Z., Liu, J., Punicalagin attenuates palmitate-induced lipotoxicity in HepG2 cells by activating the Keap1-Nrf2 antioxidant defense system. Mol. Nutr. Food Res., 2016.
44. Du, J., Zhang, M., Lu, J., Zhang, X., Xiong, Q., Xu, Y., Bao, Y., Jia, W., Osteocalcin improves nonalcoholic fatty liver disease in mice through activation of Nrf2 and inhibition of JNK. Endocrine, 2016.
45. Hatia, S., Septembre-Malaterre, A., Le Sage, F., Badiou-Beneteau, A., Baret, P., Payet, B., Lefebvre d'hellencourt, C., Gonthier, M.P., Evaluation of antioxidant properties of major dietary polyphenols and their protective effect on 3T3-L1 preadipocytes and red blood cells exposed to oxidative stress. Free Radic. Res. 48:4 (2014), 387–401.
46. Paredes-Gonzalez, X., Fuentes, F., Su, Z.Y., Kong, A.N.T., Apigenin reactivates Nrf2 anti-oxidative stress signaling in mouse skin epidermal JB6 P + cells through epigenetics modifications. Aaps J. 16:4 (2014), 727–735.
47. Cho, H.Y., Gladwell, W., Wang, X., Chorley, B., Bell, D., Reddy, S.P., Kleeberger, S.R., Nrf2-regulated PPAR{gamma} expression is critical to protection against acute lung injury in mice. Am. J. Respir. Crit. Care Med. 182:2 (2010), 170–182.
48. Ikeda, Y., Sugawara, A., Taniyama, Y., Uruno, A., Igarashi, K., Arima, S., Ito, S., Takeuchi, K., Suppression of rat thromboxane synthase gene transcription by peroxisome proliferator-activated receptor gamma in macrophages via an interaction with NRF2. J. Biol. Chem. 275:42 (2000), 33142–33150.
49. Ahmed, A., Wong, R.J., Harrison, S.A., Nonalcoholic fatty liver disease review: diagnosis, treatment, and outcomes. Clin. Gastroenterol. Hepatol. 13:12 (2015), 2062–2070.
50. Marchesini, G., Bugianesi, E., Forlani, G., Cerrelli, F., Lenzi, M., Manini, R., Natale, S., Vanni, E., Villanova, N., Melchionda, N., Rizzetto, M., Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37:4 (2003), 917–923.
51. Lehmann, J.M., Moore, L.B., Smith-Oliver, T.A., Wilkison, W.O., Willson, T.M., Kliewer, S.A., An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem. 270:22 (1995), 12953–12956.
52. Yu, S., Matsusue, K., Kashireddy, P., Cao, W.Q., Yeldandi, V., Yeldandi, A.V., Rao, M.S., Gonzalez, F.J., Reddy, J.K., Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1) overexpression. J. Biol. Chem. 278:1 (2003), 498–505.
53. Gavrilova, O., Haluzik, M., Matsusue, K., Cutson, J.J., Johnson, L., Dietz, K.R., Nicol, C.J., Vinson, C., Gonzalez, F.J., Reitman, M.L., Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J. Biol. Chem. 278:36 (2003), 34268–34276.
54. Galli, A., Crabb, D.W., Ceni, E., Salzano, R., Mello, T., Svegliati-Baroni, G., Ridolfi, F., Trozzi, L., Surrenti, C., Casini, A., Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 122:7 (2002), 1924–1940.
55. Yang, L., Stimpson, S.A., Chen, L., Wallace Harrington, W., Rockey, D.C., Effectiveness of the PPARgamma agonist, GW570, in liver fibrosis. Inflamm. Res. 59:12 (2010), 1061–1071.
56. Shin, S., Wakabayashi, J., Yates, M.S., Wakabayashi, N., Dolan, P.M., Aja, S., Liby, K.T., Sporn, M.B., Yamamoto, M., Kensler, T.W., Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur. J. Pharmacol. 620:1–3 (2009), 138–144.
57. Pi, J., Leung, L., Xue, P., Wang, W., Hou, Y., Liu, D., Yehuda-Shnaidman, E., Lee, C., Lau, J., Kurtz, T.W., Chan, J.Y., Deficiency in the nuclear factor E2-related factor-2 transcription factor results in impaired adipogenesis and protects against diet-induced obesity. J. Biol. Chem. 285:12 (2010), 9292–9300.