Betaine prevented fructose-induced NAFLD by regulating LXRα/PPARα pathway and alleviating ER stress in rats

European Journal of Pharmacology

Volumn 770, Issue , 2016, Pages 154-164

  Ge, Chen Xu ^a   Yu, Rong ^a   Xu, Min Xuan ^a   Li, Pei Qin ^a   Fan, Chen Yu ^a   Li, Jian Mei ^a   Kong, Ling Dong ^a  

^a NANJING UNIVERSITY   (China)

Author keywords

Betaine; Dietary fructose; Hepatic ER stress; LXR and PPAR ; NAFLD

Indexed keywords

ACETYL COENZYME A CARBOXYLASE; ACETYL COENZYME A CARBOXYLASE ALPHA; ACYL COENZYME A DESATURASE 1; ADIPOPHILIN; APOLIPOPROTEIN B; BETAINE; CARNITINE PALMITOYLTRANSFERASE 1ALPHA; CARNITINE PALMITOYLTRANSFERASE I; CARNITINE PALMITOYLTRANSFERASE II; CRYOPYRIN; FATTY ACID SYNTHASE; FRUCTOSE; GLYCOSYLPHOSPHATIDYLINOSITOL ANCHORED HIGH DENSITY LIPOPROTEIN BINDING PROTEIN 1; GLYCOSYLPHOSPHATIDYLINOSITOL ANCHORED PROTEIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LIVER X RECEPTOR ALPHA; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE P38; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PROTEIN KINASE B; STEROL REGULATORY ELEMENT BINDING PROTEIN 1C; TRANSCRIPTION FACTOR FKHR; UNCLASSIFIED DRUG; CARRIER PROTEIN; CYTOKINE; FATTY ACID; INFLAMMASOME; LIVER X RECEPTOR; NLRP3 PROTEIN, RAT; NR1H3 PROTEIN, RAT; ORPHAN NUCLEAR RECEPTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CONTROLLED STUDY; CYTOKINE PRODUCTION; ENDOPLASMIC RETICULUM STRESS; FATTY ACID OXIDATION; GLUCONEOGENESIS; INSULIN RESISTANCE; LIPID STORAGE; LIPOGENESIS; MALE; METABOLIC SYNDROME X; NONALCOHOLIC FATTY LIVER; NONHUMAN; PRIORITY JOURNAL; RAT; ANIMAL; BIOSYNTHESIS; CHEMICALLY INDUCED; DRUG EFFECTS; GENE EXPRESSION REGULATION; LIVER; METABOLISM; NON-ALCOHOLIC FATTY LIVER DISEASE; PATHOLOGY; SIGNAL TRANSDUCTION; SPRAGUE DAWLEY RAT;

ANIMALS; BETAINE; CARRIER PROTEINS; CYTOKINES; ENDOPLASMIC RETICULUM STRESS; FATTY ACIDS; FRUCTOSE; GENE EXPRESSION REGULATION; INFLAMMASOMES; LIVER; LIVER X RECEPTORS; MALE; NF-KAPPA B; NLR FAMILY, PYRIN DOMAIN-CONTAINING 3 PROTEIN; NON-ALCOHOLIC FATTY LIVER DISEASE; ORPHAN NUCLEAR RECEPTORS; PPAR ALPHA; RATS; RATS, SPRAGUE-DAWLEY; SIGNAL TRANSDUCTION;

EID: 84952976765     PISSN: 00142999     EISSN: 18790712     Source Type: Journal    
DOI: 10.1016/j.ejphar.2015.11.043     Document Type: Article

References (54)

1. M.F. Abdelmalek, P. Angulo, R.A. Jorgensen, P.B. Sylvestre, and K.D. Lindor Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study Am. J. Gastroenterol. 96 2001 2711 2717
2. M.F. Abdelmalek, S.O. Sanderson, P. Angulo, C. Soldevila-Pico, C. Liu, J. Peter, J. Keach, M. Cave, T. Chen, C.J. McClain, and K.D. Lindor Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial Hepatology 50 2009 1818 1826
3. M.F. Abdelmalek, A. Suzuki, C. Guy, A. Unalp-Arida, R. Colvin, R.J. Johnson, A.M. Diehl, and Nonalcoholic Steatohepatitis Clinical Research, N. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease Hepatology 51 2010 1961 1971
4. S. Asada, H. Daitoku, H. Matsuzaki, T. Saito, T. Sudo, H. Mukai, S. Iwashita, K. Kako, T. Kishi, Y. Kasuya, and A. Fukamizu Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1 Cell Signal 19 2007 519 527
5. P.W. Caton, N.K. Nayuni, N.Q. Khan, E.G. Wood, and R. Corder Fructose induces gluconeogenesis and lipogenesis through a SIRT1-dependent mechanism J. Endocrinol. 208 2011 273 283
6. J.Y. Cha, and J.J. Repa The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR J. Biol. Chem. 282 2007 743 751
7. M.V. Chakravarthy, I.J. Lodhi, L. Yin, R.R. Malapaka, H.E. Xu, J. Turk, and C.F. Semenkovich Identification of a physiologically relevant endogenous ligand for PPARalpha in liver Cell 138 2009 476 488
8. S.M. Chan, R.Q. Sun, X.Y. Zeng, Z.H. Choong, H. Wang, M.J. Watt, and J.M. Ye Activation of PPARalpha ameliorates hepatic insulin resistance and steatosis in high fructose-fed mice despite increased endoplasmic reticulum stress Diabetes 62 2013 2095 2105
9. S.A. Craig Betaine in human nutrition Am. J. Clin. Nutr. 80 2004 539 549
10. B. Dong, C.F. Kan, A.B. Singh, and J. Liu High-fructose diet downregulates long-chain acyl-CoA synthetase 3 expression in liver of hamsters via impairing LXR/RXR signaling pathway J. Lipid Res. 54 2013 1241 1254
11. P. Duewell, H. Kono, K.J. Rayner, C.M. Sirois, G. Vladimer, F.G. Bauernfeind, G.S. Abela, L. Franchi, G. Nunez, M. Schnurr, T. Espevik, E. Lien, K.A. Fitzgerald, K.L. Rock, K.J. Moore, S.D. Wright, V. Hornung, and E. Latz NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals Nature 464 2010 1357 1361
12. D.M. Erion, S. Yonemitsu, Y. Nie, Y. Nagai, M.P. Gillum, J.J. Hsiao, T. Iwasaki, R. Stark, D. Weismann, X.X. Yu, S.F. Murray, S. Bhanot, B.P. Monia, T.L. Horvath, Q. Gao, V.T. Samuel, and G.I. Shulman SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats Proc. Natl. Acad. Sci. USA 106 2009 11288 11293
13. C.Y. Fan, M.X. Wang, C.X. Ge, X. Wang, J.M. Li, and L.D. Kong Betaine supplementation protects against high-fructose-induced renal injury in rats J. Nutr. Biochem. 25 2014 353 362
14. A. Fernandez-Alvarez, M.S. Alvarez, R. Gonzalez, C. Cucarella, J. Muntane, and M. Casado Human SREBP1c expression in liver is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha) J. Biol. Chem. 286 2011 21466 21477
15. J. Folch, M. Lees, and G.H. Sloane Stanley A simple method for the isolation and purification of total lipides from animal tissues J. Biol. Chem. 226 1957 497 509
16. E.K. Go, K.J. Jung, J.Y. Kim, B.P. Yu, and H.Y. Chung Betaine suppresses proinflammatory signaling during aging: the involvement of nuclear factor-kappaB via nuclear factor-inducing kinase/IkappaB kinase and mitogen-activated protein kinases J. Gerontol. A Biol. Sci. Med. Sci. 60 2005 1252 1264
17. A. Hagiwara, M. Cornu, N. Cybulski, P. Polak, C. Betz, F. Trapani, L. Terracciano, M.H. Heim, M.A. Ruegg, and M.N. Hall Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c Cell Metab. 15 2012 725 738
18. J. Henao-Mejia, E. Elinav, C. Jin, L. Hao, W.Z. Mehal, T. Strowig, C.A. Thaiss, A.L. Kau, S.C. Eisenbarth, M.J. Jurczak, J.P. Camporez, G.I. Shulman, J.I. Gordon, H.M. Hoffman, and R.A. Flavell Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity Nature 482 2012 179 185
19. Q.H. Hu, X. Zhang, Y. Pan, Y.C. Li, and L.D. Kong Allopurinol, quercetin and rutin ameliorate renal NLRP3 inflammasome activation and lipid accumulation in fructose-fed rats Biochem. Pharmacol. 84 2012 113 125
20. G.Y. Jung, S.B. Won, J. Kim, S. Jeon, A. Han, and Y.H. Kwon Betaine alleviates hypertriglycemia and tau hyperphosphorylation in db/db mice Toxicol. Res. 29 2013 7 14
21. H. Kettunen, S. Peuranen, K. Tiihonen, and M. Saarinen Intestinal uptake of betaine in vitro and the distribution of methyl groups from betaine, choline, and methionine in the body of broiler chicks Comp. Biochem. Physiol. A Mol. Integr. Physiol. 128 2001 269 278
22. H. Kettunen, K. Tiihonen, S. Peuranen, M.T. Saarinen, and J.C. Remus Dietary betaine accumulates in the liver and intestinal tissue and stabilizes the intestinal epithelial structure in healthy and coccidia-infected broiler chicks Comp. Biochem. Physiol. A Mol. Integr. Physiol. 130 2001 759 769
23. S. Kim, Y. Joe, S.O. Jeong, M. Zheng, S.H. Back, S.W. Park, S.W. Ryter, and H.T. Chung Endoplasmic reticulum stress is sufficient for the induction of IL-1beta production via activation of the NF-kappaB and inflammasome pathways Innate Immun. 20 2013 799 815
24. A. Kinote, J.A. Faria, E.A. Roman, C. Solon, D.S. Razolli, L.M. Ignacio-Souza, C.S. Sollon, L.F. Nascimento, T.M. de Araujo, A.P. Barbosa, C. Lellis-Santos, L.A. Velloso, S. Bordin, and G.F. Anhe Fructose-induced hypothalamic AMPK activation stimulates hepatic PEPCK and gluconeogenesis due to increased corticosterone levels Endocrinology 153 2012 3633 3645
25. H.Y. Koo, M.A. Wallig, B.H. Chung, T.Y. Nara, B.H. Cho, and M.T. Nakamura Dietary fructose induces a wide range of genes with distinct shift in carbohydrate and lipid metabolism in fed and fasted rat liver Biochim. Biophys. Acta 1782 2008 341 348
26. S.M. Koshy, Z. Bobby, S.E. Jacob, P.H. Ananthanarayanan, M.G. Sridhar, and D.T. Paulose Amla prevents fructose-induced hepatic steatosis in ovariectomized rats: role of liver FXR and LXRalpha Climacteric 18 2015 299 310
27. P. Kotokorpi, N. Venteclef, E. Ellis, J.A. Gustafsson, and A. Mode The human ADFP gene is a direct liver-X-receptor (LXR) target gene and differentially regulated by synthetic LXR ligands Mol. Pharmacol. 77 2010 79 86
28. K.A. Le, M. Ith, R. Kreis, D. Faeh, M. Bortolotti, C. Tran, C. Boesch, and L. Tappy Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes Am. J. Clin. Nutr. 89 2009 1760 1765
29. J. Lee, C. Sun, Y. Zhou, J. Lee, D. Gokalp, H. Herrema, S.W. Park, R.J. Davis, and U. Ozcan p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis Nat. Med. 17 2011 1251 1260
30. J.C. Leemans, S.L. Cassel, and F.S. Sutterwala Sensing damage by the NLRP3 inflammasome Immunol. Rev. 243 2011 152 162
31. J.M. Li, C.X. Ge, M.X. Xu, W. Wang, R. Yu, C.Y. Fan, and L.D. Kong Betaine recovers hypothalamic neural injury by inhibiting astrogliosis and inflammation in fructose-fed rats Mol. Nutr. Food Res. 59 2015 189 202
32. P. Menu, A. Mayor, R. Zhou, A. Tardivel, H. Ichijo, K. Mori, and J. Tschopp ER stress activates the NLRP3 inflammasome via an UPR-independent pathway Cell Death Dis. 3 2012 e261
33. K. Olli, S. Lahtinen, N. Rautonen, and K. Tiihonen Betaine reduces the expression of inflammatory adipokines caused by hypoxia in human adipocytes Br. J. Nutr. 109 2013 43 49
34. K.T. Pfaffenbach, A.M. Nivala, L. Reese, F. Ellis, D. Wang, Y. Wei, and M.J. Pagliassotti Rapamycin inhibits postprandial-mediated X-box-binding protein-1 splicing in rat liver J. Nutr. 140 2010 879 884
35. P. Puigserver, J. Rhee, J. Donovan, C.J. Walkey, J.C. Yoon, F. Oriente, Y. Kitamura, J. Altomonte, H. Dong, D. Accili, and B.M. Spiegelman Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction Nature 423 2003 550 555
36. A. Rebollo, N. Roglans, M. Baena, A. Padrosa, R.M. Sanchez, M. Merlos, M. Alegret, and J.C. Laguna Liquid fructose down-regulates liver insulin receptor substrate 2 and gluconeogenic enzymes by modifying nutrient sensing factors in rats J. Nutr. Biochem. 25 2014 250 258
37. A. Rebollo, N. Roglans, M. Baena, R.M. Sanchez, M. Merlos, M. Alegret, and J.C. Laguna Liquid fructose downregulates Sirt1 expression and activity and impairs the oxidation of fatty acids in rat and human liver cells Biochim. Biophys. Acta 1841 2014 514 524
38. S. Slow, M. Lever, S.T. Chambers, and P.M. George Plasma dependent and independent accumulation of betaine in male and female rat tissues Physiol. Res. 58 2009 403 410
39. Z. Song, I. Deaciuc, Z. Zhou, M. Song, T. Chen, D. Hill, and C.J. McClain Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis Am. J. Physiol. Gastrointest. Liver Physiol. 293 2007 G894 G902
40. R. Stienstra, J.A. van Diepen, C.J. Tack, M.H. Zaki, F.L. van de Veerdonk, D. Perera, G.A. Neale, G.J. Hooiveld, A. Hijmans, and I. Vroegrijk Inflammasome is a central player in the induction of obesity and insulin resistance Proc. Natl. Acad. Sci. USA 108 2011 15324 15329
41. Q. Su, C. Baker, P. Christian, M. Naples, X. Tong, K. Zhang, M. Santha, and K. Adeli Hepatic mitochondrial and ER stress induced by defective PPARalpha signaling in the pathogenesis of hepatic steatosis Am. J. Physiol. Endocrinol. Metab. 306 2014 E1264 E1273
42. G. Teixeira Araujo, F. Domenici, J. Elias Jr., and H. Vannucchi Betaine: a potential agent for the treatment of hepatopathy associated with short bowel syndrome Nutr. Hosp. 29 2014 1366 1371
43. B. Vandanmagsar, Y.H. Youm, A. Ravussin, J.E. Galgani, K. Stadler, R.L. Mynatt, E. Ravussin, J.M. Stephens, and V.D. Dixit The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance Nat. Med. 17 2011 179 188
44. A. Vasiljevic, N. Velickovic, B. Bursac, A. Djordjevic, D.V. Milutinovic, N. Nestorovic, and G. Matic Enhanced prereceptor glucocorticoid metabolism and lipogenesis impair insulin signaling in the liver of fructose-fed rats J. Nutr. Biochem. 24 2013 1790 1797
45. L. Vila, A. Rebollo, G.S. Adalsteisson, M. Alegret, M. Merlos, N. Roglans, and J.C. Laguna Reduction of liver fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after atorvastatin treatment Toxicol. Appl. Pharmacol. 251 2011 32 40
46. L. Vilà, N. Roglans, M. Alegret, R.M. Sánchez, M. Vázquez-Carrera, and J.C. Laguna Suppressor of cytokine signaling-3 (SOCS-3) and a deficit of serine/threonine (Ser/Thr) phosphoproteins involved in leptin transduction mediate the effect of fructose on rat liver lipid metabolism Hepatology 48 2008 1506 1516
47. L. Wang, L. Chen, Y. Tan, J. Wei, Y. Chang, T. Jin, and H. Zhu Betaine supplement alleviates hepatic triglyceride accumulation of apolipoprotein E deficient mice via reducing methylation of peroxisomal proliferator-activated receptor alpha promoter Lipids Health Dis. 12 2013 34
48. L.J. Wang, H.W. Zhang, J.Y. Zhou, Y. Liu, Y. Yang, X.L. Chen, C.H. Zhu, R.D. Zheng, W.H. Ling, and H.L. Zhu Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high-fat diet J. Nutr. Biochem. 25 2014 329 336
49. Y.G. Wang, W.L. Fang, J. Wei, T. Wang, N. Wang, J.L. Ma, and M. Shi The involvement of NLRX1 and NLRP3 in the development of nonalcoholic steatohepatitis in mice J. Chin. Med. Assoc. 76 2013 686 692
50. Z. Wang, T. Yao, M. Pini, Z. Zhou, G. Fantuzzi, and Z. Song Betaine improved adipose tissue function in mice fed a high-fat diet: a mechanism for hepatoprotective effect of betaine in nonalcoholic fatty liver disease Am. J. Physiol. Gastrointest. Liver Physiol. 298 2010 G634 G642
51. C. Zhang, X. Chen, R.M. Zhu, Y. Zhang, T. Yu, H. Wang, H. Zhao, M. Zhao, Y.L. Ji, Y.H. Chen, X.H. Meng, W. Wei, and D.X. Xu Endoplasmic reticulum stress is involved in hepatic SREBP-1c activation and lipid accumulation in fructose-fed mice Toxicol. Lett. 212 2012 229 240
52. Q.Y. Zhang, Y. Pan, R. Wang, L.L. Kang, Q.C. Xue, X.N. Wang, and L.D. Kong Quercetin inhibits AMPK/TXNIP activation and reduces inflammatory lesions to improve insulin signaling defect in the hypothalamus of high fructose-fed rats J. Nutr. Biochem. 25 2014 420 428
53. W. Zhang, L.W. Wang, L.K. Wang, X. Li, H. Zhang, L.P. Luo, J.C. Song, and Z.J. Gong Betaine protects against high-fat-diet-induced liver injury by inhibition of high-mobility group box 1 and Toll-like receptor 4 expression in rats Dig. Dis. Sci. 58 2013 3198 3206
54. Y. Zhou, J. Lee, C.M. Reno, C. Sun, S.W. Park, J. Chung, J. Lee, S.J. Fisher, M.F. White, S.B. Biddinger, and U. Ozcan Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction Nat. Med. 17 2011 356 365