Inflammation and oxidative stress have been implicated in the pathogenesis of metabolic disturbances. Esters of fumaric acid, mainly dimethyl fumarate, exhibit immunomodulatory, anti-inflammatory, and anti-oxidative effects. In the current study, we tested the hypothesis that fumaric acid ester (FAE) treatment of an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP), will ameliorate inflammation, oxidative stress, and metabolic disturbances. We studied the effects of FAE treatment by administering Fumaderm, 10 mg/kg body weight for 4 weeks, to male SHR-CRP. Untreated male SHR-CRP rats were used as controls. All rats were fed a high sucrose diet. Compared to untreated controls, rats treated with FAE showed significantly lower levels of endogenous CRP but not transgenic human CRP, and amelioration of inflammation (reduced levels of serum IL6 and TNFα) and oxidative stress (reduced levels of lipoperoxidation products in liver, heart, kidney, and plasma). FAE treatment was also associated with lower visceral fat weight and less ectopic fat accumulation in liver and muscle, greater levels of lipolysis, and greater incorporation of glucose into adipose tissue lipids. Analysis of gene expression profiles in the liver with Affymetrix arrays revealed that FAE treatment was associated with differential expression of genes in pathways that involve the regulation of inflammation and oxidative stress. These findings suggest potentially important anti-inflammatory, anti-oxidative, and metabolic effects of FAE in a model of inflammation and metabolic disturbances induced by human CRP.

Center for Experimental Medicine Institute for Clinical and Experimental Medicine Prague Czech Republic

Institute of Molecular Genetics Academy of Sciences of the Czech Republic Prague Czech Republic

Institute of Physiology Academy of Sciences of the Czech Republic Prague Czech Republic

University of California San Francisco San Francisco California United States of America

Zobrazit více v PubMed

Meissner M, Valesky EM, Kippenberger S, Kaufmann R (2012) Dimethyl fumarate - only an anti-psoriatic medication? J Dtsch Dermatol Ges 10: 793–801. PubMed

Ye J (2013) Mechanisms of insulin resistance in obesity. Front Med 7: 14–24. PubMed PMC

Pravenec M, Kajiya T, Zídek V, Landa V, Mlejnek P, et al. (2011) Effects of human C-reactive protein on pathogenesis of features of the metabolic syndrome. Hypertension 57: 731–737. PubMed PMC

Foresti R, Bains SK, Pitchumony TS, de Castro Brás LE, Drago F, et al. (2013) Small molecules activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells. Pharmacol Res 76: 132–148. PubMed

Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, et al. (2006) Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 17: 4–12. PubMed

Bisoendial RJ, Boekholdt SM, Vergeer M, Stroes ES, Kastelein JJ (2010) C-reactive protein is a mediator of cardiovascular disease. Eur Heart J 31: 2087–2091. PubMed

Paraskevas KI, Mikhailidis DP (2008) C-reactive protein (CRP): more than just an innocent bystander? Curr Med Res Opin 24: 75–78. PubMed

Aaronson DS, Horvath CM (2002) A road map for those who don’t know JAK-STAT. Science 296: 1653–1655. PubMed

Zhang K, Guo W, Yang Y, Wu J (2011) JAK2/STAT3 pathway is involved in the early stage of adipogenesis through regulating C/EBPβ transcription. J Cell Biochem 112: 488–97. PubMed

Kang HJ, Seo HA, Go Y, Oh CJ, Jeoung NH, et al. (2013) Dimethylfumarate suppresses adipogenic differentiation in 3T3-L1 preadipocytes through inhibition of STAT3 activity. PLoS One 8: e61411. PubMed PMC

Medzhitov R (2001) Toll-like receptors and innate immunity. Nat Rev Immunol 1: 135–145. PubMed

Esche C, Stellato C, Beck LA (2005) Chemokines: key players in innate and adaptive immunity. J Invest Dermatol 125: 615–628. PubMed

Lin SX, Lisi L, Russo Dello C, Polak PE, Sharp A, et al. (2011) The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1. ASN Neuro 3: 75–84. PubMed PMC

Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, et al. (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134: 678–692. PubMed

Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, et al. (2012) Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther 341: 274–284. PubMed

Litjens NH, van Strijen E, van Gulpen C, Mattie H, van Dissel JT, et al. (2004) In vitro pharmacokinetics of anti-psoriatic fumaric acid esters. BMC Pharmacol 4: 22. PubMed PMC

Tang H, Lu JY-L, Zheng X, Yang Y, Reagan JD, et al. (2008) The psoriasis drug monomethylfumarate is a potent nicotinic acid receptor agonist. Biochem Biophys Res Commun 375: 562–565. PubMed

Hanson J, Gille A, Zwykiel S, Lukasova M, Clausen BE, et al. (2010) Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice. J Clin Invest 120: 2910–2919. PubMed PMC

Chai JT, Digby JE, Choudhury RP (2013) GPR109A and vascular inflammation. Curr Atheroscler Rep 15: 325. PubMed PMC

Koike T, Kitajima S, Yu Y, Nishijima K, Zhang J, et al. (2009) Human C-reactive protein does not promote atherosclerosis in transgenic rabbits. Circulation 120: 2088–2094. PubMed PMC

Šilhavý J, Zídek V, Landa V, Šimáková M, Mlejnek P, et al. (2014) Rosuvastatin can block pro-inflammatory actions of transgenic human CRP without reducing its circulating levels. Cardiovasc Ther 32: 59–65. PubMed

Malínská H, Oliyarnyk O, Hubová M, Zídek V, Landa V, et al. (2010) Increased liver oxidative stress and altered PUFA metabolism precede development of non-alcoholic steatohepatitis in SREBP-1a transgenic spontaneously hypertensive rats with genetic predisposition to hepatic steatosis. Mol Cell Biochem 335: 119–125. PubMed

Beneš J, Kazdová L, Drahota Z, Houštěk J, Medříková D, et al. (2011) Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats. Clin Sci (London) 121: 29–41. PubMed

Smyth GK (2005) Limma: linear models for microarray data. In: Gentleman R, Carey V, Dudoit S, Irizarry R, Huber W, editors. Bioinformatics and computational biology solutions using R and bioconductor. Springer, New York. 397–420.

Storey JD (2003) The positive false discovery rate: a Bayesian interpretation and the q-value. Annals of Statistics 31: 2013–2035.

Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, et al. (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5: R80. PubMed PMC

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, et al. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102: 15545–15550. PubMed PMC

Kanehisa M, Goto S (2000) KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28: 27–30. PubMed PMC

Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, et al. (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25: 25–9. PubMed PMC

Tian L, Greenberg SA, Kong SW, Altschuler J, Kohane IS, et al. (2005) Discovering statistically significant pathways in expression profiling studies. Proc Natl Acad Sci USA 102: 13544–13549. PubMed PMC

Tarca AL, Draghici S, Khatri P, Hassan S, Mital P, et al. (2009) A signaling pathway impact analysis for microarray experiments. Bioinformatics 25: 75–82. PubMed PMC

Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc. Series B 57: 289–300.

Salsalate ameliorates metabolic disturbances by reducing inflammation in spontaneously hypertensive rats expressing human C-reactive protein and by activating brown adipose tissue in nontransgenic controls