Exploration of Digestive Diseases

Table 2. Effect of DMF supplementation on body parameters

Parameters	ND	ND + 0.6 mg/mL DMF	HFDCA	HFDCA + 0.3 mg/mL DMF	HFDCA + 0.6 mg/mL DMF
Initial body weight (g)	19.17 ± 0.32	19.22 ± 0.23	18.88 ± 0.39	18.63 ± 0.42	18.88 ± 0.29
Final body weight (g)	28.54 ± 0.65^a	25.61 ± 0.58^bc	26.73 ± 0.83^ab	23.71± 0.59^c	23.31 ± 0.88^c
eWAT weight (g)	0.67 ± 0.06^a	0.55 ± 0.05^a	0.52 ± 0.07^a	0.28 ± 0.02^b	0.30 ± 0.04^b
eWAT: body weight (%)	2.51 ± 0.19^a	2.26 ± 0.15^a	2.05 ± 0.22^a	1.26 ± 0.08^b	1.30 ± 0.16^b
Liver weight (g)	1.07 ± 0.04^ab	0.93 ± 0.03^c	1.14 ± 0.04^a	1.00 ± 0.04^bc	1.07 ± 0.02^ab
Liver: body weight (%)	3.99 ± 0.08^b	3.82 ± 0.06^b	4.55 ± 0.15^a	4.55 ± 0.08^a	4.86 ± 0.12^a
Calories intake (kcal/mouse/day)	12.9 ± 1.38^b	10.8 ± 1.02^b	27.7 ± 9.43^a	17.6 ± 5.89^b	16.8 ± 4.58^b
Calories intake (kcal/g body weight/day)	0.55 ± 0.05^b	0.49 ± 0.03^b	1.28 ± 0.17^a	0.88 ± 0.14^ab	0.84 ± 0.11^ab
Water consumption (mL/day)	6.21 ± 0.52^a	4.15 ± 1.31^b	5.77 ± 0.88^ab	4.15 ± 0.87^b	3.98 ± 0.62^b

Return to article view

Male C57BL/6J mice aged 6–7 weeks were fed normal diet (ND), ND + 0.6 mg/mL dimethyl fumarate (DMF) by water, high-fat diet + 0.5% cholic acid (HFDCA), HFDCA + 0.3 mg/mL DMF by water, and HFDCA + 0.6 mg/mL DMF by water for 7 weeks. All values are expressed as mean ± SEM (n = 8). Values marked with different letters (a, b, c) are significantly different (p < 0.05) in the Tukey-Kramer post hoc test. eWAT: epididymal white adipose tissue

Supplementary materials

The supplementary materials for this article are available at: https://www.explorationpub.com/uploads/Article/file/100581_sup_1.pdf.

Declarations

Acknowledgments

The authors thank Dr. Adi Shpaizer for her part in the diet preparation and animals’ maintenance and Dr. Zohar Gavish at Gavish Research Services Ltd for performing the histological work.

Author contributions

DAH: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Writing—original draft, Writing—review & editing, Visualization. ER: Investigation, Formal analysis. HZ: Methodology, Formal analysis, Writing—review & editing. OT: Conceptualization, Methodology, Validation, Resources, Writing—original draft, Writing—review & editing, Supervision, Project administration, Funding acquisition. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

Prof. Oren Tirosh is an Associate Editor and Guest Editor of Exploration of Digestive Diseases. However, he was not involved in any aspect of the peer review or editorial decision-making process for this manuscript. The other authors declare no conflicts of interest.

Ethical approval

All animal procedures were performed following the guidelines of the Guide for the Care and Use of Laboratory Animals. The study was approved by the Animal Ethics Committee of the Faculty of Agriculture, Food and Environment, the Hebrew University of Jerusalem, approval number: AG-22-17063-3.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Data will be available upon request.

Funding

This work is funded by internal funding from the Hebrew University of Jerusalem. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020;73:202–9. [DOI] [PubMed]

Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67:328–57. [DOI] [PubMed]

Miao L, Targher G, Byrne CD, Cao Y, Zheng M. Current status and future trends of the global burden of MASLD. Trends Endocrinol Metab. 2024;35:697–707. [DOI] [PubMed]

Boldys A, Buldak L. Metabolic dysfunction-associated steatotic liver disease: Navigating terminological evolution, diagnostic frontiers and therapeutic horizon-an editorial exploration. World J Gastroenterol. 2024;30:2387–90. [DOI] [PubMed] [PMC]

Ciaula AD, Garruti G, Baccetto RL, Molina-Molina E, Bonfrate L, Wang DQ, et al. Bile Acid Physiology. Ann Hepatol. 2017;16:s4–14. [DOI] [PubMed]

Cai SY, Boyer JL. The role of bile acids in cholestatic liver injury. Ann Transl Med. 2021;9:737. [DOI] [PubMed] [PMC]

Chiang JYL. Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocr Rev. 2002;23:443–63. [DOI] [PubMed]

Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today. 2012;17:988–97. [DOI] [PubMed]

Cipriani S, Mencarelli A, Palladino G, Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2010;51:771–84. [DOI] [PubMed] [PMC]

10.

Cyphert HA, Ge X, Kohan AB, Salati LM, Zhang Y, Hillgartner FB. Activation of the farnesoid X receptor induces hepatic expression and secretion of fibroblast growth factor 21. J Biol Chem. 2012;287:25123–38. [DOI] [PubMed] [PMC]

11.

Torra IP, Claudel T, Duval C, Kosykh V, Fruchart J, Staels B. Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol. 2003;17:259–72. [DOI] [PubMed]

12.

Wang Y, Chen W, Wang M, Yu D, Forman BM, Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology. 2008;48:1632–43. [DOI] [PubMed] [PMC]

13.

Aranha MM, Cortez-Pinto H, Costa A, Silva IBMd, Camilo ME, Moura MCd, et al. Bile acid levels are increased in the liver of patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2008;20:519–25. [DOI] [PubMed]

14.

Xue R, Su L, Lai S, Wang Y, Zhao D, Fan J, et al. Bile Acid Receptors and the Gut-Liver Axis in Nonalcoholic Fatty Liver Disease. Cells. 2021;10:2806. [DOI] [PubMed] [PMC]

15.

Shi S, Wang L, Laan LJWvd, Pan Q, Verstegen MMA. Mitochondrial Dysfunction and Oxidative Stress in Liver Transplantation and Underlying Diseases: New Insights and Therapeutics. Transplantation. 2021;105:2362–73. [DOI] [PubMed] [PMC]

16.

Unoki T, Akiyama M, Kumagai Y. Nrf2 Activation and Its Coordination with the Protective Defense Systems in Response to Electrophilic Stress. Int J Mol Sci. 2020;21:545. [DOI] [PubMed] [PMC]

17.

Weerachayaphorn J, Mennone A, Soroka CJ, Harry K, Hagey LR, Kensler TW, et al. Nuclear factor-E2-related factor 2 is a major determinant of bile acid homeostasis in the liver and intestine. Am J Physiol Gastrointest Liver Physiol. 2012;302:G925–36. [DOI] [PubMed] [PMC]

18.

Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13:76–86. [DOI] [PubMed] [PMC]

19.

Itoh K, Wakabayashi N, Katoh Y, Ishii T, O’Connor T, Yamamoto M. Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells. 2003;8:379–91. [DOI] [PubMed]

20.

Suzuki T, Takahashi J, Yamamoto M. Molecular Basis of the KEAP1-NRF2 Signaling Pathway. Mol Cells. 2023;46:133–41. [DOI] [PubMed] [PMC]

21.

Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci U S A. 2002;99:11908–13. [DOI] [PubMed] [PMC]

22.

Hur W, Gray NS. Small molecule modulators of antioxidant response pathway. Curr Opin Chem Biol. 2011;15:162–73. [DOI] [PubMed]

23.

Ibrahim SG, El-Emam SZ, Mohamed EA, Ellah MFA. Dimethyl fumarate and curcumin attenuate hepatic ischemia/reperfusion injury via Nrf2/HO-1 activation and anti-inflammatory properties. Int Immunopharmacol. 2020;80:106131. [DOI] [PubMed]

24.

Zhang Y, Zhao S, Fu Y, Yan L, Feng Y, Chen Y, et al. Computational repositioning of dimethyl fumarate for treating alcoholic liver disease. Cell Death Dis. 2020;11:641. [DOI] [PubMed] [PMC]

25.

Wilms H, Sievers J, Rickert U, Rostami-Yazdi M, Mrowietz U, Lucius R. Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1beta, TNF-alpha and IL-6 in an in-vitro model of brain inflammation. J Neuroinflammation. 2010;7:30. [DOI] [PubMed] [PMC]

26.

Vanani AR, Kalantari H, Mahdavinia M, Rashno M, Khorsandi L, Khodayar MJ. Dimethyl fumarate reduces oxidative stress, inflammation and fat deposition by modulation of Nrf2, SREBP-1c and NF-κB signaling in HFD fed mice. Life Sci. 2021;283:119852. [DOI] [PubMed]

27.

Reeves PG, Nielsen FH, Fahey GC Jr. AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr. 1993;123:1939–51. [DOI] [PubMed]

28.

Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009;89:147–91. [DOI] [PubMed]

29.

Kobayashi M, Ikegami H, Fujisawa T, Nojima K, Kawabata Y, Noso S, et al. Prevention and treatment of obesity, insulin resistance, and diabetes by bile acid-binding resin. Diabetes. 2007;56:239–47. [DOI] [PubMed]

30.

Ponz de Leon M, Carulli N, Loria P, Iori R, Zironi F. The effect of chenodeoxycholic acid (CDCA) on cholesterol absorption. Gastroenterology. 1979;77:223–30. [PubMed]

31.

Beuers U. Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2006;3:318–28. [DOI] [PubMed]

32.

Calmus Y, Poupon R. Ursodeoxycholic acid (UDCA) in the treatment of chronic cholestatic diseases. Biochimie. 1991;73:1335–8. [DOI] [PubMed]

33.

Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 2004;113:1408–18. [DOI] [PubMed] [PMC]

34.

Voloshin I, Hahn-Obercyger M, Anavi S, Tirosh O. L-arginine conjugates of bile acids-a possible treatment for non-alcoholic fatty liver disease. Lipids Health Dis. 2014;13:69. [DOI] [PubMed] [PMC]

35.

Zhou Y, Maxwell KN, Sezgin E, Lu M, Liang H, Hancock JF, et al. Bile acids modulate signaling by functional perturbation of plasma membrane domains. J Biol Chem. 2013;288:35660–70. [DOI] [PubMed] [PMC]

36.

Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med. 1999;159:2647–58. [DOI] [PubMed]

37.

Ashby K, Almario EEN, Tong W, Borlak J, Mehta R, Chen M. Review article: therapeutic bile acids and the risks for hepatotoxicity. Aliment Pharmacol Ther. 2018;47:1623–38. [DOI] [PubMed]

38.

Allen K, Jaeschke H, Copple BL. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am J Pathol. 2011;178:175–86. [DOI] [PubMed] [PMC]

39.

Parmar HS, Kar A. Atherogenic diet induced diabetes mellitus: involvement of thyroid hormones. Eur J Pharmacol. 2007;570:244–8. [DOI] [PubMed]

40.

Sethi A, Parmar HS, Kumar A. The effect of aspirin on atherogenic diet-induced diabetes mellitus. Basic Clin Pharmacol Toxicol. 2011;108:371–7. [DOI] [PubMed]

41.

Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439:484–9. [DOI] [PubMed]

42.

Hellerstein MK. Carbohydrate-induced hypertriglyceridemia: modifying factors and implications for cardiovascular risk. Curr Opin Lipidol. 2002;13:33–40. [DOI] [PubMed]

43.

Xi Y, Li H. Role of farnesoid X receptor in hepatic steatosis in nonalcoholic fatty liver disease. Biomed Pharmacother. 2020;121:109609. [DOI] [PubMed]

44.

Song P, Zhang Y, Klaassen CD. Dose-response of five bile acids on serum and liver bile Acid concentrations and hepatotoxicty in mice. Toxicol Sci. 2011;123:359–67. [DOI] [PubMed] [PMC]

45.

Xia J, Zhou Y, Ji H, Wang Y, Wu Q, Bao J, et al. Loss of histone deacetylases 1 and 2 in hepatocytes impairs murine liver regeneration through Ki67 depletion. Hepatology. 2013;58:2089–98. [DOI] [PubMed]

46.

Moldovan G, Pfander B, Jentsch S. PCNA, the maestro of the replication fork. Cell. 2007;129:665–79. [DOI] [PubMed]

47.

Mansilla SF, de la Vega MB, Calzetta NL, Siri SO, Gottifredi V. CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication. Genes (Basel). 2020;11:593. [DOI] [PubMed] [PMC]

48.

Soria G, Gottifredi V. PCNA-coupled p21 degradation after DNA damage: The exception that confirms the rule? DNA Repair (Amst). 2010;9:358–64. [DOI] [PubMed] [PMC]

49.

Kaminsky-Kolesnikov Y, Rauchbach E, Abu-Halaka D, Hahn M, García-Ruiz C, Fernandez-Checa JC, et al. Cholesterol Induces Nrf-2- and HIF-1 α-Dependent Hepatocyte Proliferation and Liver Regeneration to Ameliorate Bile Acid Toxicity in Mouse Models of NASH and Fibrosis. Oxid Med Cell Longev. 2020;2020:5393761. [DOI] [PubMed] [PMC]

50.

Shin S, Wakabayashi J, Yates MS, Wakabayashi N, Dolan PM, Aja S, et al. Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur J Pharmacol. 2009;620:138–44. [DOI] [PubMed] [PMC]

51.

Saidu NEB, Kavian N, Leroy K, Jacob C, Nicco C, Batteux F, et al. Dimethyl fumarate, a two-edged drug: Current status and future directions. Med Res Rev. 2019;39:1923–52. [DOI] [PubMed]

52.

Lee YJ, Bae JH, Kang S, Cho SW, Chun D, Nam SM, et al. Pro-oxidant status and Nrf2 levels in psoriasis vulgaris skin tissues and dimethyl fumarate-treated HaCaT cells. Arch Pharm Res. 2017;40:1105–16. [DOI] [PubMed]

53.

Medina MV, Sapochnik D, Solá MG, Coso O. Regulation of the Expression of Heme Oxygenase-1: Signal Transduction, Gene Promoter Activation, and Beyond. Antioxid Redox Signal. 2020;32:1033–44. [DOI] [PubMed] [PMC]

54.

Takaya K, Suzuki T, Motohashi H, Onodera K, Satomi S, Kensler TW, et al. Validation of the multiple sensor mechanism of the Keap1-Nrf2 system. Free Radic Biol Med. 2012;53:817–27. [DOI] [PubMed] [PMC]

55.

Abu-Halaka D, Shpaizer A, Zeigerman H, Kanner J, Tirosh O. DMF-Activated Nrf2 Ameliorates Palmitic Acid Toxicity While Potentiates Ferroptosis Mediated Cell Death: Protective Role of the NO-Donor S-Nitroso-N-Acetylcysteine. Antioxidants (Basel). 2023;12:512. [DOI] [PubMed] [PMC]

56.

Dibbert S, Clement B, Skak-Nielsen T, Mrowietz U, Rostami-Yazdi M. Detection of fumarate-glutathione adducts in the portal vein blood of rats: evidence for rapid dimethylfumarate metabolism. Arch Dermatol Res. 2013;305:447–51. [DOI] [PubMed]

57.

Linker RA, Lee D, Ryan S, Dam AMv, Conrad R, Bista P, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011;134:678–92. [DOI] [PubMed]

58.

Ballestri S, Nascimbeni F, Baldelli E, Marrazzo A, Romagnoli D, Lonardo A. NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk. Adv Ther. 2017;34:1291–326. [DOI] [PubMed] [PMC]