Skip to main content Accessibility help

Sodium butyrate protects mice from the development of the early signs of non-alcoholic fatty liver disease: role of melatonin and lipid peroxidation

  • Cheng Jun Jin (a1), Anna Janina Engstler (a1), Cathrin Sellmann (a1), Doreen Ziegenhardt (a1), Marianne Landmann (a1) (a2), Giridhar Kanuri (a1) (a3), Hakima Lounis (a1) (a4), Markus Schröder (a5), Walter Vetter (a5) and Ina Bergheim (a1) (a6)...


Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide with universally accepted treatments still lacking. Oral supplementation of sodium butyrate (SoB) has been suggested to attenuate liver damage of various aetiologies. Our study aimed to further delineate mechanisms involved in the SoB-dependent hepatic protection using a mouse model of fructose-induced NAFLD and in in vitro models. C57BL/6J mice were either pair-fed a fructose-enriched liquid diet ±0·6 g/kg body weight per d SoB or standard chow for 6 weeks. Markers of liver damage, intestinal barrier function, glucose metabolism, toll-like receptor-4 (TLR-4) and melatonin signalling were determined in mice. Differentiated human carcinoma colon-2 (Caco-2) and J774A.1 cells were used to determine molecular mechanisms involved in the effects of SoB. Despite having no effects on markers of intestinal barrier function and glucose metabolism or body weight gain, SoB supplementation significantly attenuated fructose-induced hepatic TAG accumulation and inflammation. The protective effects of SoB were associated with significantly lower expression of markers of the TLR-4-dependent signalling cascade, concentrations of inducible nitric oxide synthase (iNOS) protein and 4-hydroxynonenal protein adducts in liver. Treatment with SoB increased melatonin levels and expression of enzymes involved in melatonin synthesis in duodenal tissue and Caco-2 cells. Moreover, treatment with melatonin significantly attenuated lipopolysaccharide-induced expression of iNOS and nitrate levels in J774A.1 cells. Taken together, our results indicated that the protective effects of SoB on the development of fructose-induced NAFLD in mice are associated with an increased duodenal melatonin synthesis and attenuation of iNOS induction in liver.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Sodium butyrate protects mice from the development of the early signs of non-alcoholic fatty liver disease: role of melatonin and lipid peroxidation
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Sodium butyrate protects mice from the development of the early signs of non-alcoholic fatty liver disease: role of melatonin and lipid peroxidation
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Sodium butyrate protects mice from the development of the early signs of non-alcoholic fatty liver disease: role of melatonin and lipid peroxidation
      Available formats


Corresponding author

* Corresponding author: I. Bergheim, email


Hide All
1. Blachier, M, Leleu, H, Peck-Radosavljevic, M, et al. (2013) The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol 58, 593608.
2. Hashimoto, E, Tokushige, K & Ludwig, J (2015) Diagnosis and classification of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: current concepts and remaining challenges. Hepatol Res 45, 2028.
3. Tilg, H & Moschen, AR (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52, 18361846.
4. Dyson, J & Day, C (2014) Treatment of non-alcoholic fatty liver disease. Dig Dis 32, 597604.
5. Miele, L, Valenza, V, La, TG, et al. (2009) Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49, 18771887.
6. Thuy, S, Ladurner, R, Volynets, V, et al. (2008) Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr 138, 14521455.
7. Volynets, V, Kuper, MA, Strahl, S, et al. (2012) Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD). Dig Dis Sci 57, 19321941.
8. Berni, CR, Di, CM & Leone, L (2012) The epigenetic effects of butyrate: potential therapeutic implications for clinical practice. Clin Epigenetics 4, 4.
9. Endo, H, Niioka, M, Kobayashi, N, et al. (2013) Butyrate-producing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis. PLOS ONE 8, e63388.
10. Liu, B, Qian, J, Wang, Q, et al. (2014) Butyrate protects rat liver against total hepatic ischemia reperfusion injury with bowel congestion. PLOS ONE 9, e106184.
11. Mattace, RG, Simeoli, R, Russo, R, et al. (2013) Effects of sodium butyrate and its synthetic amide derivative on liver inflammation and glucose tolerance in an animal model of steatosis induced by high fat diet. PLOS ONE 8, e68626.
12. Yang, F, Wang, LK, Li, X, et al. (2014) Sodium butyrate protects against toxin-induced acute liver failure in rats. Hepatobiliary Pancreat Dis Int 13, 309315.
13. Wang, HB, Wang, PY, Wang, X, et al. (2012) Butyrate enhances intestinal epithelial barrier function via up-regulation of tight junction protein Claudin-1 transcription. Dig Dis Sci 57, 31263135.
14. Jin, CJ, Sellmann, C, Engstler, AJ, et al. (2015) Supplementation of sodium butyrate protects mice from the development of non-alcoholic steatohepatitis (NASH). Br J Nutr 114, 17451755.
15. Sellmann, C, Jin, CJ, Degen, C, et al. (2015) Oral glutamine supplementation protects female mice from nonalcoholic steatohepatitis. J Nutr 145, 22802286.
16. Sellmann, C, Jin, CJ, Engstler, AJ, et al. (2016) Oral citrulline supplementation protects female mice from the development of non-alcoholic fatty liver disease (NAFLD). Eur J Nutr (epublication ahead of print version 5 August 2016).
17. Spruss, A, Kanuri, G, Stahl, C, et al. (2012) Metformin protects against the development of fructose-induced steatosis in mice: role of the intestinal barrier function. Lab Invest 92, 10201032.
18. Pelaseyed, T, Bergstrom, JH, Gustafsson, JK, et al. (2014) The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol Rev 260, 820.
19. Bergheim, I, Guo, L, Davis, MA, et al. (2006) Critical role of plasminogen activator inhibitor-1 in cholestatic liver injury and fibrosis. J Pharmacol Exp Ther 316, 592600.
20. Haub, S, Kanuri, G, Volynets, V, et al. (2010) Serotonin reuptake transporter (SERT) plays a critical role in the onset of fructose-induced hepatic steatosis in mice. Am J Physiol Gastrointest Liver Physiol 298, G335G344.
21. Jin, CJ, Engstler, AJ, Ziegenhardt, D, et al. (2016) Loss of lipopolysaccharide-binding protein attenuates the development of diet-induced non-alcoholic fatty liver disease (NAFLD) in mice. J Gastroenterol Hepatol (epublication ahead of print version 12 July 2016).
22. Wagnerberger, S, Spruss, A, Kanuri, G, et al. (2012) Toll-like receptors 1-9 are elevated in livers with fructose-induced hepatic steatosis. Br J Nutr 107, 17271738.
23. Nazih, H, Nazih-Sanderson, F, Krempf, M, et al. (2001) Butyrate stimulates ApoA-IV-containing lipoprotein secretion in differentiated Caco-2 cells: role in cholesterol efflux. J Cell Biochem 83, 230238.
24. Russo, I, Luciani, A, De, CP, et al. (2012) Butyrate attenuates lipopolysaccharide-induced inflammation in intestinal cells and Crohn’s mucosa through modulation of antioxidant defense machinery. PLOS ONE 7, e32841.
25. Kheder, RK, Hobkirk, J & Stover, CM (2016) In vitro modulation of the LPS-induced proinflammatory profile of hepatocytes and macrophages- approaches for intervention in obesity? Front Cell Dev Biol 4, 61.
26. Egorin, MJ, Yuan, ZM, Sentz, DL, et al. (1999) Plasma pharmacokinetics of butyrate after intravenous administration of sodium butyrate or oral administration of tributyrin or sodium butyrate to mice and rats. Cancer Chemother Pharmacol 43, 445453.
27. Matis, G, Kulcsar, A, Turowski, V, et al. (2015) Effects of oral butyrate application on insulin signaling in various tissues of chickens. Domest Anim Endocrinol 50, 2631.
28. Vinolo, MA, Rodrigues, HG, Festuccia, WT, et al. (2012) Tributyrin attenuates obesity-associated inflammation and insulin resistance in high-fat-fed mice. Am J Physiol Endocrinol Metab 303, E272E282.
29. Kanuri, G, Ladurner, R, Skibovskaya, J, et al. (2015) Expression of toll-like receptors 1-5 but not TLR 6-10 is elevated in livers of patients with non-alcoholic fatty liver disease. Liver Int 35, 562568.
30. Leonel, AJ & Alvarez-Leite, JI (2012) Butyrate: implications for intestinal function. Curr Opin Clin Nutr Metab Care 15, 474479.
31. Ma, X, Fan, PX, Li, LS, et al. (2012) Butyrate promotes the recovering of intestinal wound healing through its positive effect on the tight junctions. J Anim Sci 90, Suppl. 4, 266268.
32. Douhara, A, Moriya, K, Yoshiji, H, et al. (2015) Reduction of endotoxin attenuates liver fibrosis through suppression of hepatic stellate cell activation and remission of intestinal permeability in a rat non-alcoholic steatohepatitis model. Mol Med Rep 11, 16931700.
33. Zuo, G, He, S, Liu, C, et al. (2002) [Expression of lipopolysaccharide binding protein and lipopolysaccharide receptor CD14 in experimental alcoholic liver disease]. Zhonghua Gan Zang Bing Za Zhi 10, 207210.
34. Csak, T, Pillai, A, Ganz, M, et al. (2014) Both bone marrow-derived and non-bone marrow-derived cells contribute to AIM2 and NLRP3 inflammasome activation in a MyD88-dependent manner in dietary steatohepatitis. Liver Int 34, 14021413.
35. Rivera, CA, Adegboyega, P, van, RN, et al. (2007) Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol 47, 571579.
36. Spruss, A, Kanuri, G, Wagnerberger, S, et al. (2009) Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology 50, 10941104.
37. Spruss, A, Kanuri, G, Uebel, K, et al. (2011) Role of the inducible nitric oxide synthase in the onset of fructose-induced steatosis in mice. Antioxid Redox Signal 14, 21212135.
38. Zhu, JH, Zhang, X, Roneker, CA, et al. (2008) Role of copper, zinc-superoxide dismutase in catalyzing nitrotyrosine formation in murine liver. Free Radic Biol Med 45, 611618.
39. Hu, X, Zhang, K, Xu, C, et al. (2014) Anti-inflammatory effect of sodium butyrate preconditioning during myocardial ischemia/reperfusion. Exp Ther Med 8, 229232.
40. Wiechmann, AF & Burden, MA (1999) Regulation of AA-NAT and HIOMT gene expression by butyrate and cyclic AMP in Y79 human retinoblastoma cells. J Pineal Res 27, 116121.
41. Deng, MH, Lopez, G-C, Lynch, HJ, et al. (1991) Melatonin and its precursors in Y79 human retinoblastoma cells: effect of sodium butyrate. Brain Res 561, 274278.
42. Konturek, SJ, Konturek, PC, Brzozowski, T, et al. (2007) Role of melatonin in upper gastrointestinal tract. J Physiol Pharmacol 58, Suppl. 6, 2352.
43. Al-Ghoul, WM, Abu-Shaqra, S, Park, BG, et al. (2010) Melatonin plays a protective role in postburn rodent gut pathophysiology. Int J Biol Sci 6, 282293.
44. Zhang, HM & Zhang, Y (2014) Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res 57, 131146.
45. Manchester, LC, Coto-Montes, A, Boga, JA, et al. (2015) Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res 59, 403419.
46. Sharma, S & Rana, SV (2013) Melatonin improves liver function in benzene-treated rats. Arh Hig Rada Toksikol 64, 3341.
47. Hatzis, G, Ziakas, P, Kavantzas, N, et al. (2013) Melatonin attenuates high fat diet-induced fatty liver disease in rats. World J Hepatol 5, 160169.
48. Celinski, K, Konturek, PC, Slomka, M, et al. (2014) Effects of treatment with melatonin and tryptophan on liver enzymes, parameters of fat metabolism and plasma levels of cytokines in patients with non-alcoholic fatty liver disease – 14 months follow up. J Physiol Pharmacol 65, 7582.
49. Muxel, SM, Laranjeira-Silva, MF, Carvalho-Sousa, CE, et al. (2016) The RelA/cRel nuclear factor-kappaB (NF-kappaB) dimer, crucial for inflammation resolution, mediates the transcription of the key enzyme in melatonin synthesis in RAW 264.7 macrophages. J Pineal Res 60, 394404.


Type Description Title
Supplementary materials

Jin supplementary material S1
Supplementary Figure

 PDF (946 KB)
946 KB
Supplementary materials

Jin supplementary material S2
Supplementary Figure

 PDF (256 KB)
256 KB
Supplementary materials

Jin supplementary material S3
Supplementary Table

 Word (19 KB)
19 KB


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed