Role of serotonin in fatty acid-induced non-alcoholic fatty liver disease in mice

BMC Gastroenterology

Stephan C Bischoff¹  Stephan Zipfel²  Paul Enck²  Astrid Hubert¹  Synia Haub¹  Maureen Böhle¹  Yvonne Ritze¹ 

[1] Department of Nutritional Medicine, University of Hohenheim, Fruwirthstr. 12, 70599, Stuttgart, Germany;Department of Psychosomatic Medicine, University of Tübingen, Tübingen 72076, Germany

关键词: Intestinal permeability;    Serotonin;    Polyunsaturated fatty acids in diet;    Monounsaturated;    Saturated;    Non-alcoholic fatty liver disease;   

Others  :  856829
DOI  :  10.1186/1471-230X-13-169

 received in 2013-01-27, accepted in 2013-11-28,  发布年份 2013

【 摘 要 】

Background

Saturated fatty acids are thought to be of relevance for the development of non-alcoholic fatty liver disease and obesity. However, the underlying mechanisms are poorly understood. In previous studies we found that food-derived carbohydrates such as fructose alter the intestinal serotonergic system while inducing fatty liver disease in mice. Here, we examined the effect of fatty acid quantity (11% versus 15%) and quality (saturated, monounsaturated, or polyunsaturated fatty acids) on hepatic fat accumulation, intestinal barrier and the intestinal serotonergic system.

Methods

C57BL/6 mice had free access to diets enriched with one of the three fatty acids or standard diet, for 8 weeks. In an additional experiment mice were fed diets enriched with saturated, monounsaturated fatty acids or standard diet supplemented with tryptophan (0.4 g/(kg^.d), 8 weeks) or not. Hepatic fat accumulation, small intestinal barrier impairment and components of the serotonergic system were measured with RT-PCR, western blot or immunoassays. For statistical analysis t-test and one-way ANOVA with Tukey’s post hoc test and Bartlett’s test for equal variances was used.

Results

Hepatic triglycerides, liver weight and liver to body weight ratio were significantly changed depending on the fat quality but not fat quantity. In contrast, fat quantity but not quality decreased the expression of the tight junction proteins occludin and claudin-1 in the small intestine. These changes seemed to result in enhanced portal vein endotoxin concentrations and fatty liver disease after feeding diet enriched with saturated and monounsaturated fatty acids but not polyunsaturated fatty acids. Neither fatty acid quantity nor quality significantly influenced the intestinal serotonergic system. Similarly, tryptophan supplementation had no impact on small intestinal barrier or fatty liver disease.

Conclusion

In conclusion, diets rich in saturated or monounsaturated fatty acids promote the development of fatty liver disease in mice, likely by a dysfunction of the small intestinal mucosal barrier.

【 授权许可】

   
2013 Ritze et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Cortez-Pinto H, de Moura MC, Day CP: Non-alcoholic steatohepatitis: from cell biology to clinical practice. J Hepatol 2006, 44(1):197-208.
• [2]Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH: Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004, 40(6):1387-1395.
• [3]Guturu P, Duchini A: Etiopathogenesis of nonalcoholic steatohepatitis: role of obesity, insulin resistance and mechanisms of hepatotoxicity. Int J Hepatol 2012, 2012:212865.
• [4]Lazo M, Clark JM: The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 2008, 28(4):339-350.
• [5]Pagano G, Pacini G, Musso G, Gambino R, Mecca F, Depetris N, Cassader M, David E, Cavallo-Perin P, Rizzetto M: Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 2002, 35(2):367-372.
• [6]de Wit NJ, Afman LA, Mensink M, Muller M: Phenotyping the effect of diet on non-alcoholic fatty liver disease. J Hepatol 2012, 57(6):1370-1373.
• [7]Haub S, Kanuri G, Volynets V, Brune T, Bischoff SC, Bergheim I: Serotonin reuptake transporter (SERT) plays a critical role in the onset of fructose-induced hepatic steatosis in mice. Am J Physiol Gastrointest Liver Physiol 2010, 298(3):G335-G344.
• [8]Molendi-Coste O, Legry V, Leclercq IA: Dietary lipids and NAFLD: suggestions for improved nutrition. Acta Gastroenterol Belg 2010, 73(4):431-436.
• [9]Li H, Lelliott C, Hakansson P, Ploj K, Tuneld A, Verolin-Johansson M, Benthem L, Carlsson B, Storlien L, Michaelsson E: Intestinal, adipose, and liver inflammation in diet-induced obese mice. Metabolism 2008, 57(12):1704-1710.
• [10]Abete I, Goyenechea E, Zulet MA, Martinez JA: Obesity and metabolic syndrome: potential benefit from specific nutritional components. Nutr Metab Cardiovasc Dis 2011, 21(Suppl 2):B1-B15.
• [11]Brun P, Castagliuolo I, Di Leo V, Buda A, Pinzani M, Palu G, Martines D: Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2007, 292(2):G518-G525.
• [12]Seki E, Brenner DA: Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 2008, 48(1):322-335.
• [13]Kawai T, Akira S: The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010, 11(5):373-384.
• [14]Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG: The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001, 48(2):206-211.
• [15]Wagnerberger S, Spruss A, Kanuri G, Volynets V, Stahl C, Bischoff SC, Bergheim I: Toll-like receptors 1–9 are elevated in livers with fructose-induced hepatic steatosis. Br J Nutr 2011, 107(12):1727-1738.
• [16]Bischoff SC, Mailer R, Pabst O, Weier G, Sedlik W, Li Z, Chen JJ, Murphy DL, Gershon MD: Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice. Am J Physiol Gastrointest Liver Physiol 2009, 296(3):G685-G695.
• [17]Haub S, Ritze Y, Ladel I, Saum K, Hubert A, Spruss A, Trautwein C, Bischoff SC: Serotonin receptor type 3 antagonists improve obesity-associated fatty liver disease in mice. J Pharmacol Exp Ther 2011, 339(3):790-798.
• [18]Cote F, Fligny C, Bayard E, Launay JM, Gershon MD, Mallet J, Vodjdani G: Maternal serotonin is crucial for murine embryonic development. Proc Natl Acad Sci USA 2007, 104(1):329-334.
• [19]Lesurtel M, Soll C, Graf R, Clavien PA: Role of serotonin in the hepato-gastroIntestinal tract: an old molecule for new perspectives. Cell Mol Life Sci 2008, 65(6):940-952.
• [20]Ozer C, Gonul B, Ercan ZS, Take G, Erdogan D: The effect of tryptophan administration on ileum contractility and oxidant status in mice. Amino Acids 2007, 32(3):453-458.
• [21]Ozer C, Gonul B, Take G, Erdogan D, Tong E, Ercan ZS: Tryptophan administration increase contractility and change the ultrastructure of mice duodenum. Amino Acids 2004, 27(2):215-220.
• [22]Akiba Y, Takahashi K, Horiguchi M, Ohtani H, Saitoh S, Ohkawara H: L-tryptophan alleviates fatty liver and modifies hepatic microsomal mixed function oxidase in laying hens. Comp Biochem Physiol Comp Physiol 1992, 102(4):769-774.
• [23]Rogers SR, Pesti GM: Effects of tryptophan supplementation to a maize-based diet on lipid metabolism in laying hens. Br Poult Sci 1992, 33(1):195-200.
• [24]Cichoz-Lach H, Celinski K, Konturek PC, Konturek SJ, Slomka M: The effects of L-tryptophan and melatonin on selected biochemical parameters in patients with steatohepatitis. J Physiol Pharmacol 2010, 61(5):577-580.
• [25]Keszthelyi D, Troost FJ, Masclee AA: Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function. Neurogastroenterol Motil 2009, 21(12):1239-1249.
• [26]Kanuri G, Weber S, Volynets V, Spruss A, Bischoff SC, Bergheim I: Cinnamon extract protects against acute alcohol-induced liver steatosis in mice. J Nutr 2009, 139(3):482-487.
• [27]Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R: Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008, 57(6):1470-1481.
• [28]Thuy S, Ladurner R, Volynets V, Wagner S, Strahl S, Konigsrainer A, Maier KP, Bischoff SC, Bergheim I: Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr 2008, 138(8):1452-1455.
• [29]Gershon MD: Review article: serotonin receptors and transporters – roles in normal and abnormal gastrointestinal motility. Aliment Pharmacol Ther 2004, 20(Suppl 7):3-14.
• [30]Storlien LH, Jenkins AB, Chisholm DJ, Pascoe WS, Khouri S, Kraegen EW: Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid. Diabetes 1991, 40(2):280-289.
• [31]Doucet E, Almeras N, White MD, Despres JP, Bouchard C, Tremblay A: Dietary fat composition and human adiposity. Eur J Clin Nutr 1998, 52(1):2-6.
• [32]Assy N, Nassar F, Nasser G, Grosovski M: Olive oil consumption and non-alcoholic fatty liver disease. World J Gastroenterol 2009, 15(15):1809-1815.
• [33]Baum SJ, Kris-Etherton PM, Willett WC, Lichtenstein AH, Rudel LL, Maki KC, Whelan J, Ramsden CE, Block RC: Fatty acids in cardiovascular health and disease: a comprehensive update. J Clin Lipidol 2012, 6(3):216-234.
• [34]Sofi F, Giangrandi I, Cesari F, Corsani I, Abbate R, Gensini GF, Casini A: Effects of a 1-year dietary intervention with n-3 polyunsaturated fatty acid-enriched olive oil on non-alcoholic fatty liver disease patients: a preliminary study. Int J Food Sci Nutr 2010, 61(8):792-802.
• [35]Delarue J, LeFoll C, Corporeau C, Lucas D: N-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity? Reprod Nutr Dev 2004, 44(3):289-299.
• [36]Rivellese AA, De Natale C, Lilli S: Type of dietary fat and insulin resistance. Ann N Y Acad Sci 2002, 967:329-335.
• [37]Neschen S, Moore I, Regittnig W, Yu CL, Wang Y, Pypaert M, Petersen KF, Shulman GI: Contrasting effects of fish oil and safflower oil on hepatic peroxisomal and tissue lipid content. Am J Physiol Endocrinol Metab 2002, 282(2):E395-E401.
• [38]Spruss A, Bergheim I: Dietary fructose and intestinal barrier: potential risk factor in the pathogenesis of nonalcoholic fatty liver disease. J Nutr Biochem 2009, 20(9):657-662.
• [39]Farhadi A, Gundlapalli S, Shaikh M, Frantzides C, Harrell L, Kwasny MM, Keshavarzian A: Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis. Liver Int 2008, 28(7):1026-1033.
• [40]Stull MA, Pai V, Vomachka AJ, Marshall AM, Jacob GA, Horseman ND: Mammary gland homeostasis employs serotonergic regulation of epithelial tight junctions. Proc Natl Acad Sci USA 2007, 104(42):16708-16713.
• [41]Ruddell RG, Oakley F, Hussain Z, Yeung I, Bryan-Lluka LJ, Ramm GA, Mann DA: A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis. Am J Pathol 2006, 169(3):861-876.
• [42]Ferdinande L, Demetter P, Perez-Novo C, Waeytens A, Taildeman J, Rottiers I, Rottiers P, De Vos M, Cuvelier CA: Inflamed intestinal mucosa features a specific epithelial expression pattern of indoleamine 2,3-dioxygenase. Int J Immunopathol Pharmacol 2008, 21(2):289-295.
• [43]Osawa Y, Kanamori H, Seki E, Hoshi M, Ohtaki H, Yasuda Y, Ito H, Suetsugu A, Nagaki M, Moriwaki H, et al.: L-tryptophan-mediated enhancement of susceptibility to nonalcoholic fatty liver disease is dependent on the mammalian target of rapamycin. J Biol Chem 2011, 286(40):34800-34808.