Oral citrulline supplementation protects female mice from the development of non-alcoholic fatty liver disease (NAFLD)
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Impairments of intestinal barrier function are discussed as risk factors for the development and progression of non-alcoholic fatty liver disease (NAFLD). Studies suggest an association between arginine/citrulline homeostasis and the development of liver damages. Here, the effect of an oral l-citrulline (Cit) supplement on the development of a Western-style diet (WSD)-induced NAFLD was determined in mice.
Female 6- to 8-week-old C57BL/6J mice were either pair-fed a liquid Western-style or control diet (C) ± 2.5 g/kg bodyweight Cit for 6 weeks (C + Cit or WSD + Cit). Indices of liver damage, glucose metabolism, intestinal barrier function and NO synthesis were measured.
While bodyweight gain was similar between groups, markers of glucose metabolism like fasting blood glucose and HOMA index and markers of liver damage like hepatic triglyceride levels, number of neutrophils and plasminogen activator inhibitor-1 protein levels were significantly lower in WSD + Cit-fed mice when compared to WSD-fed mice only. Protein levels of the tight junction proteins occludin and zonula occludens-1 in duodenum were significantly lower in mice fed a WSD when compared to those fed a WSD + Cit (−~70 and −~60 %, respectively, P < 0.05), whereas portal endotoxin levels, concentration of 3-nitrotyrosine protein adducts in duodenum and toll-like receptor-4 mRNA expression in livers of WSD + Cit-fed mice were markedly lower than in WSD-fed mice (−~43 %, P = 0.056; −~80 and −~48 %, respectively, P < 0.05).
Our data suggest that the protective effects of supplementing Cit on the development of NAFLD in mice are associated with a decreased translocation of endotoxin into the portal vein.
KeywordsCitrulline Intestinal barrier function Endotoxin Occludin Non-alcoholic fatty liver disease
- HOMA index
Homeostasis model assessment index
Inducible nitric oxide synthase
Myeloid differentiation primary response gene 88
Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease activity score
Plasminogen activator inhibitor 1
Tumor necrosis factor alpha
Zonula occludens 1
4-Hydroxynonenal protein adducts
- 15.Wu G, Collins JK, Perkins-Veazie P, Siddiq M, Dolan KD, Kelly KA, Heaps CL, Meininger CJ (2007) Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the metabolic syndrome in Zucker diabetic fatty rats. J Nutr 137:2680–2685Google Scholar
- 16.Antunes MM, Leocadio PC, Teixeira LG, Leonel AJ, Cara DC, Menezes GB, Generoso SV, Cardoso VN, Alvarez-Leite JI, Correia MI (2015) Pretreatment with l-citrulline positively affects the mucosal architecture and permeability of the small intestine in a murine mucositis model. JPEN J Parenter Enteral Nutr 40:279–286CrossRefGoogle Scholar
- 17.Spruss A, Henkel J, Kanuri G, Blank D, Puschel GP, Bischoff SC, Bergheim I (2012) Female mice are more susceptible to nonalcoholic fatty liver disease: sex-specific regulation of the hepatic AMP-activated protein kinase-plasminogen activator inhibitor 1 cascade, but not the hepatic endotoxin response. Mol Med 18:1346–1355CrossRefGoogle Scholar
- 19.Sellmann C, Priebs J, Landmann M, Degen C, Engstler AJ, Jin CJ, Garttner S, Spruss A, Huber O, Bergheim I (2015) Diets rich in fructose, fat or fructose and fat alter intestinal barrier function and lead to the development of nonalcoholic fatty liver disease over time. J Nutr Biochem 26:1183–1192CrossRefGoogle Scholar
- 23.Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D, Orsak B, Subbarayan S, Webb A, Hecht J, Cusi K (2015) High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab 100:2231–2238CrossRefGoogle Scholar
- 32.Fu X, Li S, Jia G, Gou L, Tian X, Sun L, Ling X, Lan N, Yin X, Ma R, Liu L, Liu Y (2013) Protective effect of the nitric oxide pathway in l-citrulline renal ischaemia–reperfusion injury in rats. Folia Biol (Praha) 59:225–232Google Scholar
- 34.Du PJ, Vanheel H, Janssen CE, Roos L, Slavik T, Stivaktas PI, Nieuwoudt M, van Wyk SG, Vieira W, Pretorius E, Beukes M, Farre R, Tack J, Laleman W, Fevery J, Nevens F, Roskams T, Van der Merwe SW (2013) Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function. J Hepatol 58:1125–1132CrossRefGoogle Scholar
- 40.Chen BY, Lin DP, Su KC, Chen YL, Wu CY, Teng MC, Tsai YT, Sun CY, Wang SR, Chang HH (2011) Dietary zerumbone prevents against ultraviolet B-induced cataractogenesis in the mouse. Mol Vis 17:723–730Google Scholar