Preventive effects of citrulline on Western diet-induced non-alcoholic fatty liver disease in rats

Abstract

A Western diet induces insulin resistance, liver steatosis (non-alcoholic fatty liver disease (NAFLD)) and intestinal dysbiosis, leading to increased gut permeability and bacterial translocation, thus contributing to the progression of NAFLD to non-alcoholic steatohepatitis. In the present study, we sought, in a model of Western diet-induced NAFLD, to determine whether citrulline (Cit), an amino acid that regulates protein and energy metabolism, could decrease Western diet-induced liver injuries, as well as the mechanisms involved. Sprague-Dawley rats were fed a high-fat diet (45 %) and fructose (30 %) in drinking water or a control diet associated with water (group C) for 8 weeks. The high-fat, high-fructose diet (Western diet) was fed either alone (group WD) or with Cit (1 g/kg per d) (group WDC) or an isonitrogenous amount of non-essential amino acids (group WDA). We evaluated nutritional and metabolic status, liver function, intestinal barrier function, gut microbiota and splanchnic inflammatory status. Cit led to a lower level of hepatic TAG restricted to microvesicular lipid droplets and to a lower mRNA expression of CCAAT-enhancer-binding protein homologous protein, a marker of endoplasmic reticulum stress, of pro-inflammatory cytokines Il6 (P < 0·05) and Tnfα, and of toll-like receptor 4 (Tlr4) (P < 0·05). Cit also improved plasma TAG and insulin levels. In the colon, it decreased inflammation (Tnfα and Tlr4 expressions) and increased claudin-1 protein expression. This was associated with higher levels of Bacteroides/Prevotella compared with rats fed the Western diet alone. Cit improves Western diet-induced liver injuries via decreased lipid deposition, increased insulin sensitivity, lower inflammatory process and preserved antioxidant status. This may be related in part to its protective effects at the gut level.

Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases

“…Many studies have also associated dietary phosphatidylcholine and L-carnitine consumption with generation of specific metabolites (ie, trimethylamine (TMA) and TMA N-oxide) and future CVD events 174. Not surprisingly, dietary interventions might be able to reverse a Western-diet induced liver phenotype as shown, for example, for citrulline 175. Overall, the composition of Western diets might contribute to the development/progression of NAFLD via generation of overweight and obesity, and induce activation of specific inflammatory pathways.…”

Fructose and sugar: A major mediator of non-alcoholic fatty liver disease

“…Thus, the microbiome may have a role in fructose-induced fatty liver through an interaction with fructose metabolism in the intestinal wall. Finally, fructose has been found to alter the gut microbiome, which also favors NAFLD development along with increased gut permeability through loss of tight junctions leading to more progressive disease (92–94). …”

Fructose and NAFLD: The Multifaceted Aspects of Fructose Metabolism

“…As a consequence, their key target enzymes regulating lipid synthesis, such as Fatty Acid Synthase (FASN) and Acetyl-CoA Carboxylase (ACC), also increase as shown for example in rodents submitted to a 60% high fructose diet for eight weeks [18] or to a western diet where fructose is provided as a 30%-fructose containing beverage for eight weeks [19]. …”

“…Many studies, both in animal models [18,19] and more recently in patients with NASH, show that abnormal hepatokines production also plays a key role in the pathogenesis of NASH [38,39]. Hepatokines such as Fetuin A, Fibroblast growth factor 21 (FGF-21), Leucocyte cell-derived chemotaxin 2 (LECT2), and Angiopoietin-like protein (ANGPTL) released by the steatotic liver may contribute to peripheral organ dysfunction [40,41].…”