Effect of tryptophan supplementation on diet-induced non-alcoholic fatty liver disease in mice.

Intestinal serotonin (5-hydroxytrypamine, 5-HT) metabolism is thought to play a role in gut functions by regulating motility, permeability and other functions of the intestine. In the present study, we investigated the effect of tryptophan (TRP), the precursor of 5-HT, supplementation on intestinal barrier functions and non-alcoholic fatty liver disease (NAFLD). An established mouse model of NAFLD induced by feeding a fructose-rich diet (N group) was used in the present study. TRP was administered orally for 8 weeks to C57BL/6J control or NAFLD mice. NAFLD-related liver parameters (hepatic TAG and Oil Red O staining), intestinal barrier parameters (tight-junction protein occludin and portal plasma lipopolysaccharides (LPS)) and 5-HT-related parameters (5-HT, 5-HT transporter (SERT) and motility) were measured. We observed reduced duodenal occludin protein concentrations (P= 0·0007), high portal plasma LPS concentrations (P= 0·005) and an elevated liver weight:body weight ratio (P= 0·01) in the N group compared with the parameters in the control group. TRP supplementation led to an increase in occludin concentrations (P= 0·0009) and consecutively reduced liver weight:body weight ratio (P= 0·009) as well as overall hepatic fat accumulation in the N group (P= 0·05). In addition, the N group exhibited reduced SERT protein expression (P= 0·002), which was normalised by TRP supplementation (P= 0·02). For the first time, our data indicate that oral TRP supplementation attenuates experimental NAFLD in mice. The underlying mechanisms are not clear, but probably involve stabilisation of the intestinal barrier in the upper small intestine and amelioration of the dysregulated intestinal serotonergic system.

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

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.