L-carnitine supplementation attenuates NAFLD progression and complications in a methionine and choline deficient mouse model

Background and Aims Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in developed countries. Lipid droplets accumulation, subsequent generation of reactive oxygen species (ROS) and fibrosis deposition cause the progression to non-alcoholic steatohepatitis (NASH). L-Carnitine (LC) has been proposed to prevent liver damage of various etiologies. The aim of the study was to investigate the effects of LC supplementation on liver fat deposition, oxidative stress and fibrosis development mechanism in a mouse model of steatohepatitis induced by a methionine-choline deficient diet (MCDD). In the same model we also analyzed the role of LC on cardiac tissue, considering the highest rates of mortality in NAFLD due to cardiovascular events. Methods The MCD diet model, best approximates the histological features of human NASH. Ten-week-old male C57BL/6 mice were divided into 3 experimental groups: one group (n=10) were fed with 120g/week of normal diet (CNT) and two groups (n=10 each group) with 120g/week of MCDD for nr. 6 weeks. After the first 3 weeks, one of the MCDD food group was enriched with 200mg/kg/die oral LC (MCDD+LC) until the end of the experiments. Results The LC supplementation delayed liver lipid accumulation (-28%, p=0.0005) and increased pCAMKII protein level (p=0.0308) in respect of MCDD group. LC supplementation also showed a role in controlling liver ROS generation (p=0.0386), restored pERK protein (p=0.005) and consequently delayed hepatotoxicity by the action of PPARγ (p=0.0088) on Nf-ƙB expression (p=0.0009) compared with the MCDD group. Finally, LC supplementation caused a sharp decrease of αSMA (p=0.04) compared to the MCDD group. In parallel, we investigated the LC role to control cardiac stress and ROS production. LC decreased ROS production (p=0.01). To control fibrosis progression, LC significantly decreases pSTAT3/STAT3 (p=0.01) and pERK2/ERK2 expression (p=0.02) compared with MCDD group. As in liver, LC significantly decreased αSMA protein level (p=0.04) in relation to MCDD group. Conclusions We have demonstrated that LC decreased the severity of experimental NAFLD progression controlling lipid accumulation, oxidative stress imbalance and fibrosis progression in both liver and cardiac tissues analyzed. LC affected the shared oxidative stress mechanism pathway. Further studies are required to determine whether a long-term LC supplementation is able to control the pathophysiologic evolution of this disease and its related complications.