The FXR agonist 6ECDCA reduces hepatic steatosis and oxidative stress induced by ethanol and low-protein diet in mice.

BACKGROUND AND AIM: Excessive ethanol consumption can lead to development of hepatic steatosis. Since the FXR receptor regulates adipose cell function and liver lipid metabolism, the aim of this work was to examine the effects of the FXR agonist 6ECDCA on alcoholic liver steatosis development and on oxidative stress induced by ethanol consumption. METHODS: Swiss mice (n=24) received a low-protein diet (6%) and a liquid diet containing 10% ethanol or water for 6weeks. In the last 15days mice received oral treatment with 6ECDCA (3mgkg(-1)) or 1% tween (vehicle). The experimental groups (n=6) were: water+tween, water+6ECDCA, ethanol+tween and ethanol+6ECDCA. Moreover, as a diet control, we used a basal group (n=6), fed by a normal-proteic diet (23%) and water. After the treatment period, the animals were anesthetized for sample collection to perform plasma biochemistry assays, hepatic oxidative stress assays, hepatic cholesterol and triglycerides measurements, liver histology and hepatic gene expression. RESULTS: Ethanol associated with low-protein diet induced hepatic oxidative stress, increased plasma transaminases and induced hepatic lipid accumulation. Many of these parameters were reversed by the administration of 6ECDCA, including amelioration of lipid accumulation and lipoperoxidation, and reduction of reactive oxygen species. These effects were possibly mediated by regulation of Srebpf1 and FAS gene expression, both reduced by the FXR agonist. CONCLUSIONS: Our data demonstrated that 6ECDCA reverses the accumulation of lipids in the liver and decreases the oxidative stress induced by ethanol and low-protein diet. This FXR agonist is promising as a potential therapy for alcoholic liver steatosis.

Effects of statins on liver cell function and inflammation in septic rats.

BACKGROUND: Several studies suggest that the presence of statins may be beneficial during sepsis, but this idea is controversial. The aim of this study was to investigate the effects of long-term statin treatment in the livers of septic animals, focusing on its antioxidant, antiinflammatory, and metabolic properties. MATERIALS AND METHODS: Male Wistar rats were treated orally with simvastatin, atorvastatin, or vehicle once a d. After 30 d, sepsis was induced by cecal ligation and puncture (CLP) in Control, Simvastatin-treated, and Atorvastatin-treated groups, while the Sham group underwent only laparotomy. The Basal Simvastatin and Basal Atorvastatin groups received only their respective drugs without surgery. Twenty-four h after CLP or laparotomy, samples were collected from anesthetized rats for evaluation of hepatic oxidative stress, liver histology, hepatic mitochondria enzyme activity, leukocyte counts in blood and peritoneal cavity, gene expression of hepatic superoxide dismutase and TNF-2, and plasma biochemistry. RESULTS: Most parameters that we tested exhibited expected changes upon sepsis induction. However, statin treatment only improved liver mitochondrial enzymatic activity. In other parameters, simvastatin and atorvastatin failed to protect the liver against injuries incurred upon the CLP-induced polymicrobial sepsis model. CONCLUSIONS: Pretreatment with simvastatin or atorvastatin alone before sepsis induction improved mitochondrial activity in the liver; however, this result was not reproduced in other biomarkers of liver function and leukocyte migration during sepsis. Future studies should be performed to evaluate whether statins can be combined with other drugs to increase the efficacy of sepsis therapy.