The FXR agonist 6ECDCA reduces hepatic steatosis and oxidative stress induced by ethanol and low-protein diet in mice.
OBJECTIVE
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.
Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil.
F A R
FA
Lívero
Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil.
Aline Maria
AM
Stolf
Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil.
Arturo Alejandro
AA
Dreifuss
Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil.
Amanda Leite
AL
Bastos-Pereira
Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil.
Raphaella
R
Chicorski
Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil.
Liana Gomes
LG
de Oliveira
Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil.
Carlos Eduardo Alves
CE
de Souza
Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil.
Isabella Aviles
IA
Fabossi
Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil.
I S
IS
Rabitto
Department of Cell Biology, Federal University of Paraná, Curitiba, Brazil.
Luiza Helena
LH
Gremski
Department of Pharmacy, Federal University of Paraná, Curitiba, Brazil.
Raílson
R
Henneberg
Department of Medical Pathology, Federal University of Paraná, Curitiba, Brazil.
José Ederaldo Queiroz
JE
Telles
Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, Amsterdam, The Netherlands.
Ronald P J
RP
Oude Elferink
Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil. Electronic address: aleacco@ufpr.br.
Alexandra
A
Acco
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002374:Catalase / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D000431:Ethanol / Q000008:administration & dosage; D005234:Fatty Liver / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000378:metabolism; D006651:Histocytochemistry; D008108:Liver Diseases, Alcoholic / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D002374:Catalase; D002635:Chenodeoxycholic Acid; D002784:Cholesterol; D000431:Ethanol; D005765:Gastrointestinal Agents; D005982:Glutathione Transferase; D018160:Receptors, Cytoplasmic and Nuclear; D013482:Superoxide Dismutase; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated
6ECDCA; Ethanol; FXR; Liver; Oxidative stress; Steatosis