Carvedilol Attenuates the Progression of Alcohol Fatty Liver Disease in Rats
Reprint requests: Jinyao Liu, MD, PhD, Department of Legal Medicine, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan; Tel.: +81-836-22-2234; Fax: +81-836-22-2232; E-mail: firstname.lastname@example.org
Hepatosteatosis is an essential step in liver disease progression. However, the mechanisms that mediate the progression of hepatosteatosis and the optimal inhibitor of them remain largely unclear. The sympathetic nervous system (SNS) is responsible for the lipid metabolism and the accumulation of collagen that occurs in an injured liver. Medicines that inhibit this pathway may be a relevant treatment for the hepatosteatosis, and then reduce the liver injury that progresses through the stage of steatosis to fibrosis.
Using an ethanol-liquid-diet-fed rat model of alcohol fatty liver disease (AFLD), we studied the effects of carvedilol, which can block the SNS completely via β1, β2, and α1 adrenergic receptors, on the sympathetic tone, hepatosteatosis, and fibrosis based on histological, immunohistochemical, Western blot, and reverse transcriptase polymerase chain reaction analyses.
Carvedilol inhibited the ethanol-induced whole-body and hepatic sympathetic activities based on the serum 3-methoxy-4-hydroxyphenylglycol level and hepatic tyrosine hydroxylase expression. Carvedilol attenuated the hepatosteatosis, as evidenced by reduced hepatic triglyceride level and the accumulation of fatty droplets within hepatocytes, down-regulated fatty acid synthase and sterol regulatory element binding protein-1, and up-regulated peroxisome proliferator-activated receptor-α. No fibrosis signs were shown in our rat model. Carvedilol inhibited ethanol-induced the thickening of zone 3 vessel walls, reduced the activation of hepatic stellate cells (HSCs), and decreased the induction of collagen, transforming growth factor β1, and tissue inhibitor of metalloproteinases-1. Tumor necrosis factor α (TNF-α) was expressed on the activated HSCs and inhibited by carvedilol based on the immunohistochemical double staining analysis.
Ethanol metabolism-induced lipogenesis may trigger the SNS-activated HSCs feedback loop, and then induct the activated HSCs and the activated HSCs–derived TNF-α, the mediator of lipogenesis, overproduction. Carvedilol may block this feedback loop via antisympathetic activity and demonstrate its preventive role on the development of hepatosteatosis in rat with AFLD.