title: Carvedilol attenuates the progression of alcohol fatty liver disease in rats.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Legal Medicine, Yamaguchi University Graduate School of Medicine, Ube, Japan. czhliu@yamaguchi-u.ac.jp
authors.forename: Jinyao
authors.initials: J
authors.lastname: Liu
authors.forename: Izumi
authors.initials: I
authors.lastname: Takase
authors.forename: Ayako
authors.initials: A
authors.lastname: Hakucho
authors.forename: Nanako
authors.initials: N
authors.lastname: Okamura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fujimiya
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D015153:Blotting, Western; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D002492:Central Nervous System Depressants / Q000097:blood; D018450:Disease Progression; D000431:Ethanol / Q000097:blood; D005235:Fatty Liver, Alcoholic / Q000188:drug therapy* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D055166:Hepatic Stellate Cells / Q000187:drug effects; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000378:metabolism; D011412:Propanolamines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D002492:Central Nervous System Depressants; D011412:Propanolamines; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D000077261:Carvedilol; D000431:Ethanol; D008734:Methoxyhydroxyphenylglycol