title: Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models.
abstract: Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation that starts with steatosis and progresses to non-alcoholic steatohepatitis (NASH). Recently, the number of patients with such liver diseases has increased, but the understanding of the fundamental mechanisms and appropriate therapies are lacking. Tamoxifen (TAM) is a selective estrogen receptor modulator. We previously reported that TAM plays a protective role against drug-induced and chemical-induced acute liver injuries. However, the effects of TAM on chronic liver injury, including steatosis and NASH, remain to be addressed. We first found that the administration of TAM to mouse models of steatosis and NASH significantly decreased the plasma ALT and AST levels. The administration of TAM decreased the accumulated fat and inflammation in the livers in both mouse models. In addition, we observed decreased hepatic mRNA levels of triglyceride synthesis, acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2), proinflammatory cytokines, tumor necrosis factor (TNF) α, and chemokines, monocyte chemoattractant protein (MCP) -1. TAM increased the extracellular signal-regulated kinase (ERK) phosphorylation, which is related to the proliferation and regeneration of liver and to decreased DGAT2 gene expression. Furthermore, a decrease in eukaryotic translational initiation factor (eIF2α), which is involved in apoptosis, was observed in both models. These findings suggest that TAM treatment exerts a hepatoprotective effect against steatosis and NASH, presumably via up-regulation of the ERK pathways and attenuation of eIF2α activation. These pathways represent a potential therapeutic target for steatosis and NASH in drug development.
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Miyashita
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000235:genetics; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D020011:Protective Agents / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D013629:Tamoxifen / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D020011:Protective Agents; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014409:Tumor Necrosis Factor-alpha; D013629:Tamoxifen; C516957:DGAT2 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D002334:Carnitine O-Palmitoyltransferase; D064429:Fatty Acid Synthases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D017346:Protein Serine-Threonine Kinases; C531557:eIF2alpha kinase, mouse; D048049:Extracellular Signal-Regulated MAP Kinases