title: Activation of the aryl hydrocarbon receptor induces hepatic steatosis via the upregulation of fatty acid transport.
abstract: The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix/Per-ARNT-Sim domain transcription factor, which is activated by various xenobiotic ligands. AHR is known to be abundant in liver tissue and to be associated with hepatic steatosis. However, it has not yet been elucidated how the activation of AHR promotes hepatic steatosis. The aim of this study is to clarify the role of AHR in hepatic steatosis. The intraperitoneal injection of 3-methylcholanthrene (3MC), a potent AHR ligand, into C57BL/6J mice significantly increased the levels of triglycerides and six long-chain monounsaturated fatty acids in the livers of mice, resulting in hepatic microvesicular steatosis. 3MC significantly enhanced the expression level of fatty acid translocase (FAT), a factor regulating the uptake of long-chain fatty acids into hepatocytes, in the liver. In an in vitro experiment using human hepatoma HepG2 cells, 3MC increased the expression level of FAT, and the downregulation of AHR by AHR siRNA led to the suppression of 3MC-induced FAT expression. In addition, the mRNA level of peroxisome proliferator-activated receptor (PPAR) α, an upstream factor of FAT, was increased in the livers of 3MC-treated mice. Taking together, AHR activation induces hepatic microvesicular steatosis by increasing the expression level of FAT.
authors.affiliation: Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kawano
authors.forename: Shin
authors.initials: S
authors.lastname: Nishiumi
authors.forename: Shinwa
authors.initials: S
authors.lastname: Tanaka
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nobutani
authors.forename: Akira
authors.initials: A
authors.lastname: Miki
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yano
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Seo
authors.forename: Hiromu
authors.initials: H
authors.lastname: Kutsumi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ashida
authors.forename: Takeshi
authors.initials: T
authors.lastname: Azuma
authors.forename: Masaru
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D001692:Biological Transport; D018955:CD36 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000096:biosynthesis; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D018955:CD36 Antigens; D005227:Fatty Acids; D008024:Ligands; D047493:PPAR alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D047490:Retinoid X Receptor alpha; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D008748:Methylcholanthrene; D019363:Cytochrome P-450 CYP1A1