Activation of the aryl hydrocarbon receptor induces hepatic steatosis via the upregulation of fatty acid transport.
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.
Kawano
Yuki
Y
Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan.
Nishiumi
Shin
S
Tanaka
Shinwa
S
Nobutani
Kentaro
K
Miki
Akira
A
Yano
Yoshihiko
Y
Seo
Yasushi
Y
Kutsumi
Hiromu
H
Ashida
Hitoshi
H
Azuma
Takeshi
T
Yoshida
Masaru
M
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
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