title: Aryl Hydrocarbon Receptor Plays Protective Roles against High Fat Diet (HFD)-induced Hepatic Steatosis and the Subsequent Lipotoxicity via Direct Transcriptional Regulation of Socs3 Gene Expression.
abstract: Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor regulating the expression of genes involved in xenobiotic response. Recent studies have suggested that AhR plays essential roles not only in xenobiotic detoxification but also energy metabolism. Thus, in this study, we studied the roles of AhR in lipid metabolism. Under high fat diet (HFD) challenge, liver-specific AhR knock-out (AhR LKO) mice exhibited severe steatosis, inflammation, and injury in the liver. Gene expression analysis and biochemical study revealed thatde novolipogenesis activity was significantly increased in AhR LKO mice. In contrast, induction of suppressor of cytokine signal 3 (Socs3) expression by HFD was attenuated in the livers of AhR LKO mice. Rescue of theSocs3gene in the liver of AhR LKO mice cancelled the HFD-induced hepatic lipotoxicities. Promoter analysis established Socs3 as novel transcriptional target of AhR. These results indicated that AhR plays a protective role against HFD-induced hepatic steatosis and the subsequent lipotoxicity effects, such as inflammation, and that the mechanism of protection involves the direct transcriptional regulation ofSocs3expression by AhR.
authors: From the Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan.
authors: Taira
authors: T
authors: Wada
authors: From the Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan.
authors: Hiroshi
authors: H
authors: Sunaga
authors: From the Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan.
authors: Kazuki
authors: K
authors: Miyata
authors: From the Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan.
authors: Haruno
authors: H
authors: Shirasaki
authors: From the Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan.
authors: Yuki
authors: Y
authors: Uchiyama
authors: From the Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan shimba.shigeki@nihon-u.ac.jp.
authors: Shigeki
authors: S
authors: Shimba
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics*; D001665:Binding Sites; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004041:Dietary Fats; D018336:Receptors, Aryl Hydrocarbon; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C484722:Ahr protein, mouse; C491411:Socs3 protein, mouse
keywords: aryl hydrocarbon receptor (AhR); inflammation; lipid metabolism; liver; liver injury; liver metabolism; suppressor of cytokine signal 3 (Socs3)