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

Wada, Taira; Sunaga, Hiroshi; Miyata, Kazuki; Shirasaki, Haruno; Uchiyama, Yuki; Shimba, Shigeki

doi:10.1074/jbc.m115.693655

Cited by 66 publications

(43 citation statements)

References 59 publications

(65 reference statements)

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“…CYP1A1/1A2/1B1 knockout mice have lower cholesterol45. Whether AHR is related to circulating cholesterol remains elusive; AHR knockout mice have higher hepatic triglycerides in response to high-fat diet46. However, SNPs from CYP1A1/2 have not featured in GWAS of CVD or diabetes27282947, consistent with the lack of association with these two conditions.…”

Section: Discussionmentioning

confidence: 99%

Habitual coffee consumption and risk of type 2 diabetes, ischemic heart disease, depression and Alzheimer’s disease: a Mendelian randomization study

Kwok

Leung

Schooling

2016

Sci Rep

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Observationally, coffee is inversely associated with type 2 diabetes mellitus (T2DM), depression and Alzheimer’s disease, but not ischemic heart disease (IHD). Coffee features as possibly protective in the 2015 Dietary Guidelines for Americans. Short-term trials suggest coffee has neutral effect on most glycemic traits, but raises lipids and adiponectin. To clarify we compared T2DM, depression, Alzheimer’s disease, and IHD and its risk factors by genetically predicted coffee consumption using two-sample Mendelian randomization applied to large extensively genotyped case-control and cross-sectional studies. Childhood cognition was used as a negative control outcome. Genetically predicted coffee consumption was not associated with T2DM (odds ratio (OR) 1.02, 95% confidence interval (CI) 0.76 to 1.36), depression (0.89, 95% CI 0.66 to 1.21), Alzheimer’s disease (1.17, 95% CI 0.96 to 1.43), IHD (0.96, 95% CI 0.80 to 1.14), lipids, glycemic traits, adiposity or adiponectin. Coffee was unrelated to childhood cognition. Consistent with observational studies, coffee was unrelated to IHD, and, as expected, childhood cognition. However, contrary to observational findings, coffee may not have beneficial effects on T2DM, depression or Alzheimer’s disease. These findings clarify the role of coffee with relevance to dietary guidelines and suggest interventions to prevent these complex chronic diseases should be sought elsewhere.

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Section: Discussionmentioning

confidence: 99%

Habitual coffee consumption and risk of type 2 diabetes, ischemic heart disease, depression and Alzheimer’s disease: a Mendelian randomization study

Kwok

Leung

Schooling

2016

Sci Rep

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“…22,23 AhR activation often disrupts hepatic glucose and lipid metabolism producing disease, 54,[56][57][58][59][60][61][62][63] while inhibition of AhR is protective for metabolic illnesses. 28,41,55 Beneficial effects of AhR activity on liver glucose and lipid metabolism have also been shown, 41,42,64 demonstrating the need to examine each experimental design closely. Effects of species, strain, sex and age of animals are likely to be important.…”

Section: Liver Energy Metabolismmentioning

confidence: 99%

“…AhR activation promotes Socs3 expression suggesting that Socs3 is the target of AhR activation. 64 Several studies have shown that endogenous AhR suppresses transcription of genes required for cholesterol and fatty acid synthesis through a DRE-independent mechanism. Female C57BL/6J mice aged 10-12 weeks expressing total body AhRs with low or high binding affinity for ligand were examined.…”

Section: Liver Energy Metabolismmentioning

confidence: 99%

Environmental factors act through aryl hydrocarbon receptor activation and circadian rhythm disruption to regulate energy metabolism

Khazaal¹,

Jaeger²,

Bottum³

et al. 2018

JRLCR

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“…abundant in expression in the liver (44), our data suggested that AhR's transcriptional activity was elevated in HCV-infected cells. This observation is consistent with a previous report showing that kynurenine, an endogenous AhR agonist, is produced to high levels in HCV-infected patients (47).…”

Section: Ahr-cyp1a1 Regulates Production Of Hepatic Lipid and Hcvmentioning

confidence: 55%

“…In one exam-ple, hepatic lipid was reported to accumulate in mouse liver following TCDD treatment and activation of AhR (43). In contrast, high-fat-diet-induced lipid accumulation was potentiated in the liver of AhR Ϫ/Ϫ mice compared with the effect in WT mice (44). Previous papers have also suggested a correlation between activation of the AhR signaling pathway and lipid metabolism-related genes, most notably with expression of the gene encoding the CD36, a free fatty acid transporter (45).…”

Section: Ahr-cyp1a1 Regulates Production Of Hepatic Lipid and Hcvmentioning

confidence: 92%

The aryl hydrocarbon receptor–cytochrome P450 1A1 pathway controls lipid accumulation and enhances the permissiveness for hepatitis C virus assembly

Ohashi

Nishioka

Nakajima

et al. 2018

Journal of Biological Chemistry

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Viruses hijack and modify host cell functions to maximize viral proliferation. Hepatitis C virus (HCV) reorganizes host cell metabolism to produce specialized membrane structures and to modify organelles such as double-membrane vesicles and enlarged lipid droplets (LDs), thereby enabling virus replication and assembly. However, the molecular bases of these host-HCV interactions are largely unknown. Here, using a chemical screen, we demonstrate that the benzamide derivative flutamide reduces the host capacity to produce infectious HCV. Flutamide disrupted the formation of enlarged LDs in HCV-infected cells, thereby abolishing HCV assembly. We also report that aryl hydrocarbon receptor (AhR), a known flutamide target, plays a key role in mediating LD accumulation and HCV production. This AhR function in lipid production was also observed in HCV-uninfected Huh-7 cells and primary human hepatocytes, suggesting that AhR signaling regulates lipid accumulation independently of HCV infection. We further observed that a downstream activity, that of cytochrome P450 1A1 (CYP1A1), was the primary regulator of AhR-mediated lipid production. Specifically, blockade of AhR-induced CYP1A1 up-regulation counteracted LD overproduction, and overproduction of CYP1A1, but not of CYP1B1, in AhR-inactivated cells restored lipid accumulation. Of note, HCV infection up-regulated the AhR-CYP1A1 pathway, resulting in the accumulation of enlarged LDs. In conclusion, we demonstrate that the AhR-CYP1A1 pathway has a significant role in lipid accumulation, a hallmark of HCV infection that maximizes progeny virus production. Our chemicalgenetic analysis reveals a new strategy and lead compounds to control hepatic lipid accumulation as well as HCV infection.Viruses have minimum structures and lack metabolic pathways. To ensure their own survival, viruses hijack host cellular machineries and reorganize cellular environments to achieve efficient production of progeny virus (1, 2). Hepatitis C virus (HCV) 2 infection dynamically alters membrane structures or organelles in host hepatocytes, leading to the formation of unique membrane compartments. These novel structures include double membrane vesicles that serve as factories for viral genome replication, as well as lipid droplets (LDs) that allow efficient particle assembly (3-8). However, the molecular mechanism underlying this HCV-induced cellular reorganization remains poorly understood.After replication of HCV, viral RNA accumulates inside the double membrane vesicles, which are isolated membrane structures derived from the endoplasmic reticulum/Golgi or related membranes. HCV RNA then combines with viral structural proteins to assemble into progeny particles in association with the LDs. We previously reported that the surface membranes of the enlarged LDs serve as a platform for particle assembly (3), suggesting that LD metabolism in hepatocytes is closely related to permissivity for HCV production. In addition, it has been reported that the overproduction of lipids is a risk factor for hepatoc...

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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

Cited by 66 publications

References 59 publications

Habitual coffee consumption and risk of type 2 diabetes, ischemic heart disease, depression and Alzheimer’s disease: a Mendelian randomization study

Habitual coffee consumption and risk of type 2 diabetes, ischemic heart disease, depression and Alzheimer’s disease: a Mendelian randomization study

Environmental factors act through aryl hydrocarbon receptor activation and circadian rhythm disruption to regulate energy metabolism

The aryl hydrocarbon receptor–cytochrome P450 1A1 pathway controls lipid accumulation and enhances the permissiveness for hepatitis C virus assembly

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