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

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2016 Feb 12

PMID 26865635

Citations 41

Authors

Taira Wada

Hiroshi Sunaga

Kazuki Miyata

Haruno Shirasaki

Yuki Uchiyama

Shigeki Shimba

Affiliations

Soon will be listed here.

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.

Citing Articles

AhR governs lipid metabolism: the role of gut microbiota.

Zheng W, Liu M, Lv X, He C, Yin J, Ma J Front Microbiol. 2025; 16:1442282.

PMID: 39944639 PMC: 11817270. DOI: 10.3389/fmicb.2025.1442282.

PAMK Ameliorates Non-Alcoholic Steatohepatitis and Associated Anxiety/Depression-like Behaviors Through Restoring Gut Microbiota and Metabolites in Mice.

Yang J, Ou W, Lin G, Wang Y, Chen D, Zeng Z Nutrients. 2024; 16(22).

PMID: 39599623 PMC: 11597619. DOI: 10.3390/nu16223837.

Branched-chain amino acids alleviate NAFLD via inhibiting de novo lipogenesis and activating fatty acid β-oxidation in laying hens.

Jian H, Li R, Huang X, Li J, Li Y, Ma J Redox Biol. 2024; 77:103385.

PMID: 39426289 PMC: 11536022. DOI: 10.1016/j.redox.2024.103385.

Drug-Induced Fatty Liver Disease (DIFLD): A Comprehensive Analysis of Clinical, Biochemical, and Histopathological Data for Mechanisms Identification and Consistency with Current Adverse Outcome Pathways.

Lopez-Pascual E, Rienda I, Perez-Rojas J, Rapisarda A, Garcia-Llorens G, Jover R Int J Mol Sci. 2024; 25(10).

PMID: 38791241 PMC: 11121209. DOI: 10.3390/ijms25105203.

Aryl Hydrocarbon Receptor (AhR) Signaling in Colonic Cells and Tumors.

Safe S, Han H, Jayaraman A, Davidson L, Allred C, Ivanov I Receptors (Basel). 2024; 2(1):93-99.

PMID: 38651159 PMC: 11034912. DOI: 10.3390/receptors2010005.

References

Xie W, Barwick J, Simon C, Pierce A, Safe S, Blumberg B . Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev. 2000; 14(23):3014-23. PMC: 317112. DOI: 10.1101/gad.846800. View

Lu P, Yan J, Liu K, Garbacz W, Wang P, Xu M . Activation of aryl hydrocarbon receptor dissociates fatty liver from insulin resistance by inducing fibroblast growth factor 21. Hepatology. 2015; 61(6):1908-19. PMC: 4441569. DOI: 10.1002/hep.27719. View

Seidel S, Winters G, Rogers W, Ziccardi M, Li V, Keser B . Activation of the Ah receptor signaling pathway by prostaglandins. J Biochem Mol Toxicol. 2001; 15(4):187-96. DOI: 10.1002/jbt.16. View

Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, Hilton D . SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem. 2001; 276(51):47944-9. DOI: 10.1074/jbc.M104602200. View

Ohtake F, Takeyama K, Matsumoto T, Kitagawa H, Yamamoto Y, Nohara K . Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature. 2003; 423(6939):545-50. DOI: 10.1038/nature01606. View

Zhang S, Qin C, Safe S . Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environ Health Perspect. 2003; 111(16):1877-82. PMC: 1241760. DOI: 10.1289/ehp.6322. View

Steinberg G, Smith A, Wormald S, Malenfant P, Collier C, Dyck D . Endurance training partially reverses dietary-induced leptin resistance in rodent skeletal muscle. Am J Physiol Endocrinol Metab. 2003; 286(1):E57-63. DOI: 10.1152/ajpendo.00302.2003. View

Alexander W, Hilton D . The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu Rev Immunol. 2004; 22:503-29. DOI: 10.1146/annurev.immunol.22.091003.090312. View

Ueki K, Kondo T, Kahn C . Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol. 2004; 24(12):5434-46. PMC: 419873. DOI: 10.1128/MCB.24.12.5434-5446.2004. View

10.

Bradford M . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54. DOI: 10.1016/0003-2697(76)90527-3. View

11.

JAMDAR S . Glycerolipid biosynthesis in rat adipose tissue. Influence of adipose-cell size and site of adipose tissue on triacylglycerol formation in lean and obese rats. Biochem J. 1978; 170(1):153-60. PMC: 1183872. DOI: 10.1042/bj1700153. View

12.

Poland A, Knutson J . 2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol. 1982; 22:517-54. DOI: 10.1146/annurev.pa.22.040182.002505. View

13.

Ema M, Sogawa K, Watanabe N, Chujoh Y, Matsushita N, Gotoh O . cDNA cloning and structure of mouse putative Ah receptor. Biochem Biophys Res Commun. 1992; 184(1):246-53. DOI: 10.1016/0006-291x(92)91185-s. View

14.

Reyes H, Hankinson O . Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor. Science. 1992; 256(5060):1193-5. DOI: 10.1126/science.256.5060.1193. View

15.

Burbach K, Poland A, Bradfield C . Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc Natl Acad Sci U S A. 1992; 89(17):8185-9. PMC: 49882. DOI: 10.1073/pnas.89.17.8185. View

16.

Pineau T, Hilbert D, McPhail T, Lee S, Kimura S, Nebert D . Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science. 1995; 268(5211):722-6. DOI: 10.1126/science.7732381. View

17.

Hankinson O . The aryl hydrocarbon receptor complex. Annu Rev Pharmacol Toxicol. 1995; 35:307-40. DOI: 10.1146/annurev.pa.35.040195.001515. View

18.

Schmidt J, Su G, Reddy J, Simon M, Bradfield C . Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. Proc Natl Acad Sci U S A. 1996; 93(13):6731-6. PMC: 39095. DOI: 10.1073/pnas.93.13.6731. View

19.

Schmidt J, Bradfield C . Ah receptor signaling pathways. Annu Rev Cell Dev Biol. 1996; 12:55-89. DOI: 10.1146/annurev.cellbio.12.1.55. View

20.

Sinal C, Bend J . Aryl hydrocarbon receptor-dependent induction of cyp1a1 by bilirubin in mouse hepatoma hepa 1c1c7 cells. Mol Pharmacol. 1997; 52(4):590-9. DOI: 10.1124/mol.52.4.590. View