Hepatic steatosis, or fatty liver, is strongly associated with metabolic syndrome. Understanding the mechanism of hepatic steatosis will help to prevent and treat this common medical problem. The aryl hydrocarbon receptor (AhR), highly expressed in the liver, is a transcriptional factor originally cloned as a """"""""xenobiotic receptor."""""""" AhR regulates the expression of xenobiotic enzymes by binding to the dioxin response elements (DREs) present in target gene promoters. Subsequent studies suggest that AhR may also have endobiotic functions by affecting physiology, but the molecular mechanism for the endobiotic function of AhR remains largely unknown. Our preliminary results showed that: (1) Transgenic mice expressing the constitutively activated AhR (CA-AhR) exhibited hepatic steatosis when maintained in chow diet, a phenotype that has been recapitulated in wild type mice treated with the AhR agonist;(2) Activation of AhR in transgenic mice induced the expression of CD36/FAT, a fatty acid transporter important for hepatic fatty acid uptake and steatosis;(3) Activation of CD36 gene expression was also seen in wild type mice treated with the AhR agonist and this activation was abolished in AhR-/- mice;(4) Treatment of human hepatoma cells with AhR agonist induced the expression of CD36 and increased the uptake of free fatty acids;(5) The mouse and human CD36 gene promoters were activated by AhR;(6) Activation of AhR inhibited very-low density lipoprotein (VLDL)-triglyceride secretion;(7) Activation of AhR suppressed peroxisomal fatty acid 2-oxidation;and 8) CA-AhR transgenic mice in third generation of backcross to C57BL/6J showed spontaneous steatosis and signs of compromised glucose tolerance. Based on our preliminary data, we hypothesize that activation of AhR promotes hepatic steatosis through multiple mechanisms, including the activation of fatty acid transporter CD36, suppression of fatty acid oxidation, and inhibition of export of triglycerides. By using the """"""""gain-of-function"""""""" CA-AhR transgenic, """"""""loss-of-function"""""""" AhR-/- and CD36-/-, and AhR ligand-treated wild type mice, we propose four specific aims: (1) To determine whether activation of AhR is sufficient and necessary to induce hepatic steatosis;(2) To characterize AhR-induced hepatic steatosis;(3) To determine whether the fatty acid transporter CD36 is necessary for the steatotic effect of AhR;and (4) To determine the molecular mechanism by which AhR regulates the expression of CD36. To our knowledge, the current study represents the first attempt to determine the pathophysiological role of AhR in hepatic steatosis and associated metabolic abnormalities. The tetracycline inducible AhR transgenic mice, exhibiting fatty liver even when maintained in chow diet, represent a novel, convenient and reversible model of nonalcoholic fatty liver disease (NAFLD). It is hoped that results from this study may help to establish AhR and its target fatty acid transporter as novel therapeutic targets for fatty liver in human patients.
The aryl hydrocarbon receptor (AhR) is a transcriptional factor originally cloned as a xenobiotic receptor to sense xenobiotic toxicants. The goal of this study is to determine whether AhR has an endobiotic role in promoting hepatic steatosis. Hepatic steatosis, or fatty liver, is a common medical problem strongly associated with metabolic syndrome. It is hoped that results from this study may help to establish AhR as a novel therapeutic target for fatty liver in human patients.
|Choi, You-Jin; Zhou, Dong; Barbosa, Anne Caroline S et al. (2018) Activation of Constitutive Androstane Receptor Ameliorates Renal Ischemia-Reperfusion-Induced Kidney and Liver Injury. Mol Pharmacol 93:239-250|
|Bi, Yuhan; Jiang, Mengxi; Guo, Weiwei et al. (2018) Sex-Dimorphic and Sex Hormone-Dependent Role of Steroid Sulfatase in Adipose Inflammation and Energy Homeostasis. Endocrinology 159:3365-3377|
|Bi, Yuhan; Shi, Xiongjie; Zhu, Junjie et al. (2018) Regulation of Cholesterol Sulfotransferase SULT2B1b by Hepatocyte Nuclear Factor 4? Constitutes a Negative Feedback Control of Hepatic Gluconeogenesis. Mol Cell Biol 38:|
|Garbacz, Wojciech G; Uppal, Hirdesh; Yan, Jiong et al. (2018) Chronic Activation of Liver X Receptor Sensitizes Mice to High Cholesterol Diet-Induced Gut Toxicity. Mol Pharmacol 94:1145-1154|
|Niu, Yongdong; Xu, Meishu; Slagle, Betty L et al. (2017) Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein-induced hepatocarcinogenesis. Hepatology 65:893-906|
|Garbacz, Wojciech G; Jiang, Mengxi; Xu, Meishu et al. (2017) Sex- and Tissue-Specific Role of Estrogen Sulfotransferase in Energy Homeostasis and Insulin Sensitivity. Endocrinology 158:4093-4104|
|Jiang, Mengxi; Xu, Meishu; Ren, Songrong et al. (2017) Transgenic Overexpression of Steroid Sulfatase Alleviates Cholestasis. Liver Res 1:63-69|
|Garbacz, Wojciech G; Lu, Peipei; Miller, Tricia M et al. (2016) Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance. Mol Cell Biol 36:2715-2727|
|Wei, Yuan; Tang, Chenxiao; Sant, Vinayak et al. (2016) A Molecular Aspect in the Regulation of Drug Metabolism: Does PXR-Induced Enzyme Expression Always Lead to Functional Changes in Drug Metabolism? Curr Pharmacol Rep 2:187-192|
|Zhao, Zanmei; Xu, Dan; Li, Shuqiang et al. (2016) Activation of Liver X Receptor Attenuates Oleic Acid-Induced Acute Respiratory Distress Syndrome. Am J Pathol 186:2614-22|
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