Metabolic syndrome (MetS) is a multi-factorial disease that can develop from steatosis and contribute to the etiology of non-alcoholic fatty liver disease, cardiovascular disease, diabetes, and hepatocellular carcinoma. It is characterized by dyslipidemia, obesity, and increased hepatic triglycerides (TRGs) due to the accumulation of lipids from adipose lipolysis and increased absorption of dietary fat. 2,3,7,8- Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds have been implicated in MetS development, as well as diabetes and dyslipidemia. TCDD induces hepatic steatosis by increasing fatty acid and TRG levels, inhibiting adipocyte proliferation, decreasing glucose transport, and disrupting lipid and carbohydrate metabolism and transport. In this proposal, we will investigate aryl hydrocarbon receptor (AhR)-mediated systemic alterations in lipid metabolism and transport that contribute to hepatic steatosis, the initial step in Mets development. More specifically, we will test the hypothesis that AhR-mediates intestinal, circulatory and hepatic lipid uptake, metabolism, and transport effects leading to hepatic steatosis that involve dioxin response element (DRE)-independent mechanisms. Our preliminary data suggest that AhR-mediated changes in lipid transport and metabolism involve non-canonical AhR-mediated gene expression.
Our specific aims will examine (1) dietary fat as a lipid source in AhR-mediated hepatic steatosis, (2) AhR peroxisome proliferator activated receptor (PPAR) signaling pathways interactions that disrupt lipid transport and metabolism gene expression contributing to hepatic fat accumulation, (3) AhR/COUP-TF-mediated inhibition of hepatocyte nuclear factor 4 alpha (HNF4a)-regulated lipid transport and metabolism gene expression, (4) lipid composition and transport gene expression in human and mouse primary hepatocytes, and (5) the effects of AhR-ligands on serum lipid levels and composition in mice. These studies will not only elucidate the AhR-mediated mechanisms involved in steatosis, but also provide further evidence that TCDD and related compound exposure plays a contributory role in the etiology of MetS and its related diseases using non-canonical DRE-independent mechanisms. These studies also complement Project 4 (Hashsham) which examines effects on choline uptake and metabolism in the intestine and liver. In addition, collaborations with Project 2 (Thomas) and Research Support Core A (Zhang/Conolly) will identify other genetic traits relevant to AhR-mediated dyslipidemia and provide data to support the development of bioenergetic computational models regulated by the AhR, respectively.
Mets incidence is approaching pandemic proportions. Although genetics, sedentary lifestyle and increased caloric intake are significant factors, accumulating evidence suggests TCDD and related compounds have an underappreciated role in disease development. These studies will investigate the role of AhR in TCDD elicited steatosis, the initial step in the etiology of MetS. In addition to elucidating mechanisms, our results will support public health policies to reduce TCDD and related compound exposure, and establish the AhR as a potential therapeutic target for the treatment of MetS and its associated diseases.
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