Tiparp in diet and AHR-ligand dependent fatty liver disease
Obesity and its associated disorders such as metabolic syndrome, including type 2 diabetes (T2D), have reached epidemic proportions in Western countries. Nonalcoholic fatty liver disease (NAFLD) is closely associated with metabolic syndrome. However, the molecular mechanisms of NAFLD remain to be defined. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the activity of numerous environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin; TCDD). However, many commonly consumed dietary compounds, including dietary indoles also activate this receptor. Activation of AHR by dioxin causes several metabolic alterations in exposed rodents, including steatohepatitis. We found that loss of TCDD-inducible poly-ADP-ribose polymerase (TIPARP), which is an AHR target gene, a mono-ADP-ribosyltransferase and a repressor of transcription, increases the sensitivity to AHR ligand (dioxin)-induced steatohepatitis. This effect was also dependent on TIPARP´s catalytic activity. However, it is not if dietary activators of AHR, such as indoles, also increase sensitivity to fatty liver disease in a Tiparp-dependent manner.
We have recently observed that TIPARP also negatively regulates PPARs, which are prominent therapeutic targets for T2D. Since PPARs play crucial roles in lipid homeostasis, energy metabolism and metabolic disease, TIPARP and ADP-ribosylation may have broad and fundamentally important roles in liver homeostasis and metabolic regulation. Our working hypothesis is that TIPARP and ADP-ribosylation are key regulators of metabolically important nuclear receptors and represent new therapeutic targets for NAFLD and/or NASH, which are serious health concerns with limited pharmacotherapeutic options. To test this hypothesis we will place wild-type and genetically modified Tiparp mouse models on a variety of different dietary interventions, including high fat diet (western diet), diet high in plant-derived AHR ligands (known as indoles), fasting and re-feeding studies. In another set of experiments, we will expose mice to the PPAR ligands to determine the impact of Tiparp loss on the regulation of PPAR function. We anticipate that the loss of Tiparp will result in increased lipid accumulation and body weight gain and increased NAFLD/NASH, which will be exemplified by presence of AHR ligands. We also anticipate that PPAR responses will be increased in the absence of Tiparp. Obesity and NAFLD/NASH are serious human health concerns that are closely linked to metabolic disease, but have limited pharmacotherapeutic or dietary intervention options. We have identified TIPARP and ADP-ribosylation as important mediators of AHR ligand-induced steatohepatitis and hepatic and lipid homeostasis, making them potential therapeutic targets for fatty liver disease. Although it is anticipated that the mice used in the proposed work will experience moderate distress, results from our studies have the potential to improve healthcare through the development of novel treatment strategies for chronic human diseases, such as metabolic syndrome.
We have recently observed that TIPARP also negatively regulates PPARs, which are prominent therapeutic targets for T2D. Since PPARs play crucial roles in lipid homeostasis, energy metabolism and metabolic disease, TIPARP and ADP-ribosylation may have broad and fundamentally important roles in liver homeostasis and metabolic regulation. Our working hypothesis is that TIPARP and ADP-ribosylation are key regulators of metabolically important nuclear receptors and represent new therapeutic targets for NAFLD and/or NASH, which are serious health concerns with limited pharmacotherapeutic options. To test this hypothesis we will place wild-type and genetically modified Tiparp mouse models on a variety of different dietary interventions, including high fat diet (western diet), diet high in plant-derived AHR ligands (known as indoles), fasting and re-feeding studies. In another set of experiments, we will expose mice to the PPAR ligands to determine the impact of Tiparp loss on the regulation of PPAR function. We anticipate that the loss of Tiparp will result in increased lipid accumulation and body weight gain and increased NAFLD/NASH, which will be exemplified by presence of AHR ligands. We also anticipate that PPAR responses will be increased in the absence of Tiparp. Obesity and NAFLD/NASH are serious human health concerns that are closely linked to metabolic disease, but have limited pharmacotherapeutic or dietary intervention options. We have identified TIPARP and ADP-ribosylation as important mediators of AHR ligand-induced steatohepatitis and hepatic and lipid homeostasis, making them potential therapeutic targets for fatty liver disease. Although it is anticipated that the mice used in the proposed work will experience moderate distress, results from our studies have the potential to improve healthcare through the development of novel treatment strategies for chronic human diseases, such as metabolic syndrome.