The Imprinted Gene Network in the Programming of Non-Alcoholic Fatty Liver Disease by Early Life Cadmium Exposure

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Project summary Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation, inflammation and tissue damage in the liver. NAFLD affects 30-40 % of the US adult population, and patients with NAFLD have a higher risk of developing liver cancer. An increasing body of evidence supports a role for the developmental environment in the programming of NAFLD in later life. In support of this, we have demonstrated that exposure to the toxic metal cadmium (Cd) during development causes NAFLD in young mice. Cd is one of the top ten chemicals of major public health concern identified by the World Health Organization, and it has been detected in newborn cord blood, suggesting that Cd exposure in humans can begin during in utero development. In an effort to identify potential therapeutic targets that could prevent the onset of NAFLD in response to developmental Cd exposure, we have studied the underlying molecular mechanisms. We have identified the Imprinted Gene Network (IGN) as a novel player in activating prosteatotic and profibrotic pathways – two of the major pathophysiological processes that underlie NAFLD. However, it is unclear if this mechanism is specific to Cd or if it is relevant to a broader set of toxicants that also program this disease. To address this, we propose three specific aims: 1) perform a meta-analysis of hepatic transcriptome datasets from mouse models of NAFLD programmed by the developmental environment to determine if the IGN is activated in response to a diverse set of stressors; 2) screen toxicants for their ability to activate the IGN in a cell autonomous manner in hepatocytes; 3) use in vitro models of toxicant exposure to test whether prosteatotic and/or profibrotic mechanisms are dependent on the IGN. This work will considerably enhance the impact of the parent award by demonstrating whether this mechanism is specific to Cd or also relevant to a broader set of toxicants. This will be critical knowledge in the drive to identify druggable targets that could be used to prevent the onset of NAFLD after early life exposures.