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Hepatic steatosis is characterized by the intracellular increase of free fatty acids (FFAs) in the form of triglycerides in hepatocytes. This hepatic adverse outcome can be caused by many factors, including the exposure to environmental toxicants or drugs. Mechanistically, accumulation of lipids in the liver can take place via several mechanisms such FFAs de novo synthesis and/or uptake from serum via high fat content diets. FFAs de novo synthesis and uptake into the liver are mediated through the liver X (LXR), and pregnane X (PXR) receptors; respectively. A biologically based quantitative model for hepatic lipid content incorporated both mechanisms based on earlier published models. The impact of chemical exposure on FFAs hepatic content via the nuclear receptors liver X (LXR), and pregnane X (PXR) activation was quantitively investigated. This was accomplished by connecting chemical exposure to liver tissue dosimetry, using a physiologically based pharmacokinetic (PBPK) models for three known agonists of LXR and/or PXR: T0901317 (both receptors), GW3965 (LXR only), and Rifampicin (PXR only). In agreement with literature, model predictions showed that T0901317 caused more fatty acid build-up in the liver, with less accumulation observed with Rifampicin followed by GW3965 exposures. These results highlight the importance of PXR activation while suggesting that increased FA de novo synthesis alone may not be enough to cause appreciable accumulation of lipids in the liver under normal environmental exposure levels. The overall PBPK-hepatic lipids quantitative model can be used to screen chemicals for their potential to cause in vivo hepatic lipid content buildup in view of their in vitro potential to activate the nuclear receptors and their exposure levels. |
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