Journal
TOXICOLOGY LETTERS
Volume 295, Issue -, Pages 153-161Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2018.06.1066
Keywords
Hepatocyte; Autophagy; Ammonia; Pregnane X receptor
Categories
Funding
- National Natural Science Foundation of China [81470872]
- Scientific and Technological Innovation Foundation of Fujian province [2017Y9100]
- Construction Project of National Key Clinical Subject of General Surgery
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Pregnane X Receptor (PXR), a nuclear receptor transcription factor, participates in a wide range of physiological activities, but the regulation of ammonia-induced hepatocyte autophagy by PXR is not yet clear. In this study, the levels of down-regulated LC3B-II and up-regulated SQSTM1 were found in ammonia-induced PXR-overexpressing (PXR+) liver cells, but the opposite appeared in PXR-knockdown (PXR-) liver cells. Rifampicin, a PXR-activating agent, elicits a similar effect as PXR+ cells. The mechanism analysis reveals that the levels of the energy-sensitive molecule AMPK beta 1 and phosphorylated AMPK beta 1 (p-AMPK beta 1) in PXR- cells are higher than those in control cells, whereas the levels of this molecule in PXR+ cells are lower than those in control cells. Two active sites that bind to P53 exist in -253 to -19 at the promoter region of AMPK beta 1, and their mutation can reduce the transactivating effect of AMPK beta 1 that P53 relies on. A protein interaction also exists between PXR and P53. These findings indicate that PXR is a factor interfering the formation of ammonia-induced hepatocyte autophagy, and its inhibitory effect is achieved when P53 downregulates the expression and activity of AMPK beta 1. This conclusion provides an appropriate clinical explanation for hepatotoxicity caused by the inhibitory effect of PXR-activating agent on hepatocyte autophagy.
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