Activating transcription factor 5 (ATF5), a member of the ATF/cAMP response element-binding proteins, is extremely highly expressed in the liver, the significance of which is unknown. A recent study suggested its participating in hepatic stress process. We here investigated the effect of ATF5 on regulating liver ischemia/reperfusion (I/R) injury, for which the ATF5 knockout mice were developed. Homozygous (ATF5^-/-) pups had ~85% perinatal mortality – difficult to obtain sufficient ATF5^-/- mice. Alternatively, we generated the conditional ATF5 knockout (cATF5^-/-) mice using an albumin-Cre-LoxP approach. The cATF5^-/- mice were identified via genotyping (Neo⁺Cre⁺Loxp⁺) and confirmed by null expression of ATF5 in hepatocytes (qPCR and western). A nonlethal model of segmental (30%) hepatic warm ischemia (60 min) followed by 6h reperfusion (an optimal condition based on blood ALT test) was used for I/R study. Deficiency in ATF5 results in marked increase in blood ATL levels (U/L) in a dose dependent manner: 3320±124 (WT), 5875±884 (ATF5^+/-) and 9096±133 (ATF5^+/+) (n=3, p<0.05). Histological I/R scores were well correlated with ATL changes, indicating that ATF5 is a crucial transcription factor in regulating liver I/R injury. Surprisingly, blood ALT in cATF5^-/- group (3370±116, n=3) were comparable to WT (p>0.05), markedly lower than ATF5^+/- and ATF5^+/+ groups (p<0.05). Conditional knockout status of those cATF5^-/- mice were reexamined and confirmed by qPCR and western blotting. These data strongly suggest that liver I/R injury is unlikely regulated by ATF5 in hepatocytes, while ATF5 in non-parenchymal cells (NPC) plays a critical role in protect hepatocytes from I/R injury. Our lab is focusing on determining what cells mediate the transcription regulation of liver I/R injury, and the underling molecular mechanisms.

CITATION INFORMATION: Shen G.-Q, Morita M, Fung J, Lu L, Qian S. Activating Transcription Factor 5 (ATF5) Regulates Liver Ischemia/Reperfusion Injury. Am J Transplant. 2016;16 (suppl 3).

« Back to 2016 American Transplant Congress