Apobec-1 complementation factor modulates liver regeneration by post-transcriptional regulation of interleukin-6 mRNA stability.
Apobec-1 complementation factor (ACF) is the RNA binding subunit of a core complex that mediates C to U RNA editing of apolipoprotein B (apoB) mRNA. Targeted deletion of the murine Acf gene is early embryonic lethal and Acf(-/-) blastocysts fail to implant and proliferate, suggesting that ACF plays a key role in cell growth and differentiation. Here we demonstrate that heterozygous Acf(+/-) mice exhibit decreased proliferation and impaired liver mass restitution following partial hepatectomy (PH). To pursue the mechanism of impaired liver regeneration we examined activation of interleukin-6 (IL-6) a key cytokine required for induction of hepatocyte proliferation following PH. Peak induction of hepatic IL-6 mRNA abundance post PH was attenuated >80% in heterozygous Acf(+/-) mice, along with decreased serum IL-6 levels. IL-6 secretion from isolated Kupffer cells (KC) was 2-fold greater in wild-type compared with heterozygous Acf(+/-) mice. Recombinant ACF bound an AU-rich region in the IL-6 3'-untranslated region with high affinity and IL-6 mRNA half-life was significantly shorter in KC isolated from Acf(+/-) mice compared with wild-type controls. These findings suggest that ACF regulates liver regeneration following PH at least in part by controlling the stability of IL-6 mRNA. The results further suggest a new RNA target and an unanticipated physiological function for ACF beyond apoB RNA editing.
Blanc
Valerie
V
Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Sessa
Kimberly J
KJ
Kennedy
Susan
S
Luo
Jianyang
J
Davidson
Nicholas O
NO
D020413:3' Untranslated Regions; D000071479:APOBEC-1 Deaminase; D000818:Animals; D049109:Cell Proliferation; D003564:Cytidine Deaminase / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D022781:Hepatocytes / Q000378:metabolism; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism* / Q000502:physiology; D006579:Heterozygote; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008115:Liver Regeneration; D051379:Mice; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism*
D020413:3' Untranslated Regions; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D015850:Interleukin-6; D012333:RNA, Messenger; C503503:apobec-1 complementation factor, mouse; D000071479:APOBEC-1 Deaminase; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase
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