Poster abstracts
Poster number 67 submitted by Katie Toohill
Polypyrimidine tract-binding protein 1 coordinates the proliferative and inflammatory responses of hepatocytes during toxin-induced liver injury and regeneration
Katie Toohill (Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, United States), Ullas Valiya Chembazhi (Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, United States), Cody Lund (Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, United States), Miranda Gurra (Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, United States), Auinash Kalsotra (Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, United States)
Abstract:
Dynamic remodeling of mRNA splicing and translation within hepatocytes is pivotal for proper
liver regeneration1. The regenerative process in the liver is associated with a reversible adult-toneonatal switch in splicing patterns of multiple proliferation-related genes, orchestrated by a set of developmentally regulated RNA binding proteins (RBPs). Polypyrimidine tract-binding protein
1 (PTBP1) is one of these RBPs, which functions as an alternative splicing factor, apart from its
roles in regulating mRNA stability, localization, and translation (2). Although PTBP1 is abundantly
expressed in mature hepatocytes, its protein levels are significantly increased in regenerating
hepatocytes (1). Here, we demonstrate that while no basal phenotypes are apparent following
hepatocyte-specific PTBP1 knockout (PTBP1-HKO) during normal mouse liver development,
the lack of PTBP1 is detrimental to the adult liver when exposed to hepatotoxins. We find that
toxin-induced chronic liver damage by diethoxycarbonyl-1,4-dihydrocollidine (DDC) results in
widespread porphyrin accumulation in the PTBP1-HKO livers. Intriguingly, PTBP1 HKOs exhibit
resistance to liver fibrosis and show reduced hepatocyte proliferation in response to DDCmediated hepatocellular injury. PTBP1 HKO mice also present significantly lower levels of serum
bilirubin, bile acids, and other biochemical markers of liver injury after chronic exposure to DDC.
Finally, we demonstrate that the impaired regenerative response in the absence of PTBP1 is
associated with reduced expression of inflammatory signals, but is independent of alternative
splicing and accumulation of PTBP2, a neuronal paralog of PTBP1 that is normally suppressed
in non-neuronal tissues due to its unproductive splicing by PTBP1. Thus, our findings reveal a
crucial role for PTBP1 in determining the regenerative response of hepatocytes to toxin-induced
liver injury and damage.
References:
1 Bangru, S. et al. Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote
liver regeneration. Nat Struct Mol Biol 25, 928-939, doi:10.1038/s41594-018-0129-2 (2018).
2 Romanelli, M. G., Diani, E. & Lievens, P. M. New insights into functional roles of the
polypyrimidine tract-binding protein. Int J Mol Sci 14, 22906-22932, doi:10.3390/ijms141122906
(2013).
Keywords: Polypyrimidine tract-binding protein