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The Novel Growth Factor, Progranulin, Regulates Autophagy in a Mouse Model of Cholestasis
Author(s) -
DeMorrow Sharon,
Francis Heather
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.53.9
Subject(s) - cholangiocyte , autophagy , microbiology and biotechnology , downregulation and upregulation , cholestasis , cell growth , programmed cell death , lysosome , biology , cancer research , apoptosis , chemistry , endocrinology , biochemistry , gene , enzyme
Cholestatic liver diseases are characterized by hyperplastic cholangiocyte proliferation followed by ductopenia. We have previously shown that the novel growth factor progranulin (PGRN) is upregulated during, and contributes to, hyperplastic cholangiocyte proliferation. The mechanism by which PGRN triggers cholangiocyte proliferation and associated liver pathology is poorly understood. Autophagy is a self‐degradative process whereby cytoplasmic constituents are delivered to the lysosome and degraded. In cholangiocytes, strategies to induce autophagy increases apoptotic cell death and inhibition of autophagy significantly increased cell proliferation in vitro . Our aim was to define a mechanism by which PGRN may induce cholangiocyte proliferation. After bile duct ligation (BDL), markers of autophagy were increased in cholangiocytes. Strategies to inhibit autophagy (chloroquin) increased intrahepatic biliary mass, whereas strategies to stimulate autophagy (Rapamycin) reduced intrahepatic biliary mass after BDL. Treatment with recombinant PGRN reduced the expression of autophagy markers in cholangiocytes and increased cholangiocyte proliferation in vitro and in vivo . Associated with these effects was a PGRN‐induced suppression of the pro‐autophagic molecule, Sirt1. Indeed, the inhibitory effect of PGRN on autophagy was alleviated in cholangiocytes overexpression Sirt1. Our data suggest that autophagy is upregulated during hyperplastic cholangiocyte proliferation, presumably as a compensatory mechanism to prevent overt proliferation, and that PGRN may induce cholangiocyte proliferation by inhibiting autophagy via the suppression of Sirt1 expression.