Activation of hepatic stellate cell in Pten null liver injury model.
BACKGROUND
Hepatic fibrosis is a prominent pathological feature associated with chronic liver disease including non-alcoholic hepatosteatosis (NASH), and a precursor for liver cancer development. We previously reported that PTEN loss in the liver, which leads to hyperactivated liver insulin signaling results in NASH development. Here we used the same mouse model to study the progression from steatosis to fibrosis.


RESULTS
The Pten null livers develop progressive liver fibrosis as indicated by Sirius Red staining and increased expression of collagen I, Timp 1, SMAα, and p75NTR. Consistently, hepatic stellate cells (HSCs) isolated from Pten null livers are readily activated when compared with that from mice with intact PTEN. Deletion of AKT2, the downstream target of PTEN signal, blocked NASH development, and alleviated fibrosis. HSCs from the Pten/Akt2 double null mice are quiescent like those isolated from the control livers. Our analysis shows that the activation of HSCs does not depend on the intrinsic signals regulated by PI3K/AKT, the target of PTEN, but does depend on steatosis and injury to the liver. During the progression of liver fibrosis in the Pten null model, Wnt ligands and signaling receptor are induced, concurrent with the reduction of sFRP5, a Wnt antagonist. We showed that treatment of HSCs with Wnt receptor antagonist blocks the observed morphological changes when HSCs undergo activation in culture. This signal appears to be mediated by β-catenin, as manipulating β-catenin signaling alters marker gene expressions of HSC activation.


CONCLUSIONS
Wnt/β-catenin activation serves as an important mediator for fibrosis development resulting from NASH using a mouse model where NASH is mimicked by PTEN loss.
Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033 USA.
Lina
L
He
Imperial College, London, England.
James
J
Gubbins
Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033 USA.
Zhechu
Z
Peng
Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033 USA.
Vivian
V
Medina
Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033 USA.
Fan
F
Fei
Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA.
Kinji
K
Asahina
Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA.
Jiaohong
J
Wang
Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033 USA ; Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA.
Michael
M
Kahn
Department of Pediatrics and Pharmacology, Pennsylvania State University College of Medicine, 500 University Drive, H085, Hershey, PA 17033 USA.
Carl B
CB
Rountree
Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033 USA ; Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA ; Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy PSC402, 1985 Zonal Ave, Los Angeles, CA 90089 USA.
Bangyan L
BL
Stiles
AKT; Fatty liver; Fibrosis; PTEN; Steatosis; Wnt