Research Papers: Pathology:
RASAL1 is a potent regulator of hepatic stellate cell activity and liver fibrosis
Metrics: PDF 226 views | HTML 193 views | ?
Akemi Takata1, Motoyuki Otsuka1, Takahiro Kishikawa1, Mari Yamagami1, Rei Ishibashi1, Kazuma Sekiba1, Tatsunori Suzuki1, Motoko Ohno1, Yui Yamashita2,3, Takaya Abe3, Ryota Masuzaki1, Tsuneo Ikenoue4 and Kazuhiko Koike1
1 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
2 Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe, Japan
3 Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan
4 Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Motoyuki Otsuka, email:
Keywords: RASGAP; AGTR1; AMPK; SRF; MAPK; Pathology Section
Received: April 19, 2017 Accepted: April 24, 2017Published: May 04, 2017
Liver fibrosis, leading to cirrhosis and liver failure, can occur after chronic liver injury. The transition of hepatic stellate cells (HSCs) from quiescent cells into proliferative and fibrogenic cells is a central event in liver fibrosis. Here, we show that RAS protein activator like-1 (RASAL1), a RAS-GTPase-activating protein, which switches off RAS activity, is significantly decreased during HSC activation, and that HSC activation can be antagonized by forced expression of the RASAL1 protein. We demonstrate that RASAL1 suppresses HSC proliferation by regulating the Ras-MAPK pathway, and that RASAL1 suppresses HSC fibrogenic activity by regulating the PKA-LKB1-AMPK-SRF pathway by interacting with angiotensin II receptor, type 1. We also show that RASAL1-deficient mice are more susceptible to liver fibrosis. These data demonstrate that deregulated RASAL1 expression levels and the affected downstream intracellular signaling are central mediators of perpetuated HSC activation and fibrogenesis in the liver.
Primary Contact _
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.