Abstract
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.
Highlights
Liver fibrosis, observed clinically as liver cirrhosis, is a common consequence of chronic liver injury, such as that caused by chronic hepatitis viral infection, overload of alcohol or drugs, and steatosis
The expression levels of α-smooth muscle actin (SMA) increased over time in culture, which is characteristic of activated hepatic stellate cell (HSC) (Figure 1b)
While no change in the phosphorylation status of serum response factor (SRF) was observed under AMPactivated protein kinase (AMPK) inhibitor treatment (Supplementary Figure 3), phosphorylation of the SRF coactivator megakaryoblastic leukemia 1 (MKL1), which affects SRF activity negatively [25], was induced by RAS protein activator like-1 (RASAL1) expression and was antagonized by an AMPK inhibitor (Figure 4b). These results suggested that the negative effects of AMPK on SRF activity are induced by RASAL1 expression, and that these effects are canceled by an AMPK inhibitor
Summary
Liver fibrosis, observed clinically as liver cirrhosis, is a common consequence of chronic liver injury, such as that caused by chronic hepatitis viral infection (especially hepatitis B and C viruses), overload of alcohol or drugs, and steatosis. It is characterized by the progressive accumulation of extracellular matrix (ECM) proteins, such as type I and III collagens [1]. HSCs are activated, characterized by loss of vitamin A, to transdifferentiate into smooth muscle α-actin (α-SMA)positive myofibroblast-like cells [3]. The prolonged and repeated accumulation of ECM proteins disturbs the hepatic architecture by forming fibrotic scars and nodules, resulting in hepatic dysfunction [5]
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