In chronic liver diseases, the development of fibrosis is the first step toward the progression to cirrhosis, portal hypertension and hepatocellular carcinoma (HCC). Until now, there are no FDA-approved drugs for the treatment of liver cirrhosis; therefore, it is urgent to clarify the mechanisms of liver fibrosis and treat liver fibrosis/cirrhosis. Recently, free cholesterol rather than cholesterol ester have been reported to play an important role in hepatic stellate cells (HSCs) activation and the development of liver fibrosis. Niemann-Pick Type C2 (NPC2) plays an important role in regulating intracellular free cholesterol trafficking and homeostasis through direct binding with free cholesterol. Loss of NPC2 results in free cholesterol accumulation in the cells. Previously, we reported that the patients with NPC2 down-regulation expressed much higher α-fetoprotein, multiple tumor type, vascular invasion, later pathological stage and shorter survival rate. In-vitro and in-vivo xenografts data demonstrated that the expression of NPC2 regulates cell proliferation, migration and tumorigenesis through regulates ERK1/2 activation. However, the roles of NPC2 in liver fibrosis have not been explored in detail. Our recent publication and preliminary data showed that NPC2 is down regulated in both mouse and human liver fibrosis tissues. Knockdown of NPC2 increased the sensitization of HSCs to TGF-β1 and PDGF-BB induced fibrogenesis and proliferation. However, the expression of NPC2 did not affect LPS-induced inflammation signals and cytokines expression in HSCs. And we also showed that free cholesterol accumulation enhanced the susceptibility of HSCs to TGF-β1 and PDGF-BB. Accordingly, we propose that NPC2 overexpression may act as a therapeutic strategy to decrease the susceptibility of HSCs to TGF-β1 and PDGF-BB; as well as retard liver fibrosis progression. The goals of this two-year project are: a) to prove that NPC2 overexpression in HSCs can decrease free cholesterol overload induced HSCs activation and proliferation; b) to establish in-vivo hepatic NPC2 overexpression and knockdown mouse models; and c) verify that NPC2 knockdown will promote CCl4-induced liver fibrosis in mice; d) to evaluate the prevention or therapeutic effects of NPC2 overexpression in CCl4 or BDL-treated mice. This study will clarify the roles of NPC2 in liver fibrosis and may shed light on the treatment modality for liver fibrosis in the future.
|Effective start/end date||8/1/18 → 7/1/19|
- Niemann-Pick Type C2 (NPC2)
- hepatic stellate cells (HSCs)
- liver fibrosis treatment