Abstract
Liver X receptors (LXR) α and β serve important roles in cholesterol homeostasis, anti-inflammatory processes and the activation of hepatic stellate cells (HSCs). However, the development of therapies for liver fibrosis based on LXR agonists have been hampered due to side-effects such as liver steatosis. In this study, we demonstrated that HSCs expressed high levels of LXRβ, but not LXRα, and that overexpression of LXRβ suppressed fibrosis and HSC activation in a carbon tetrachloride (CCl4)-induced fibrosis mouse model, without resulting in liver steatosis. Furthermore, Hedgehog (Hh)-regulated proteins, markedly increased in the CCl4-affected liver and mainly expressed in activated HSCs, were repressed under conditions of LXRβ overexpression. In addition, LXRβ knockout led to activation of Hh signaling and triggering of HSC activation, while overexpression of LXRβ led to the inhibition of the Hh pathway and suppression of HSC activation. These results suggest that LXRβ suppresses the activation mechanism of HSCs by inhibiting Hh signaling. In conclusion, LXRβ, by restoring the differentiation of HSCs, may be a promising therapeutic target for liver fibrosis without the adverse side-effects of LXRα activation.
Footnotes
※ And * all Authors have made a significant contribution to the paper. Each author approves the final version of the submitted manuscript and the submission to JOURNAL OF CELL SCIENCE.
Competing interests: The authors declare no conflict of interest
Abbreviations
- LXRα
- liver X receptor α
- LXRβ
- liver X receptor β
- HSCs
- hepatic stellate cells
- α-SMA or Acta2
- smooth muscle alpha actin
- collagen I
- collagen, mainly of type I
- HCs
- hepatocytes
- siRNA
- small interfering RNA
- Hh
- Hedgehog
- CCl4
- carbon tetrachloride