Liver X Receptor β Controls Hepatic Stellate Cell Activation via Hedgehog Signaling

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.

Targeting cell-intrinsic metabolism for antifibrotic therapy

“…86 Moreover, the overexpression of LXRb has recently been shown to suppress fibrosis and HSC activation, without inducing steatosis, in a mouse model of carbon tetrachloride-induced fibrosis. 87 However, to further consider the potential therapeutic value of LXR agonists, the specific contribution of LXRa vs. LXRb needs to be addressed, considering the lipogenic properties of LXRa and the potential steatogenic side effects of non-selective LXRab-targeting molecules.…”

Brazing of Copper Foam Using Cu-4.0Sn-9.9Ni-7.8P Filler Foil: Effect of Brazing Temperature and Copper Foam Pore Density

“…The filler tends to excessively flow and lead to a poor and incomplete joint. Zhong et al (2012) investigate joining of iron-nickel-cobalt alloy: Kovar® and glass using Cu-7.0Ni-9.0Sn-6.0P filler at brazing temperature 660 °C to 700 °C. Authors found initially the shear strength increase maximum to 11.6 MPa at 680 °C before drop at 700 °C [27].…”

“…Zhong et al (2012) investigate joining of iron-nickel-cobalt alloy: Kovar® and glass using Cu-7.0Ni-9.0Sn-6.0P filler at brazing temperature 660 °C to 700 °C. Authors found initially the shear strength increase maximum to 11.6 MPa at 680 °C before drop at 700 °C [27]. The finding is in agreement with the current study where further increasing brazing temperature will lead to reduce the shear strength.…”