Liver X receptor α is essential for the capillarization of liver sinusoidal endothelial cells in liver injury

Liver X receptors (LXRs) play essential roles in lipogenesis, anti-inflammatory action and hepatic stellate cells (HSCs) activation in the liver. However, the effects of LXRs on the capillarization of liver sinusoidal endothelial cells (LSECs) in liver fibrosis remain undetermined. Here, we demonstrated that LXR alpha plays an important role in LSECs capillarization in a manner that involved Hedgehog (Hh) signaling. We found that LXR alpha expression in LSECs was increased in the carbon tetrachloride (CCl4)-induced fibrosis model. LXR alpha deletion markedly exacerbated CCl4-induced lesions assessed by histopathology, as well as inflammation and collagen deposition. Furthermore, capillarization of the sinusoids was aggravated in CCl4 -treated LXR alpha-deficient mice, as evidenced by increased CD34 expression, the formation of continuous basement membranes and aggravation of the loss of fenestrae. In vitro, LXR agonist could maintain freshly isolated LSECs differentiation on day 3. Furthermore, LXR alpha deletion led to increased expression of Hedgehog (Hh)-regulated gene in LSECs in the injured liver. Conversely, the LXR agonist could inhibit the Hh pathway in cultured LSECs. These responses indicated that LXR alpha suppressed the process of LSECs capillarization by repressing Hh signaling. Overall, our findings suggest that LXR alpha, by restoring the differentiation of LSECs, may be critical for the regression of liver fibrosis.