Liver X Receptor Signaling Is a Determinant of Stellate Cell Activation and Susceptibility to Fibrotic Liver Disease

BACKGROUND & AIMS: Liver X receptors (LXRs) are lipid-activated nuclear receptors with important roles in cholesterol transport, lipogenesis, and anti-inflammatory signaling. Hepatic stellate cells activate during chronic liver injury and mediate the fibrotic response. These cells are also major repositories for lipids, but the role of lipid metabolism during stellate cell activation remains unclear. We investigated the role of LXR signaling stellate cell activation and susceptibility to fibrotic liver disease. METHODS: Immortalized and primary stellate cells purified from mice were treated with highly specific LXR ligands. Carbon tetrachloride and methionine/choline deficiency were used as chronic liver injury models. Reciprocal bone marrow transplants were performed to test the importance of hematopoietically derived cells to the fibrotic response. RESULTS: LXR ligands suppressed markers of fibrosis and stellate cell activation in primary mouse stellate cells. Lxr alpha beta(-/-) stellate cells produce increased levels of inflammatory mediators, and conditioned media from Lxr alpha beta(-/-) cells increases the fibrogenic program of wild-type cells. Furthermore, Lxr alpha beta(-/-) stellate cells exhibit altered lipid morphology and increased expression of fibrogenic genes, suggesting they are primed for activation. In vivo, Lxr alpha beta(-/-) mice have marked susceptibility to fibrosis in 2 injury models. Bone marrow transplants point to altered stellate cell function, rather than hematopoietic cell inflammation, as the primary basis for the Lxr alpha beta(-/-) phenotype. CONCLUSIONS: These results reveal an unexpected role for LXR signaling and lipid metabolism in the modulation of hepatic stellate cell function.