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

Abstract

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 (HSCs) 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. Here we show that LXR signaling is an important determinant of 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 (CCl4) and methionine choline deficiency (MCD) 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. Lxrαβ −/− stellate cells produce increased levels of inflammatory mediators and conditioned media from Lxrαβ−/− cells increases the fibrogenic program of wild-type cells. Furthermore, Lxrαβ−/− stellate cells exhibit altered lipid morphology and increased expression of fibrogenic genes, suggesting they are primed for activation. In vivo, Lxrαβ−/− mice have marked susceptibility to fibrosis in two injury models. Bone marrow transplants point to altered stellate cell function, rather than hematopoietic cell inflammation, as the primary basis for the Lxrαβ−/− phenotype. Conclusions These results reveal an unexpected role for LXR signaling and lipid metabolism in the modulation of hepatic stellate cell function.

Activation of Liver X Receptors Attenuates Endotoxin-Induced Liver Injury in Mice with Nonalcoholic Fatty Liver Disease

“…Interestingly, LXR agonists suppress markers of fibrosis and stellate cell activation in primary mouse stellate cells. In vivo, Lxrab-/-mice showed marked susceptibility to fibrosis in two injury models, suggesting an unexpected role for LXR signaling in the modulation of hepatic stellate cell function [32].…”

Stellate Cells and Hepatic Fibrosis

“…In normal liver, Rev-erbα helps maintain the adipogenic, quiescent HSC phenotype, but when exposed to fibrogenic stimuli it acquires new functions and promotes transdifferentiation and increased contractility of HSCs. Other examples of metabolic reprogramming in HSCs include: (i) PPARγ, a master inhibitor of HSC activation that affects lipid metabolism and maintains an adipogenic phenotype [57]; (ii) Hedgehog ligands, which induce aerobic glycolysis, suppression of normal glucose homeostatic functions, and HSC activation [149]; (iii) deletion of the HSC nuclear receptor, liver X receptor (LXR), which results in deranged lipid metabolism, HSC activation, and fibrosis [150]; and (iv) the nuclear receptor, farnesoid X receptor (FXR), which is central to bile acid, lipid, and carbohydrate metabolism in the liver as well as a negative regulator of HSC activation [151]. Overall, tight control of metabolic homeostasis promotes a quiescent phenotype; any signals that interrupt this balance may favor transdifferentiation of HSCs into an activated myofibroblast.…”

Vitamin A enrichment: Caution with encapsulation strategies used for food applications

“…New areas of research are now emerging because of vitamin A interferences with other nuclear receptors involved in the signaling pathways of vitamins, hormones and/or nutrients. For example, a lot of current data concern the interactions of vitamin A with lipid signaling pathways (see Bairras et al, 2010;Beaven et al, 2011;Bonet, Ribot, Felipe, & Palou, 2003;Redonnet et al, 2008;Sauvant et al, 2011;She, Xiong, Hazra, & Tsukamoto, 2005). As a result of these investigations, recent studies strongly suggest that vitamin A could be involved, directly or indirectly (via RXR and/or RAR) in multiple pathological diseases, such as Alzheimer's (Mingaud et al, 2008), plurimetabolic syndrome and its hepatic complications such as Non-Alcoholic Steato-Hepatitis (NASH) (for review see Sauvant et al, 2011), obesity (Bairras et al, 2010;Redonnet et al, 2008) and the therapeutic role of all-trans-retinoic acid (ATRA) in the treatment of some cancers such as promyelocytic leukemia (Chomienne et al, 1989;Fenaux & Degos, 2000) and the therapeutic role of 13-cis RA in the treatment of some skin, head, and neck cancers.…”